CA2337179A1 - Therapeutic composition based on flavonoids, intended to be used in the treatment of tomours by cytotoxic - Google Patents
Therapeutic composition based on flavonoids, intended to be used in the treatment of tomours by cytotoxic Download PDFInfo
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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Abstract
The invention concerns a composition having an activity on the proliferation of clonogenic cells in tumours and comprising a therapeutically efficient amount of a flavonoid, in particular a compound selected among the compounds of formula (I) wherein: R1, R2, R3 and R4, R5 and R6 are as defined in Claim 2. Said composition is designed for use in the treatment of tumours with cytotoxic agents.
Description
x CA 02337179 2001-O1-11 ~~
x, .
Therapeutic composition based on flavonoids, intended to be used in the treatment of tumours by cytotoxic agents The present invention relates to the use of compounds of flavonoid type in the treatment of cancers by cytotoxic agents.
A cancer is a disorder of the somatic genes, in the course of which genetic dysfunctions worsen as the tumour progresses from the state of precancerous lesion to that of malignant transformation, the cancerous tumour becoming metastatic and often. resistant to cytotoxic medicines. -Despite the very considerable efforts conducted in all the developed countries, in particular through experimental and clinical research programmes, mortality due to the various cancers (solid tumours and haematological neoplasias) remains unacceptably high.
In many countries, cancer is placed second, just after cardiovascular diseases, as the cause of mortality.
In terms of newly diagnosed cancers, the distribution between solid tumours and haematological (bone marrow, blood, lymphatic system) neoplasias shows that 9 cancers out of 10 are solid tumours. Unlike that which is observed in haematological oncology (therapeutic success in 40 to 900 of blood cell cancers), only a small number of advanced or disseminated solid tumours respond to only chemotherapeutic treatments. It is partly for this reason that the overall mortality due to cancer increased in the U.S.A. between 1973 and 1992.
It is not, unfortunately, certain that this tendency may be reversed only by the appearance, alongside the'established ehemotherapeutic arsenal, of novel antitumour medicines such as taxanes (paclitaxel and docetaxel), which interfere with the formation of microtubules (W. P. McGuire et al., Am. Intern. Med., 1989), camptothecin-derived topoisomerase I inhibitors ~ .n ~.r (topotecan and irinotecan), vinorelbine (novel alkaloid derived from the periwinkle), gemcitabine (novel cytotoxic antimetabolic agent), raltitrexed (thymidylate synthetase inhibitor) or miltefosine (first representative of the alkylphosphocholine family). These treatments add, either as a first choice or as a second choice, to the medicines for which the specific activity is now well recognized, such as doxorubicin, cisplatin, vincristine, methotrexate, 5 fluorouracil.
One of the most difficult current problems of anticancer chemotherapy is due to the fact that numerous populations of malignant- -cells exhibit considerable resistance to established cytotoxic substances. Most commonly, this situation results from the existence of multiresistance genes or from the frequency of genetic mutations in certain types of tumour. Thus, the treatment of cancers requires novel approaches which are complementary to those currently implemented, and which are intended to more successfully combat the extension and heterogeneity of the tumour load, and the acquisition of "multi-cytotoxic-drug" resistance.
Among these novel approaches, some are already promising. This is the case of the induction of apoptosis, and the inhibition of tumour angiogenesis and of metastatic processes, not to mention gene therapy or immunotherapy.
. The inventors were interested in a different approach. The objective sought was to make the population of tumour cells more sensitive to reference anticancer treatments, in order to achieve a double benefit:
1) increase the cytotoxic activity and therefore the effectiveness, and 2) decrease the frequency and severity of certain side effects, due to the reduction in dosage which might follow the induction of the increase in the antitumour effectiveness.
a .3.a ,~ _ 3 _ It is this strategy which is behind the_ discovery of an original mechanism caused by substances - which have weak antitumour power, or are lacking this power - but which are capable of inducing a very significant increase in the cytotoxic activity of proven anticancer medicines. This original mechanism comes from the possibility for these substances either to stimulate the recruitment of clonogenic cells within the tumour, making it more sensitive to the conventional treatment with cytotoxic agents, or to inhibit the proliferation of clonogenic cells, thus contributing to the regression of the tumour.
A subj ect of the present invention is thus the use, in the treatment of cancers with at least one antitumour agent chosen from cytotoxic agents, of a compound having activity on the proliferation of clonogenic cells, chosen from flavonoids and in particular the compounds of formula:
this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a Cl-CQ alkoxy group and an -OCOR~
group, R~ being a Cl-C4 alkyl group, at least one of the substituents R1, R2, R3 or RQ being other than H, and R2 --_ and R3 possibly forming together a methylenedioxy group, - RS is chosen from H, OH, a C1-CQ alkoxy group and an O-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups chosen from H, OH and a C1-C4 alkoxy group, - and ....... designates either a double bond or a single bond.
~ ,.,::, jf The cytotoxic agents can be used at their conventional dose, and in this case, their effectiveness is improved, or at lower doses given the increase in their antitumour effectiveness.
~i A subject of the present invention is also a composition having activity on the proliferation of clonogenic cells by interfering with the generation of clonogenic cells, either by stimulating the proliferation and recruitment, or by inhibiting the proliferation, comprising a therapeutically effective amount of a flavonoid and in particular of a compound of formula I chosen from the compounds of formula:
i this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkoxy group and an -OCOR7 group, R7 being a C1-C9 alkyl group, at least one of the substituents Rl, R2, R3 or RQ being other than H, and RZ
and R3 possibly forming together a methylenedioxy group, - RS is chosen from H, OH, a C1-Cq aikoxy group and an 0-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups y 25 chosen from H, OH and a C1-C4 alkoxy group, - and ....... designates either a double bond or a single bond.
A subject of the present invention is also the use of a flavonoid and in particular of a compound of formula I as defined above, for manufacturing a medicine intended to interfere (by induction or inhibition) with the generation of clonogenic cells in tumours during treatment with at least one cytotoxic agent.
i , t~
_ 5 _ In the chemotherapeutic treatment of cancers with cytotoxic agents, flavonoids, and in particular the compounds of formula I, can be administered at the start of the chemotherapeutic treatments, either in a single dosage intake or over several days at the start of these treatments (for example for 5 to 7 days) and, depending on the .chemotherapeutic protocol, at the start of each cycle of treatment (for example for 2 to 5 days) in the course of each therapy.
The compounds of formula I are advantageously administered by infusion (generally in 1 to 3 hours) at doses of 5 to 50 mg/kg/day or 200 to 2000 mg/m2/day.
In order to obtain a maximum- effect on the production of clonbgenic cells, the flavonoids should be administered such that the tissue concentrations obtained are as high as conceivably possible.
For protocols of treatment in the acute phases of therapies, the intravenous route is to be favoured uslna:
- ready-to-use infusion solutes (bags, bottles, etc.) intended to be administered without modification by intravenous infusion using an infusion line and according to the recommended flow rate:
lyophilizates to be resuspended for intravenous infusion, using pharmaceutical solutes known 'to those skilled in the art;
- for maintenance treatments, it is also _ __ possible to envisage the oral route when the chemotherapy treatment favours the oral administration of cytostatic agents. For this purpose, oral lyophilizates (for oral or perlingual absorption) immediate- or delayed-release tablets, oral solutions, suspensions, granules, capsules, etc. may be used.
The compounds of formula (I) are, for the most part, compounds of natural origin, or are derivatives of compounds of natural origin. As examples, mention may be made of:
1) flavones such as:
- quercetin, ii 4-hydroxyflavone, 6-hydroxyflavone, 7-hydroxyflavone, 5-methoxyflavone, - 6-methoxyflavone, - 7-methoxyflavone, - 2-cyclohexyl-5-hydroxychromone, - 2-cyclohexyl-6-hydroxychromone, - 2-cyclohexyl-7-hydroxychromone, - wogonin or 5,7-dihydroxy-8-methoxyflavone, - acacetin or 5,7-dihydroxy-4'-methoxyflavone, - pedalitin or 5,6,3',4'=tetrahydroxy-7-methoxyflavone, - apigenin or 5,7,4'-trihydroxyflavone, - luteolin or 5,7,3',4'-tetrahydroxyflavone, - baica.lein or 5,6,7-trihydroxyfiavone, - scutellarein or 5,6,7,4'-tetrahydroxyflavone, - fisetin or 7,3',4'-trihydroxyflavonol, - ~robinetin or 7, 3' , 4' , 5' -tetrahydroxyflavonol, 25' - kaempferol or 5,7,4'-trihydroxyflavonol, - kaempferide or 5,7-dihydroxy-4'-methoxyflavonol, - morin or 5,7,2',4-'-tetrahydroxyflavonol, - myricetin or 5,7,3',4',5'-pentahydroxyflavonol, - 2) flavanolols such as:
- aromadendrin or 5,7,4'-trihydroxyflavanolol, - fustin or 7,3',4'-trihydroxyflavanolol, - hydroxyrobinetin or 7,3',4',5'-tetrahydroxyflavanolol, 1 =.x n -- taxifolin or 5,7,3' 4'-, trihydroxyflavanolol , 3) flavanones such as naringenin or 5,6,4'-trihydroxyflavanone;
- 7,4'-dihydroxyflavanone , eriodictyol or 5,73' q~_ , tetrahydroxyflavanone , - hesperetin or 5,7;3'-trihydroxyflavanone.
Flavones are the preferred compounds.
The cytotoxic agents can be chosen from:
i) intercalating agents, in particular daunorubicin, epirubicin, idarubicin , aorubicin, aclarubicin, pirarubicin, acridine , mitoxantrone, actinomycin D, eptilinium acetate;
ii) alkylating agents chosen from platinum derivatives (cisplatin, carboplatin , oxaliplatin);
iii) a compound chosen from the other groups of alkylating agents:
- cyclophosphamide, ifosfamide, chlormetrine , melphalan, chlorambucil, estramustine , - busulphan, mitomycin C, - nitrosoureas: BCNU (carmustine), CCNU
(lomustine), fotemustine, streptozotocin , - triazines or derivatives: procarbazine , decarbazine w , - pipobroman , ethyleneimines: altretami.ne , triethylenethiophosphoramide , iv) a compound chosen from the other groups of antimetabolic agents:
- antifolates: methotrexate, raltitrexed , - antipyrimidines: 5-fluorouracil (5-FU), cytarabine (Ara-C), - hydroxyurea, I
,U
- antipurines: purinethol, thioguanine , pentostatin, cladribine - inducers of cytotoxic nucleoside synthesis:
gemcitabine, v) a compound chosen from the other groups of agents with affinity for tubulin:
- vinca-alkaloids which disorganize the mitotic spindle: vincristine, vinblastine, vindesine , navelbine agents which block the depolymerization of the mitotic spindle: paclitaxel, docetaxel - agents which induce breaks in the DNA by topoisomerase II inhibition: etoposide , teniposide _ -- topoisomerase I inhibitors which induce cleavages of the DNA: topotecan, irinotecan , vi) a splitting agent, which fragments the DNA, such as bleomycin, vii) one of the following compounds; plicamycin L
, asparaginase, mitoguazone, decarbazine , viii) an anticancer progestative steroid:
medroxyprogesterone, megestrol, ix) an anticancer oestrogenic steroid:
diethylstilbestrol, tetrasodium fosfestrol , x) an anti-oestrogen: tamoxifen, droloxifen , raloxifen, aminogluthetimide , xi) a steroidal anti-androgen (ex cyproterone) or a nonsteroidal anti-androgen (flutamide , nilutamide).
In particular, the compounds of formula I
can be combined with all treatments with the major i cytotoxic agents used in polychemotherapies f or solid tumours, such as:
- alkylating agents: oxazophorines (cyclophosphamide, ifosfamide, chlorambucil , melphalan) r - nitrosoureas - mitomycin C
r - antimetabolites, such as methotrexate, 5-FU, Ara-C, capacitabine - agents which interfere with tubulin: vinca-alkaloids (vincristine, vinblastine, vindesine, navelbine), taxoids (paclitaxel, docetaxel), epipodophyllotoxin derivatives (etoposide, teniposide) i - bleomycin - topoisomerase I inhibitors: topotecan, irinotecan.
Similarly, the compounds of formula I can be combined with treatments with the major cytotoxic agents used in oncohaematology for the treatment of blood cancers:
- Hodgkin's disease: cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;
- acute leukaemias: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase;
- non-Hodgkin's malignant lymphomas:
mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunorubicin, carmustine, lomustine, cisplatin;
- chronic lymphoid leukaemias: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.
Results of pharmacological trials demonstrating . the properties of the compounds of formula (I) used alone or in combination with cytotoxic agents will be given hereinafter.
Interaction (stimulation or inhibition of proliferation) with the generation of clonogenic cells (clonogenic assay) 1 J~ j -The assay used is that described by Hamburger et al., (Science, 1977; 197, 461-463) and Salmon et al., (New England J. Med., 298, 1321-1327). A cell is considered to be clonogenic if it has the capacity to 5 proliferate and to give rise to a cell colony. Human tumour stem cells are the cells behind the neoplastic cells which constitute a given tumour. These tumour stem cells are responsible for the processes of recurrence which can be observed after surgical 10 resection of primary tumours; and are also responsible for the formation of metastases. In a tumour or a tumour cell line, these clonogenic stem cells differ from the other cells of the tumour or of the neoplastic cell line under consideration, by the fact that they conserve their capacity to proliferate in the absence of any solid support.
In this assay, the tumour cells are cultured on a semi-solid support consisting of agar. Only cells which do not require a solid support for their growth (i.e. the very tumorigenic cells termed "anchorage-independent cells" by M.I. Dawson et al., Cancer Res.
1995; 55: 4446-4451; also named clonogenic cells with reference to "clonal growth") are capable of developing on such an agar-based support. Specifically, on such a medium, normal cells - which grow in "adherent mode"
("anchorage-dependence cells" according to the terminology of M.I. Dawson) - such as, for example, fibroblasts, do not survive. Within a tumour cell population, cultured on such a -support, it is these clonogenic cells (associated with an unlimited number of cell divisions, and the proliferation of which is termed "anchorage-independent [clonal] growth" by . M.I. Dawson) which are capable of growing. The percentage of these clonogenic cells within a tumour or a cell line various between 0.1% and O.OOlo. The nonclonogenic cells (associated with a limited number of cell divisions) do not develop in this assay since they require a solid support for their growth which must take place in "adherent mode" ("anchorage-'e . _.
dependent (adherent] growth", according to M.I. Dawson et al., Cancer Res. 1995; 55: 4446-51).
The influence of compounds of formula (I) on the growth of the cell colonies obtained by culturing, for example, the mammary tumour lines MCF7 and MXT, and the colorectal line HT-29, on the semi-liquid culture medium termed "soft agar" was measured. On such a medium, only the clonogenic cells termed "anchorage-independent (clonal) cells" by M.I. Dawson survive and develop. The growth of these cells in such a "nonadherent" mode indicates their degree of tumorigenicity. The inhibition of the growth of the size of a tumour in which a greater number of clonogenic cells have developed then becomes the sign of reinforced cytotoxic activity.
Conversely, this assay can also reveal that a compound is capable of inhibiting the generation/
proliferation of clonogenic cells, which makes the tumour less able to develop, and therefore decreases the population of tumour cells.
The tumour cell lines studied are maintained in culture in 25 cm2 falcon dishes. They are then trypsinized and the cells are well dissociated from each other. The percentage of live cells is determined after trypan blue staining. A cell suspension at the concentration of 5 x 109 to 15 x 109 cells/ml (depending on the cell type under consideration) is prepared in a solution of agar at 0.30. Next, 200 ~1 of this - suspension are seeded int o petri dishes 35 mm in diameter, into which 3 ml of a base layer consisting of a solution of agar at 0.5% are placed. The 200 ~1 of cell suspension are themselves covered with 1.8 mL of an upper layer consisting of a solution of agar at 0.30. The dishes are then placed in an incubator at 37°C, 5o COZ and 70o humidity until treatment. The latter is carried out approximately l to 2 hours after seeding. The compounds to be assayed are prepared at a concentration 100 times greater than the concentration desired, and 50 ~1 of these treating solutions are wi i deposited onto the upper agar layer of the corresponding dishes. In the present study, the final concentration of the products assayed is 10-5, 10-7 and 10-9 M. The dishes are then maintained for 21 days in an incubator. On the 21st day, the dishes are treated by depositing on the upper layer 100 ~l of a solution of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide). at 1 mg/ml prepared with RPMI 1640 medium, for 3 h at 37°C. After this lapse of time, the cell colonies are fixed by adding 2 ml of formol per dish. After fixing for 24 hours, the formol is evaporated off and the number of cell colonies stained, and therefore consisting of cells which are metabolically active and which have- a surface area greater than 100 ~mz is determined using an inverted microscope.
The mean number of clonogenic cell clones, determined for each experimental condition studied, is expressed as a percentage with respect to the mean number of clonogenic cell clones counted in the control condition and taken to,be equal to 100%. These values, expressed as a percentage with respect to the control condition, are given in Table l, for quercetin.
CELL LINES Quercetin (in mol.l-1) MCF7 67.4 ~ 3.4 101.2 ~ 3.2 ** NS
HT-29 45.6 ~ 1.2 103.4 ~ 2.2 ** NS
MXT ~ 80.8 ~ 3.6 I 93.4 ~ 3.2 ** ~ NS
- The results given in this table represent the mean values ~ the standard error of the mean (SEM) established on at least 6 cupules - Control condition = 100 y . i - (NS: p>0.05; *: p<0.05; ** p<0.01; **~ p<0,001).
On the three cell lines MCF7, HT-29 and MXT, quercetin is capable of partially inhibiting the proliferation of the clonogenic cells within the tumour; i.e. of inducing a significant decrease in the number of colonies of these cells with respect to that w obtained in the control condition (from 20o to 50%), and therefore contributes to making the tumours from which they are derived more sensitive to the conventional treatment with cytotoxic agents.
Cytotoxic activity on -the nonclonogenic cells: "MTT assay" . -The influence of the compounds of formula (I) on the nonclonogenic cells was evaluated using the MTT
colorimetric assay.
The principle of the MTT assay is based on the mitochondrial reduction, by metabolically active live cells, of the yellow-coloured product MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into a blue-coloured product, formazan. The amount of formazan thus obtained is directly proportional to the amount df live cells present in the culture well(s).
This formazan amount is measured by spectrophotometry.
The cell lines are maintained in monolayer culture at 37°C in closed-cap dishes containing MEM 25 MM HEPES basic medium (Minimum Essential Medium). This medium is suitable for the growth' of a range of varied diploid or primary mammalian cells. This medium is then supplemented with:
- a 5o amount of FCS (foetal calf serum) decomplemented at 56°C for, 1 hour, - with 0.6 mg/ml of L-glutamine, - with 200 IU/ml of penicillin, - with 200 ~g/ml of streptomycin, - with 0.1 mg/ml of gentamicin.
:.. d The 12 human cancer cell lines which were used were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA).
These 12 cell lines are:
U-373MG (ATCC code: HTB-17) and U-87MG (ATCC
code': HTB-14) which are two glioblastomas, - SW1088 (ATCC code: HTB-12) which is an astrocytoma, - A549 (ATCC code: CCL-185) and A-427 (ATCC
code: HTB-53) which are two non-small-cell lung cancers, - HCT-15 (ATCC code: CCL-225) and LoVo (ATCC
code: CCL-229) which are .two colorectal cancers, - T-47D (ATCC code: HTB-133) and MCF7 (ATCC
code: HTB-22) which are two breast cancers, - J82 (ATCC code: HTB-1) and T24 (ATCC code:
HTB-4) which are two bladder cancers, - PC-3 (ATCC code: CRL-1435) which is a prostate cancer.
In experimental terms: 100 ~l of a cell suspension containing 20 000 to 50 000 (depending on the cell type used) cells/ml of culture medium are seeded into flat-bottomed 96-well multi-well plates and are incubated at 37°C under an atmosphere comprising 50 COz and 70% of humidity. After 24 hours of incubation, the culture medium is replaced with 100 ~,l of fresh medium containing either the various compounds to be tested at concentrations ranging from 10-5 to 10-1° M, or the solvent which was used in order to dissolve the products to be tested (control condition). After 72 hours of incubation under the above conditions, the culture medium is replaced with 100 ~1 of a yellowish solution of MTT dissolved, at a rate of 1 mg/ml, in RPMI 1640. The microplates are re-incubated for 3 hours at 37°C, and then centrifuged for 10 minutes at 400 g:
The yellowish solution of MTT is removed a.nd the blue formazane crystals formed at the cellular level are ,, s dissolved in 100 ~1 of DMSO. The microplates are then shaken for 5 minutes. The intensity of the blue coloration resulting, therefore, from the transformation of the yellow MTT product into blue forrnazane by the cells still alive at the end of the experiment is quantified' by spectrophotometry using a machine of type DYNATECFF IMMUNOASSAY SYSTEM at the wavelengths of 570 nm and 630 nm corresponding, respectively, to the wavelengths of maximum absorbence of the formazane and to the background noise. Software integrated into the spectrophotometer calculates the mean values of optical density, and the standard deviation (Std. Dev.) and standard error of the mean (SEM) values. - -By way of example, the results of the mean optical density, expressed as percentage with respect to the mean optical density measured in the control condition (taken to be equal to 100$), obtained - by way of nonlimiting example - with a flavonoid:
quercetin, on the 5 tumour cell lines Li-373MG, T24, LoVo, MCF7 and A549, will be given in Table II.
TABLE II
CELL
Quer cetin LINES 10 5* 10 6* 10 ~ 10 e* 10 9* 10 io*
U-373I~96.4 105.2 104. 1 98.5 101.5 97.7 t 3.1 NS 2.2 NS 2.9 NS 2.4 NS 3.2 NS 1.7 NS
T24 102.5 102.4 99.7 107.4 105.2 110.2 0.7 NS 1.7 NS 2.0 NS 3.B NS 2.0 NS 2.4 **
- Lovo 97.8 94,5 101.9 103.1 101.6 112.0 t 3.1 NS 2.2 NS 4.7 NS 2.1 NS 3.0 NS 4.2 I~F7 81.5 84.5 82.1 t 90.7 89.6 103.8 2.5 *** 2.3 *** 2.1 NS 3.8 NS 2.0 ** 2.9 NS
A549 86.0 100.3 94.9 f 98.2 97.3 97.7 t 3.6 * 3.7 NS 2.3 NS 3.5 NS 2.2 NS 1.7 NS
- Concentrations expressed in mol.l-1 xx ~ yy = mean value ~ standard error of the mean - Control conditions = 100 - (NS/p > 0.05; *: p < 0.05; **: p < 0.01; p < 0.001).
T
These results show that quercetin has weak antitumour power. This product, which is non-cytotoxic, induces inhibition of the overall cell proliferation of these lines only at the concentration of 10-5 M, and this inhibition doe s not exceed 200: At the other concentrations assayed; only a few minor effects can be detected, 3. Determination of the maximum tolerated dose (MTD):
The evaluation of the maximum tolerated dose was carried out in 4- to 6-week-old B6D2F1/Jico mice.
The compounds were administered via the intraperitoneal route at increasing doses ranging. ~ from - 2.5 to 160 mg/kg. The value of the MTD (expressed in mg/kg) is determined based on the observation of the survival rate of the animals over a period of 14 days after a single administration of the product under consideration. The evolution of the weight of the animals is also monitored during this period. When the value of the MTD is greater than 160 mg/kg, the value of the MTD is assimilated to 160 mg/kg by default.
The quercetin is assocated by default with an MTD equal to 160 mg/kg. This result emphasizes that the products belonging to the flavonoid family have no direct toxicity and can be used at high tissue concentrations, and therefore at high doses.
Examples of methods of use of the compounds of --formula (I) in protocols of mono- or polychemotherapy with cytotoxic agents will be given hereinafter.
A. Solid tumours 1°/ Lung cancers 1.1 non-small-cell lung cancers (advanced stage):
i - added to the recommended protocol (T. Le Chevalier et al., J. Clin. Oncol. 1994; 12: 360-367) are the intravenous infusions of a compound of formula I:
dose route days flavonoid 200-2000 mg/m2/day Di, De: Dis. Dz or 5-50 mg/kgfday i.v. D~9 and D3s 1 h infusion ' navelbine 3O mg/mz/day i.v: D,; De; Di;; D~~;
D29 and D36 cisplatin 120 mg/m2 i.v. D1 and Dig This therapy is to be repeated-8 times.
1.2 small cell lung cancers (advanced stage):
- added to the recommended CAV or VAC protocol (B.
J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291) are the flavonoid infusions:
dose route days flavonoid 200-2000 mg/m'/day Di or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 1000 mg/m' i.v. D
bolus doxorubicin 40 to 50 mg/m'- i.v. D
bolus vincristine 1 to 1.4 mg/m' i.v. D
bolus (max 2 mg) This therapy is to be repeated 6 times every 21 days.
- added to the recommended Pt-E protocol (B . J . Roth et al., J. Clin. Oncol. 1992; 10: 282-291) are the flavonoid infusions:
1uLe days flavonoid 200-2000 mg/mz/day D1 - Ds _or 5-50 mg/kg/day i.v.
1 h infusion ----cisplatin - i.v.
20 mg/mz/day 20 to 60 minute infusion etopos~ide 80 mg/m=/day i . v. D1 - Ds 60 minute infusion each cycle is repeated every 21 days, and the therapy comprises 6 cycles. .
1.3. locally advanced or metastatic non-small-cell bronchial cancer:
~ monochemotherapy dose route days flavonoid 200-2000 mg/m'/day Di. Da, Dls or 5-50 mg/kg/day i.v. then 1 w eek/rest 1 h infusion gemcitabine 1000 mg/m=/day i.v. Di. Day D~;s 0.5 hour infusion then 1 week/rest the therapy possibly comprising the repetition of this 4-week cycle.
~ gemcitabine/cisplatin combination:
x .. , CA 02337179 2001-O1-11 dose route days flavonoid 200-2000 mg/m2/day Dl - D5, De -Dls or 5-50 mg/kg/day i.v.
1 h infusion gemcitabine 1000 mg/mz/day i.v. D1, Ds. Dls 0.5 hour infusion cisplatin 20 mg/m2/day D1 20-60 minute i.v.
infusion the therapy comprising the repetition of this cycle every 21 days.
5 2°/ Breast cancers - CMF protocol as an adjuvant treatment of operable breast cancer (G. Bonnadonna et al., N. Engl. J.
Med.; 1976; 294: 405-410):
dose route days flavonoid 200-2000 mg/m~/day D1 to D14 or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 100 mg/m'/day oral D, to D.9 methotrexate 40 mg/m' i.v. D1 and De bolus 5-FU 600 mg/m- i.v. D1 and De each cycle is repeated every 28 days, and the therapy comprises 6 cycles.
- AC protocol (B. Fisher et al., J. Clin. Oncol.;
1990; 8: 1483-1496) as an adjuvant treatment:
dose route days flavonoid 200-2000 mg/m2/day or 5-50 mg/kg/day i.v. D1 1 h infusion doxorubicin 60 mg/m2 i.v.
bolus cyclophosphamide 600 mg/m2 i.v.
bolus each cycle is repeated every 21 days, and the therapy comprises 4 cycles.
- breast cancers with metastases:
- in the FAC protocol (A. U. Buzdar et al., Cancer 1981; 47: 2537-2542) and its various adaptations, the flavonoid infusions are added according to the i0 following scheme (nonlimiting):
dose route days flavonoid 200-2000 mg/m-/day _ D1 DS and or 5-50 mg/kg/day i.v.
1 h infusion or D1 - D5 5-FU 500 mg/m-'/day i . v. D1 and De or bolus Di _ D
doxorubicin 50 mg/m' i.v. D1 or bolus D1 and D
cyclophosphamide 500 mg/m'- oral or i.v. D, bolus each cycle is repeated every 3 weeks until a new progression of the disease is diagnosed.
- in the CAF protocol (G. Falkson et al., Cancer 1985; 56: 219-224):
y a___ Lvu~e days flavonoid 200-2000 mg/mz/day D1 - Dla or 5-50 mg/kg/day .v.
i 1 h infusion cyclophosphamide 100 mg/m2/day oral D1 - D1q doxorubicin. 3~ mg/mz l,v. Dl and' DB
bolus 5-FU 500 mg/m2 i.v. Dl and D8 bolus each cycle is repeated every 28 days until a new progression of the disease is diagnosed.
- in the CMF protocol: -dose route days flavonoid 200-2000 mg/m~/day D1 DS and -or 5-50 mg/kg/day i.v. De -D
1 h infusion cyclophosphamide 600 mg/m-/day i.v. D1 and DB
bolus methotrexate 40 mg/m-/day i.v. Dl and De bolus 5-FU 600 mg/m=/day i.v. D1 and De bolus this cycle is to be repeated every 3 to 5 ., weeks, and the therapy comprises 6 cycles.
- in the CMF-VP protocol:
a dose route days flavonoid 200-2000 mg/mz/day D1 - Ds ~r 5-50 mg/kg/day i . v De - Dlz .
1 h infusion Des -DL~ - Dzs cyclophosphamide 2 to 2.5 mg/kg/dayoral each day methotrexate 25 to 50 mg/mz/dayi.v. D1, D8, Dls, D
5-FU 300 to 500 i.v. D~. Ds. Des mg/m2/day D, vincristine 0 . 6 to i . v D1, D8, Dls, .
1.2 mg/mz/day prednisone 30 mg/mz/day oral from D1 to Dia this therapy is to be repeated every 4 weeks.
- in the FEC protocol:
dose route days flavonoid 200-2000 mg/mz/day D1 ~- Ds or 5-50 mg/kg/day i.v. and 1 h infusion Da - Diz 5-FU 600 mg/mz/day i . v. D1 and De epirubicin 50 mg/mz i.v.
cyclophosphamide 600 mg/mz i.v. Di this therapy is to be repeated every 3 weeks.
- in the MMC-VBC protocol (C. Brambilla et al., Tumori, 1989; 75: 141-144):
dose route days flavonoid 200-2000 mg/kg/day D1 - Ds and or 5-50 mg/kg/day i . Dls - Di9 v.
1 h infusion mitomyoin C 10 mg/mz i.v.
bolus vinblastin _ 50 mg/m2/day i.v. Dl and Dls bolus this therapy is to be repeated every 28 days until progression of the disease is diagnosed.
- in the NFL protocol (S. E. Jones et. al., J. Clin.
Oncol. 1991; 9: 1736-1739):
dose route days flavonoid 200-2000 mg/m'/day D1 - Ds or 5-50 mg/kg/day i.v.
1 h infusion mitoxantrone 10 mg/m- i.v. Di bolus 5-FU 1000 mg/m' i.v.
in a 24 hour infusion leucovorin 100 mg/m' i.v. D1 bolus the therapy comprises two cycles 21 days apart, and then requires am evaluation.
The flavonoid infusions can also be combined with the treatment of breast cancers with metastases, when a taxoid is used, for example:
- with paclitaxel (F. A. Holmes et al., J. Natl.
Cancer Inst. 1991; 83: 1797-1805) in the treatment of forms with metastases possibly resistant to anthracyclines:
dose route days flavonoid 200-2Q00 mg/m2/day D1 - Ds or 5-50 mg/kg/day i.v.
1 h infusion paclitaxel 175 mg/m2 i.v. Di in a 3 to 24 hour infusion This cycle is repeated every 21 days until a new progression of the disease is diagnosed.
- with docetaxel (C. A. Hudis et al., J. Clin. Oncol.
1996; 14: 58-65), in locall-y, advanced or metastatic breast cancer which is- resistant or in relapse after cytotoxic chemotherapy (having comprised an anthracycline), or in relapse during an adjuvant treatment:
dose route days flavonoid 200-2000 mg/m-/day D1 - Ds or 5-50 mg/kg/day i.v.
1 h infusion docetaxel 100 mg/m- i.v.
or 60-100 mg/m= in a 1 hour (or 24 hour) infusion This cycle is repeated every 21 days for a 2 cycle therapy, or until the appearance of progression of the disease.
- in dose increase protocols, combining transplant - of autologous medullary cells and of peripheral blood stem cells, as reinforcement for the first choice treatment, for example:
- CPB protocol (W. P. Peters et al., J. Clin. Oncol.
1993; 11: 132-1143) in which the i.v. infusion of stem cells takes place on days D_1, Do and D1:
dose route days flavonoid 200-2000 mglmz/day D_6 to D_1 or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 1875 mg/m2 i . D_6 to D_4 v.
in a 1 hour infusion cisplatin 55 mg/m'/day i.v. D_6 to D_q in a 24 hour - -continuous infusion carmustine 600 mg/mz/day i.v. D-s (BCNU) in a 2 hour infusion - CTCb protocol (K. Amman et al., J. Clin. Oncol.
1992; 10: 102-110), in which the i.v. infusion of stem cells takes place on Do:
a j~u~e Clays flavonoid 200-2000 mg/m'/day D_, to D_1 or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 1500 mg/m2 i . D_7 to D_3 v.
in a 24 hour continuous infusion (4 doses) thiotepa 125 mg/m2 i . D_, to D_3 v.
in a 24 hour continuous infusion (4 doses) carboplatin 200 mg/m2 i.v. _ D_, to D_3 in a 24 hour continuous infusion (4 doses) - CTM protocol (L. E. Damon et al., J. Clin. Oncol.
1989; 7: 560-571 and I.C. Henderson et al., J.
Cellular Biochem, 1994 (Suppl 18B): 95) in which the i.v, infusion of haematopoietic stem cells takes place on Do dose route days flavonoid 200-2000 mg/m=/day D_6 to D_1 or 5-50 mg/kg/day i.v.
1 hinfusion cyclophosphamide 1500 mg/m'/day i , D_6 to D_3 v.
in a 1 hour infusion thiotepa 150 mg/m'/day i.v. D_6 to D_3 in a 2 hour infusion mitoxantrone 10-15 mg/m- i . D_6 to D_3 v.
in a 1 hour infusion 3°/ Gynaecological cancers 3.1 Ovarian cancer:
- for the treatment of ovarian carcinomas, in particular metastatic ovarian carcinomas:
i) PAC protocol (G. A. Omura et al., J. Clin.
Oncol: 19$9; 7: 457=465): the,flavonoid infusions are administered according to the following scheme:
~~ _ route days flavonoid 200-2000 mg/m'/day D1 - DS
or 5-50 mg/kg/day i.v.
1 h infusion cisplatin 50 mg/mz i.v. Di (or 40-90 mg/mz) 1 to 2 hour infusion doxorubicin 50 mg/mz bolus i.v. D
(or 30 to 50 mg/m=) cyclophosphamide 1000 mg/m= i.v. Di 1 to 2 hour infusion (or 200 to 600 mg/mz) this cycle is repeated every 21 to 28 days, and the therapy comprises 8 cycles.
ii) altretamine protocol, according to A. Marietta et al., (Gynecol. Oncol. 1990; 36: 93-96):
dose route days ~ flavonoid 200-2000 mg/mz/day D~ - D;
or 5-50 mg/kg/day i . v. Da - Dlz 1 h infusion ~ altretamine 200 mg/mz/day oral divided into 4 doses the therapy comprising two cycles, 28 days apart.
ii) paclitaxel protocol: the flavonoids can be added to the paclitaxel protocol as has been described by W.P. McGuire et al., (Ann. Intern.
Med. 1989; 111: 273-279):
dose route days flavonoid _ 200-2000 mg/m2/day Dl -or 5-50 mg/kg/day i.v.
1 h infusion paclitaxel 135 mg/m- i.v.
3 hour or 24 hour infusion the therapy comprising two of these cycles, 28 days apart (with evaluation at the end).
- for the treatment of metastatic and resistant ovarian carcinomas, the flavonoids can be added to the second choice protocol, based on topotecan:
dose route days flavonoid 200-2000 mg/m'/day i.v. D1-D;
or 5-50 mg/kg/day 1 h infusion topotecan 1.5 mg/m'/day i.v. D1-Ds 0.5 hour infusion the cure comprising two cycles, 21 days apart (with evaluation at the end) according to A. P. Kudelka et al: (J. Clin. Oncol.
' 1996; 14: 1552-1557).
3.2 Trophoblastic tumours:
- in patients at low risk, the flavonoids may be combined with the protocol described by H. Takamizawa et al. (Semin. Surg. Oncol. 1987;
36-44):
,i .I _ 29 _ dose route days flavonoid 200-2000 mg/m2/day i .v. DI-D
or 5-50 mg/kg/day s 1 h in usion methotrexate (MTX) f 20 mg/d i .m. D1-Ds r dactinomycin 0.5 mg/day i b n a i.v. D1-D
r: ; ( DACT ) olus (MTX-DATC protocol).
3.3 Cancers of the uterus:
- the flavonoids can also be combined with the CAV
(or VAC) protocol according to the- scheme below:
dose route days flavonoid 200-2000 mg/m'-/day or 5-50 mg/kg/day 1 h infusion i.v. Di-Ds cyclophosphamide X50-1200 mg/m=
in an infusion i.v. D1 doxorubicin 45-50 mg/m' in an infusion i.v. D1 vincristine 1.4 mg/m'-i,v, n, the therapy comprising the repetition of this cycle every 21 days.
- in the FAP protocol:
dose route days flavonoid 200-2000 mg/m~/day or 5-50 mg/kg/day i ,v. D,-Ds 1 h infusion fluorouracil 600 mg/m'/day i . v. D1, (5-FU) De doxorubicin 340 mg/m' i .v. D
cisplatin ~5 mg/m' i .v. D, the therapy comprising the repetition of this cycle every 21 or 28 days.
_:_ . , 4°/ Cancers of the testicle and of the rostate - the flavonoids can also be combined with protocols for cancer of the testicles:
BEP protocol:
__dose flavonoid --- route y da s 200-2000 mg/mz/day or 5-50 mg/kg/day i .v. D1_DS
1 h infusion bleomycin 30 mg/m2 in an infusion i.v. D1 etoposide 100 mg/m'/day in an infusion-i.v. D
cisplatin 20 mg/m'/day i .v, D,-DS
the therapy comprising 3 cycles, at a rate of 1 cycle every 21 days.
x, .
Therapeutic composition based on flavonoids, intended to be used in the treatment of tumours by cytotoxic agents The present invention relates to the use of compounds of flavonoid type in the treatment of cancers by cytotoxic agents.
A cancer is a disorder of the somatic genes, in the course of which genetic dysfunctions worsen as the tumour progresses from the state of precancerous lesion to that of malignant transformation, the cancerous tumour becoming metastatic and often. resistant to cytotoxic medicines. -Despite the very considerable efforts conducted in all the developed countries, in particular through experimental and clinical research programmes, mortality due to the various cancers (solid tumours and haematological neoplasias) remains unacceptably high.
In many countries, cancer is placed second, just after cardiovascular diseases, as the cause of mortality.
In terms of newly diagnosed cancers, the distribution between solid tumours and haematological (bone marrow, blood, lymphatic system) neoplasias shows that 9 cancers out of 10 are solid tumours. Unlike that which is observed in haematological oncology (therapeutic success in 40 to 900 of blood cell cancers), only a small number of advanced or disseminated solid tumours respond to only chemotherapeutic treatments. It is partly for this reason that the overall mortality due to cancer increased in the U.S.A. between 1973 and 1992.
It is not, unfortunately, certain that this tendency may be reversed only by the appearance, alongside the'established ehemotherapeutic arsenal, of novel antitumour medicines such as taxanes (paclitaxel and docetaxel), which interfere with the formation of microtubules (W. P. McGuire et al., Am. Intern. Med., 1989), camptothecin-derived topoisomerase I inhibitors ~ .n ~.r (topotecan and irinotecan), vinorelbine (novel alkaloid derived from the periwinkle), gemcitabine (novel cytotoxic antimetabolic agent), raltitrexed (thymidylate synthetase inhibitor) or miltefosine (first representative of the alkylphosphocholine family). These treatments add, either as a first choice or as a second choice, to the medicines for which the specific activity is now well recognized, such as doxorubicin, cisplatin, vincristine, methotrexate, 5 fluorouracil.
One of the most difficult current problems of anticancer chemotherapy is due to the fact that numerous populations of malignant- -cells exhibit considerable resistance to established cytotoxic substances. Most commonly, this situation results from the existence of multiresistance genes or from the frequency of genetic mutations in certain types of tumour. Thus, the treatment of cancers requires novel approaches which are complementary to those currently implemented, and which are intended to more successfully combat the extension and heterogeneity of the tumour load, and the acquisition of "multi-cytotoxic-drug" resistance.
Among these novel approaches, some are already promising. This is the case of the induction of apoptosis, and the inhibition of tumour angiogenesis and of metastatic processes, not to mention gene therapy or immunotherapy.
. The inventors were interested in a different approach. The objective sought was to make the population of tumour cells more sensitive to reference anticancer treatments, in order to achieve a double benefit:
1) increase the cytotoxic activity and therefore the effectiveness, and 2) decrease the frequency and severity of certain side effects, due to the reduction in dosage which might follow the induction of the increase in the antitumour effectiveness.
a .3.a ,~ _ 3 _ It is this strategy which is behind the_ discovery of an original mechanism caused by substances - which have weak antitumour power, or are lacking this power - but which are capable of inducing a very significant increase in the cytotoxic activity of proven anticancer medicines. This original mechanism comes from the possibility for these substances either to stimulate the recruitment of clonogenic cells within the tumour, making it more sensitive to the conventional treatment with cytotoxic agents, or to inhibit the proliferation of clonogenic cells, thus contributing to the regression of the tumour.
A subj ect of the present invention is thus the use, in the treatment of cancers with at least one antitumour agent chosen from cytotoxic agents, of a compound having activity on the proliferation of clonogenic cells, chosen from flavonoids and in particular the compounds of formula:
this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a Cl-CQ alkoxy group and an -OCOR~
group, R~ being a Cl-C4 alkyl group, at least one of the substituents R1, R2, R3 or RQ being other than H, and R2 --_ and R3 possibly forming together a methylenedioxy group, - RS is chosen from H, OH, a C1-CQ alkoxy group and an O-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups chosen from H, OH and a C1-C4 alkoxy group, - and ....... designates either a double bond or a single bond.
~ ,.,::, jf The cytotoxic agents can be used at their conventional dose, and in this case, their effectiveness is improved, or at lower doses given the increase in their antitumour effectiveness.
~i A subject of the present invention is also a composition having activity on the proliferation of clonogenic cells by interfering with the generation of clonogenic cells, either by stimulating the proliferation and recruitment, or by inhibiting the proliferation, comprising a therapeutically effective amount of a flavonoid and in particular of a compound of formula I chosen from the compounds of formula:
i this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkoxy group and an -OCOR7 group, R7 being a C1-C9 alkyl group, at least one of the substituents Rl, R2, R3 or RQ being other than H, and RZ
and R3 possibly forming together a methylenedioxy group, - RS is chosen from H, OH, a C1-Cq aikoxy group and an 0-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups y 25 chosen from H, OH and a C1-C4 alkoxy group, - and ....... designates either a double bond or a single bond.
A subject of the present invention is also the use of a flavonoid and in particular of a compound of formula I as defined above, for manufacturing a medicine intended to interfere (by induction or inhibition) with the generation of clonogenic cells in tumours during treatment with at least one cytotoxic agent.
i , t~
_ 5 _ In the chemotherapeutic treatment of cancers with cytotoxic agents, flavonoids, and in particular the compounds of formula I, can be administered at the start of the chemotherapeutic treatments, either in a single dosage intake or over several days at the start of these treatments (for example for 5 to 7 days) and, depending on the .chemotherapeutic protocol, at the start of each cycle of treatment (for example for 2 to 5 days) in the course of each therapy.
The compounds of formula I are advantageously administered by infusion (generally in 1 to 3 hours) at doses of 5 to 50 mg/kg/day or 200 to 2000 mg/m2/day.
In order to obtain a maximum- effect on the production of clonbgenic cells, the flavonoids should be administered such that the tissue concentrations obtained are as high as conceivably possible.
For protocols of treatment in the acute phases of therapies, the intravenous route is to be favoured uslna:
- ready-to-use infusion solutes (bags, bottles, etc.) intended to be administered without modification by intravenous infusion using an infusion line and according to the recommended flow rate:
lyophilizates to be resuspended for intravenous infusion, using pharmaceutical solutes known 'to those skilled in the art;
- for maintenance treatments, it is also _ __ possible to envisage the oral route when the chemotherapy treatment favours the oral administration of cytostatic agents. For this purpose, oral lyophilizates (for oral or perlingual absorption) immediate- or delayed-release tablets, oral solutions, suspensions, granules, capsules, etc. may be used.
The compounds of formula (I) are, for the most part, compounds of natural origin, or are derivatives of compounds of natural origin. As examples, mention may be made of:
1) flavones such as:
- quercetin, ii 4-hydroxyflavone, 6-hydroxyflavone, 7-hydroxyflavone, 5-methoxyflavone, - 6-methoxyflavone, - 7-methoxyflavone, - 2-cyclohexyl-5-hydroxychromone, - 2-cyclohexyl-6-hydroxychromone, - 2-cyclohexyl-7-hydroxychromone, - wogonin or 5,7-dihydroxy-8-methoxyflavone, - acacetin or 5,7-dihydroxy-4'-methoxyflavone, - pedalitin or 5,6,3',4'=tetrahydroxy-7-methoxyflavone, - apigenin or 5,7,4'-trihydroxyflavone, - luteolin or 5,7,3',4'-tetrahydroxyflavone, - baica.lein or 5,6,7-trihydroxyfiavone, - scutellarein or 5,6,7,4'-tetrahydroxyflavone, - fisetin or 7,3',4'-trihydroxyflavonol, - ~robinetin or 7, 3' , 4' , 5' -tetrahydroxyflavonol, 25' - kaempferol or 5,7,4'-trihydroxyflavonol, - kaempferide or 5,7-dihydroxy-4'-methoxyflavonol, - morin or 5,7,2',4-'-tetrahydroxyflavonol, - myricetin or 5,7,3',4',5'-pentahydroxyflavonol, - 2) flavanolols such as:
- aromadendrin or 5,7,4'-trihydroxyflavanolol, - fustin or 7,3',4'-trihydroxyflavanolol, - hydroxyrobinetin or 7,3',4',5'-tetrahydroxyflavanolol, 1 =.x n -- taxifolin or 5,7,3' 4'-, trihydroxyflavanolol , 3) flavanones such as naringenin or 5,6,4'-trihydroxyflavanone;
- 7,4'-dihydroxyflavanone , eriodictyol or 5,73' q~_ , tetrahydroxyflavanone , - hesperetin or 5,7;3'-trihydroxyflavanone.
Flavones are the preferred compounds.
The cytotoxic agents can be chosen from:
i) intercalating agents, in particular daunorubicin, epirubicin, idarubicin , aorubicin, aclarubicin, pirarubicin, acridine , mitoxantrone, actinomycin D, eptilinium acetate;
ii) alkylating agents chosen from platinum derivatives (cisplatin, carboplatin , oxaliplatin);
iii) a compound chosen from the other groups of alkylating agents:
- cyclophosphamide, ifosfamide, chlormetrine , melphalan, chlorambucil, estramustine , - busulphan, mitomycin C, - nitrosoureas: BCNU (carmustine), CCNU
(lomustine), fotemustine, streptozotocin , - triazines or derivatives: procarbazine , decarbazine w , - pipobroman , ethyleneimines: altretami.ne , triethylenethiophosphoramide , iv) a compound chosen from the other groups of antimetabolic agents:
- antifolates: methotrexate, raltitrexed , - antipyrimidines: 5-fluorouracil (5-FU), cytarabine (Ara-C), - hydroxyurea, I
,U
- antipurines: purinethol, thioguanine , pentostatin, cladribine - inducers of cytotoxic nucleoside synthesis:
gemcitabine, v) a compound chosen from the other groups of agents with affinity for tubulin:
- vinca-alkaloids which disorganize the mitotic spindle: vincristine, vinblastine, vindesine , navelbine agents which block the depolymerization of the mitotic spindle: paclitaxel, docetaxel - agents which induce breaks in the DNA by topoisomerase II inhibition: etoposide , teniposide _ -- topoisomerase I inhibitors which induce cleavages of the DNA: topotecan, irinotecan , vi) a splitting agent, which fragments the DNA, such as bleomycin, vii) one of the following compounds; plicamycin L
, asparaginase, mitoguazone, decarbazine , viii) an anticancer progestative steroid:
medroxyprogesterone, megestrol, ix) an anticancer oestrogenic steroid:
diethylstilbestrol, tetrasodium fosfestrol , x) an anti-oestrogen: tamoxifen, droloxifen , raloxifen, aminogluthetimide , xi) a steroidal anti-androgen (ex cyproterone) or a nonsteroidal anti-androgen (flutamide , nilutamide).
In particular, the compounds of formula I
can be combined with all treatments with the major i cytotoxic agents used in polychemotherapies f or solid tumours, such as:
- alkylating agents: oxazophorines (cyclophosphamide, ifosfamide, chlorambucil , melphalan) r - nitrosoureas - mitomycin C
r - antimetabolites, such as methotrexate, 5-FU, Ara-C, capacitabine - agents which interfere with tubulin: vinca-alkaloids (vincristine, vinblastine, vindesine, navelbine), taxoids (paclitaxel, docetaxel), epipodophyllotoxin derivatives (etoposide, teniposide) i - bleomycin - topoisomerase I inhibitors: topotecan, irinotecan.
Similarly, the compounds of formula I can be combined with treatments with the major cytotoxic agents used in oncohaematology for the treatment of blood cancers:
- Hodgkin's disease: cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;
- acute leukaemias: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase;
- non-Hodgkin's malignant lymphomas:
mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunorubicin, carmustine, lomustine, cisplatin;
- chronic lymphoid leukaemias: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.
Results of pharmacological trials demonstrating . the properties of the compounds of formula (I) used alone or in combination with cytotoxic agents will be given hereinafter.
Interaction (stimulation or inhibition of proliferation) with the generation of clonogenic cells (clonogenic assay) 1 J~ j -The assay used is that described by Hamburger et al., (Science, 1977; 197, 461-463) and Salmon et al., (New England J. Med., 298, 1321-1327). A cell is considered to be clonogenic if it has the capacity to 5 proliferate and to give rise to a cell colony. Human tumour stem cells are the cells behind the neoplastic cells which constitute a given tumour. These tumour stem cells are responsible for the processes of recurrence which can be observed after surgical 10 resection of primary tumours; and are also responsible for the formation of metastases. In a tumour or a tumour cell line, these clonogenic stem cells differ from the other cells of the tumour or of the neoplastic cell line under consideration, by the fact that they conserve their capacity to proliferate in the absence of any solid support.
In this assay, the tumour cells are cultured on a semi-solid support consisting of agar. Only cells which do not require a solid support for their growth (i.e. the very tumorigenic cells termed "anchorage-independent cells" by M.I. Dawson et al., Cancer Res.
1995; 55: 4446-4451; also named clonogenic cells with reference to "clonal growth") are capable of developing on such an agar-based support. Specifically, on such a medium, normal cells - which grow in "adherent mode"
("anchorage-dependence cells" according to the terminology of M.I. Dawson) - such as, for example, fibroblasts, do not survive. Within a tumour cell population, cultured on such a -support, it is these clonogenic cells (associated with an unlimited number of cell divisions, and the proliferation of which is termed "anchorage-independent [clonal] growth" by . M.I. Dawson) which are capable of growing. The percentage of these clonogenic cells within a tumour or a cell line various between 0.1% and O.OOlo. The nonclonogenic cells (associated with a limited number of cell divisions) do not develop in this assay since they require a solid support for their growth which must take place in "adherent mode" ("anchorage-'e . _.
dependent (adherent] growth", according to M.I. Dawson et al., Cancer Res. 1995; 55: 4446-51).
The influence of compounds of formula (I) on the growth of the cell colonies obtained by culturing, for example, the mammary tumour lines MCF7 and MXT, and the colorectal line HT-29, on the semi-liquid culture medium termed "soft agar" was measured. On such a medium, only the clonogenic cells termed "anchorage-independent (clonal) cells" by M.I. Dawson survive and develop. The growth of these cells in such a "nonadherent" mode indicates their degree of tumorigenicity. The inhibition of the growth of the size of a tumour in which a greater number of clonogenic cells have developed then becomes the sign of reinforced cytotoxic activity.
Conversely, this assay can also reveal that a compound is capable of inhibiting the generation/
proliferation of clonogenic cells, which makes the tumour less able to develop, and therefore decreases the population of tumour cells.
The tumour cell lines studied are maintained in culture in 25 cm2 falcon dishes. They are then trypsinized and the cells are well dissociated from each other. The percentage of live cells is determined after trypan blue staining. A cell suspension at the concentration of 5 x 109 to 15 x 109 cells/ml (depending on the cell type under consideration) is prepared in a solution of agar at 0.30. Next, 200 ~1 of this - suspension are seeded int o petri dishes 35 mm in diameter, into which 3 ml of a base layer consisting of a solution of agar at 0.5% are placed. The 200 ~1 of cell suspension are themselves covered with 1.8 mL of an upper layer consisting of a solution of agar at 0.30. The dishes are then placed in an incubator at 37°C, 5o COZ and 70o humidity until treatment. The latter is carried out approximately l to 2 hours after seeding. The compounds to be assayed are prepared at a concentration 100 times greater than the concentration desired, and 50 ~1 of these treating solutions are wi i deposited onto the upper agar layer of the corresponding dishes. In the present study, the final concentration of the products assayed is 10-5, 10-7 and 10-9 M. The dishes are then maintained for 21 days in an incubator. On the 21st day, the dishes are treated by depositing on the upper layer 100 ~l of a solution of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide). at 1 mg/ml prepared with RPMI 1640 medium, for 3 h at 37°C. After this lapse of time, the cell colonies are fixed by adding 2 ml of formol per dish. After fixing for 24 hours, the formol is evaporated off and the number of cell colonies stained, and therefore consisting of cells which are metabolically active and which have- a surface area greater than 100 ~mz is determined using an inverted microscope.
The mean number of clonogenic cell clones, determined for each experimental condition studied, is expressed as a percentage with respect to the mean number of clonogenic cell clones counted in the control condition and taken to,be equal to 100%. These values, expressed as a percentage with respect to the control condition, are given in Table l, for quercetin.
CELL LINES Quercetin (in mol.l-1) MCF7 67.4 ~ 3.4 101.2 ~ 3.2 ** NS
HT-29 45.6 ~ 1.2 103.4 ~ 2.2 ** NS
MXT ~ 80.8 ~ 3.6 I 93.4 ~ 3.2 ** ~ NS
- The results given in this table represent the mean values ~ the standard error of the mean (SEM) established on at least 6 cupules - Control condition = 100 y . i - (NS: p>0.05; *: p<0.05; ** p<0.01; **~ p<0,001).
On the three cell lines MCF7, HT-29 and MXT, quercetin is capable of partially inhibiting the proliferation of the clonogenic cells within the tumour; i.e. of inducing a significant decrease in the number of colonies of these cells with respect to that w obtained in the control condition (from 20o to 50%), and therefore contributes to making the tumours from which they are derived more sensitive to the conventional treatment with cytotoxic agents.
Cytotoxic activity on -the nonclonogenic cells: "MTT assay" . -The influence of the compounds of formula (I) on the nonclonogenic cells was evaluated using the MTT
colorimetric assay.
The principle of the MTT assay is based on the mitochondrial reduction, by metabolically active live cells, of the yellow-coloured product MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into a blue-coloured product, formazan. The amount of formazan thus obtained is directly proportional to the amount df live cells present in the culture well(s).
This formazan amount is measured by spectrophotometry.
The cell lines are maintained in monolayer culture at 37°C in closed-cap dishes containing MEM 25 MM HEPES basic medium (Minimum Essential Medium). This medium is suitable for the growth' of a range of varied diploid or primary mammalian cells. This medium is then supplemented with:
- a 5o amount of FCS (foetal calf serum) decomplemented at 56°C for, 1 hour, - with 0.6 mg/ml of L-glutamine, - with 200 IU/ml of penicillin, - with 200 ~g/ml of streptomycin, - with 0.1 mg/ml of gentamicin.
:.. d The 12 human cancer cell lines which were used were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA).
These 12 cell lines are:
U-373MG (ATCC code: HTB-17) and U-87MG (ATCC
code': HTB-14) which are two glioblastomas, - SW1088 (ATCC code: HTB-12) which is an astrocytoma, - A549 (ATCC code: CCL-185) and A-427 (ATCC
code: HTB-53) which are two non-small-cell lung cancers, - HCT-15 (ATCC code: CCL-225) and LoVo (ATCC
code: CCL-229) which are .two colorectal cancers, - T-47D (ATCC code: HTB-133) and MCF7 (ATCC
code: HTB-22) which are two breast cancers, - J82 (ATCC code: HTB-1) and T24 (ATCC code:
HTB-4) which are two bladder cancers, - PC-3 (ATCC code: CRL-1435) which is a prostate cancer.
In experimental terms: 100 ~l of a cell suspension containing 20 000 to 50 000 (depending on the cell type used) cells/ml of culture medium are seeded into flat-bottomed 96-well multi-well plates and are incubated at 37°C under an atmosphere comprising 50 COz and 70% of humidity. After 24 hours of incubation, the culture medium is replaced with 100 ~,l of fresh medium containing either the various compounds to be tested at concentrations ranging from 10-5 to 10-1° M, or the solvent which was used in order to dissolve the products to be tested (control condition). After 72 hours of incubation under the above conditions, the culture medium is replaced with 100 ~1 of a yellowish solution of MTT dissolved, at a rate of 1 mg/ml, in RPMI 1640. The microplates are re-incubated for 3 hours at 37°C, and then centrifuged for 10 minutes at 400 g:
The yellowish solution of MTT is removed a.nd the blue formazane crystals formed at the cellular level are ,, s dissolved in 100 ~1 of DMSO. The microplates are then shaken for 5 minutes. The intensity of the blue coloration resulting, therefore, from the transformation of the yellow MTT product into blue forrnazane by the cells still alive at the end of the experiment is quantified' by spectrophotometry using a machine of type DYNATECFF IMMUNOASSAY SYSTEM at the wavelengths of 570 nm and 630 nm corresponding, respectively, to the wavelengths of maximum absorbence of the formazane and to the background noise. Software integrated into the spectrophotometer calculates the mean values of optical density, and the standard deviation (Std. Dev.) and standard error of the mean (SEM) values. - -By way of example, the results of the mean optical density, expressed as percentage with respect to the mean optical density measured in the control condition (taken to be equal to 100$), obtained - by way of nonlimiting example - with a flavonoid:
quercetin, on the 5 tumour cell lines Li-373MG, T24, LoVo, MCF7 and A549, will be given in Table II.
TABLE II
CELL
Quer cetin LINES 10 5* 10 6* 10 ~ 10 e* 10 9* 10 io*
U-373I~96.4 105.2 104. 1 98.5 101.5 97.7 t 3.1 NS 2.2 NS 2.9 NS 2.4 NS 3.2 NS 1.7 NS
T24 102.5 102.4 99.7 107.4 105.2 110.2 0.7 NS 1.7 NS 2.0 NS 3.B NS 2.0 NS 2.4 **
- Lovo 97.8 94,5 101.9 103.1 101.6 112.0 t 3.1 NS 2.2 NS 4.7 NS 2.1 NS 3.0 NS 4.2 I~F7 81.5 84.5 82.1 t 90.7 89.6 103.8 2.5 *** 2.3 *** 2.1 NS 3.8 NS 2.0 ** 2.9 NS
A549 86.0 100.3 94.9 f 98.2 97.3 97.7 t 3.6 * 3.7 NS 2.3 NS 3.5 NS 2.2 NS 1.7 NS
- Concentrations expressed in mol.l-1 xx ~ yy = mean value ~ standard error of the mean - Control conditions = 100 - (NS/p > 0.05; *: p < 0.05; **: p < 0.01; p < 0.001).
T
These results show that quercetin has weak antitumour power. This product, which is non-cytotoxic, induces inhibition of the overall cell proliferation of these lines only at the concentration of 10-5 M, and this inhibition doe s not exceed 200: At the other concentrations assayed; only a few minor effects can be detected, 3. Determination of the maximum tolerated dose (MTD):
The evaluation of the maximum tolerated dose was carried out in 4- to 6-week-old B6D2F1/Jico mice.
The compounds were administered via the intraperitoneal route at increasing doses ranging. ~ from - 2.5 to 160 mg/kg. The value of the MTD (expressed in mg/kg) is determined based on the observation of the survival rate of the animals over a period of 14 days after a single administration of the product under consideration. The evolution of the weight of the animals is also monitored during this period. When the value of the MTD is greater than 160 mg/kg, the value of the MTD is assimilated to 160 mg/kg by default.
The quercetin is assocated by default with an MTD equal to 160 mg/kg. This result emphasizes that the products belonging to the flavonoid family have no direct toxicity and can be used at high tissue concentrations, and therefore at high doses.
Examples of methods of use of the compounds of --formula (I) in protocols of mono- or polychemotherapy with cytotoxic agents will be given hereinafter.
A. Solid tumours 1°/ Lung cancers 1.1 non-small-cell lung cancers (advanced stage):
i - added to the recommended protocol (T. Le Chevalier et al., J. Clin. Oncol. 1994; 12: 360-367) are the intravenous infusions of a compound of formula I:
dose route days flavonoid 200-2000 mg/m2/day Di, De: Dis. Dz or 5-50 mg/kgfday i.v. D~9 and D3s 1 h infusion ' navelbine 3O mg/mz/day i.v: D,; De; Di;; D~~;
D29 and D36 cisplatin 120 mg/m2 i.v. D1 and Dig This therapy is to be repeated-8 times.
1.2 small cell lung cancers (advanced stage):
- added to the recommended CAV or VAC protocol (B.
J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291) are the flavonoid infusions:
dose route days flavonoid 200-2000 mg/m'/day Di or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 1000 mg/m' i.v. D
bolus doxorubicin 40 to 50 mg/m'- i.v. D
bolus vincristine 1 to 1.4 mg/m' i.v. D
bolus (max 2 mg) This therapy is to be repeated 6 times every 21 days.
- added to the recommended Pt-E protocol (B . J . Roth et al., J. Clin. Oncol. 1992; 10: 282-291) are the flavonoid infusions:
1uLe days flavonoid 200-2000 mg/mz/day D1 - Ds _or 5-50 mg/kg/day i.v.
1 h infusion ----cisplatin - i.v.
20 mg/mz/day 20 to 60 minute infusion etopos~ide 80 mg/m=/day i . v. D1 - Ds 60 minute infusion each cycle is repeated every 21 days, and the therapy comprises 6 cycles. .
1.3. locally advanced or metastatic non-small-cell bronchial cancer:
~ monochemotherapy dose route days flavonoid 200-2000 mg/m'/day Di. Da, Dls or 5-50 mg/kg/day i.v. then 1 w eek/rest 1 h infusion gemcitabine 1000 mg/m=/day i.v. Di. Day D~;s 0.5 hour infusion then 1 week/rest the therapy possibly comprising the repetition of this 4-week cycle.
~ gemcitabine/cisplatin combination:
x .. , CA 02337179 2001-O1-11 dose route days flavonoid 200-2000 mg/m2/day Dl - D5, De -Dls or 5-50 mg/kg/day i.v.
1 h infusion gemcitabine 1000 mg/mz/day i.v. D1, Ds. Dls 0.5 hour infusion cisplatin 20 mg/m2/day D1 20-60 minute i.v.
infusion the therapy comprising the repetition of this cycle every 21 days.
5 2°/ Breast cancers - CMF protocol as an adjuvant treatment of operable breast cancer (G. Bonnadonna et al., N. Engl. J.
Med.; 1976; 294: 405-410):
dose route days flavonoid 200-2000 mg/m~/day D1 to D14 or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 100 mg/m'/day oral D, to D.9 methotrexate 40 mg/m' i.v. D1 and De bolus 5-FU 600 mg/m- i.v. D1 and De each cycle is repeated every 28 days, and the therapy comprises 6 cycles.
- AC protocol (B. Fisher et al., J. Clin. Oncol.;
1990; 8: 1483-1496) as an adjuvant treatment:
dose route days flavonoid 200-2000 mg/m2/day or 5-50 mg/kg/day i.v. D1 1 h infusion doxorubicin 60 mg/m2 i.v.
bolus cyclophosphamide 600 mg/m2 i.v.
bolus each cycle is repeated every 21 days, and the therapy comprises 4 cycles.
- breast cancers with metastases:
- in the FAC protocol (A. U. Buzdar et al., Cancer 1981; 47: 2537-2542) and its various adaptations, the flavonoid infusions are added according to the i0 following scheme (nonlimiting):
dose route days flavonoid 200-2000 mg/m-/day _ D1 DS and or 5-50 mg/kg/day i.v.
1 h infusion or D1 - D5 5-FU 500 mg/m-'/day i . v. D1 and De or bolus Di _ D
doxorubicin 50 mg/m' i.v. D1 or bolus D1 and D
cyclophosphamide 500 mg/m'- oral or i.v. D, bolus each cycle is repeated every 3 weeks until a new progression of the disease is diagnosed.
- in the CAF protocol (G. Falkson et al., Cancer 1985; 56: 219-224):
y a___ Lvu~e days flavonoid 200-2000 mg/mz/day D1 - Dla or 5-50 mg/kg/day .v.
i 1 h infusion cyclophosphamide 100 mg/m2/day oral D1 - D1q doxorubicin. 3~ mg/mz l,v. Dl and' DB
bolus 5-FU 500 mg/m2 i.v. Dl and D8 bolus each cycle is repeated every 28 days until a new progression of the disease is diagnosed.
- in the CMF protocol: -dose route days flavonoid 200-2000 mg/m~/day D1 DS and -or 5-50 mg/kg/day i.v. De -D
1 h infusion cyclophosphamide 600 mg/m-/day i.v. D1 and DB
bolus methotrexate 40 mg/m-/day i.v. Dl and De bolus 5-FU 600 mg/m=/day i.v. D1 and De bolus this cycle is to be repeated every 3 to 5 ., weeks, and the therapy comprises 6 cycles.
- in the CMF-VP protocol:
a dose route days flavonoid 200-2000 mg/mz/day D1 - Ds ~r 5-50 mg/kg/day i . v De - Dlz .
1 h infusion Des -DL~ - Dzs cyclophosphamide 2 to 2.5 mg/kg/dayoral each day methotrexate 25 to 50 mg/mz/dayi.v. D1, D8, Dls, D
5-FU 300 to 500 i.v. D~. Ds. Des mg/m2/day D, vincristine 0 . 6 to i . v D1, D8, Dls, .
1.2 mg/mz/day prednisone 30 mg/mz/day oral from D1 to Dia this therapy is to be repeated every 4 weeks.
- in the FEC protocol:
dose route days flavonoid 200-2000 mg/mz/day D1 ~- Ds or 5-50 mg/kg/day i.v. and 1 h infusion Da - Diz 5-FU 600 mg/mz/day i . v. D1 and De epirubicin 50 mg/mz i.v.
cyclophosphamide 600 mg/mz i.v. Di this therapy is to be repeated every 3 weeks.
- in the MMC-VBC protocol (C. Brambilla et al., Tumori, 1989; 75: 141-144):
dose route days flavonoid 200-2000 mg/kg/day D1 - Ds and or 5-50 mg/kg/day i . Dls - Di9 v.
1 h infusion mitomyoin C 10 mg/mz i.v.
bolus vinblastin _ 50 mg/m2/day i.v. Dl and Dls bolus this therapy is to be repeated every 28 days until progression of the disease is diagnosed.
- in the NFL protocol (S. E. Jones et. al., J. Clin.
Oncol. 1991; 9: 1736-1739):
dose route days flavonoid 200-2000 mg/m'/day D1 - Ds or 5-50 mg/kg/day i.v.
1 h infusion mitoxantrone 10 mg/m- i.v. Di bolus 5-FU 1000 mg/m' i.v.
in a 24 hour infusion leucovorin 100 mg/m' i.v. D1 bolus the therapy comprises two cycles 21 days apart, and then requires am evaluation.
The flavonoid infusions can also be combined with the treatment of breast cancers with metastases, when a taxoid is used, for example:
- with paclitaxel (F. A. Holmes et al., J. Natl.
Cancer Inst. 1991; 83: 1797-1805) in the treatment of forms with metastases possibly resistant to anthracyclines:
dose route days flavonoid 200-2Q00 mg/m2/day D1 - Ds or 5-50 mg/kg/day i.v.
1 h infusion paclitaxel 175 mg/m2 i.v. Di in a 3 to 24 hour infusion This cycle is repeated every 21 days until a new progression of the disease is diagnosed.
- with docetaxel (C. A. Hudis et al., J. Clin. Oncol.
1996; 14: 58-65), in locall-y, advanced or metastatic breast cancer which is- resistant or in relapse after cytotoxic chemotherapy (having comprised an anthracycline), or in relapse during an adjuvant treatment:
dose route days flavonoid 200-2000 mg/m-/day D1 - Ds or 5-50 mg/kg/day i.v.
1 h infusion docetaxel 100 mg/m- i.v.
or 60-100 mg/m= in a 1 hour (or 24 hour) infusion This cycle is repeated every 21 days for a 2 cycle therapy, or until the appearance of progression of the disease.
- in dose increase protocols, combining transplant - of autologous medullary cells and of peripheral blood stem cells, as reinforcement for the first choice treatment, for example:
- CPB protocol (W. P. Peters et al., J. Clin. Oncol.
1993; 11: 132-1143) in which the i.v. infusion of stem cells takes place on days D_1, Do and D1:
dose route days flavonoid 200-2000 mglmz/day D_6 to D_1 or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 1875 mg/m2 i . D_6 to D_4 v.
in a 1 hour infusion cisplatin 55 mg/m'/day i.v. D_6 to D_q in a 24 hour - -continuous infusion carmustine 600 mg/mz/day i.v. D-s (BCNU) in a 2 hour infusion - CTCb protocol (K. Amman et al., J. Clin. Oncol.
1992; 10: 102-110), in which the i.v. infusion of stem cells takes place on Do:
a j~u~e Clays flavonoid 200-2000 mg/m'/day D_, to D_1 or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide 1500 mg/m2 i . D_7 to D_3 v.
in a 24 hour continuous infusion (4 doses) thiotepa 125 mg/m2 i . D_, to D_3 v.
in a 24 hour continuous infusion (4 doses) carboplatin 200 mg/m2 i.v. _ D_, to D_3 in a 24 hour continuous infusion (4 doses) - CTM protocol (L. E. Damon et al., J. Clin. Oncol.
1989; 7: 560-571 and I.C. Henderson et al., J.
Cellular Biochem, 1994 (Suppl 18B): 95) in which the i.v, infusion of haematopoietic stem cells takes place on Do dose route days flavonoid 200-2000 mg/m=/day D_6 to D_1 or 5-50 mg/kg/day i.v.
1 hinfusion cyclophosphamide 1500 mg/m'/day i , D_6 to D_3 v.
in a 1 hour infusion thiotepa 150 mg/m'/day i.v. D_6 to D_3 in a 2 hour infusion mitoxantrone 10-15 mg/m- i . D_6 to D_3 v.
in a 1 hour infusion 3°/ Gynaecological cancers 3.1 Ovarian cancer:
- for the treatment of ovarian carcinomas, in particular metastatic ovarian carcinomas:
i) PAC protocol (G. A. Omura et al., J. Clin.
Oncol: 19$9; 7: 457=465): the,flavonoid infusions are administered according to the following scheme:
~~ _ route days flavonoid 200-2000 mg/m'/day D1 - DS
or 5-50 mg/kg/day i.v.
1 h infusion cisplatin 50 mg/mz i.v. Di (or 40-90 mg/mz) 1 to 2 hour infusion doxorubicin 50 mg/mz bolus i.v. D
(or 30 to 50 mg/m=) cyclophosphamide 1000 mg/m= i.v. Di 1 to 2 hour infusion (or 200 to 600 mg/mz) this cycle is repeated every 21 to 28 days, and the therapy comprises 8 cycles.
ii) altretamine protocol, according to A. Marietta et al., (Gynecol. Oncol. 1990; 36: 93-96):
dose route days ~ flavonoid 200-2000 mg/mz/day D~ - D;
or 5-50 mg/kg/day i . v. Da - Dlz 1 h infusion ~ altretamine 200 mg/mz/day oral divided into 4 doses the therapy comprising two cycles, 28 days apart.
ii) paclitaxel protocol: the flavonoids can be added to the paclitaxel protocol as has been described by W.P. McGuire et al., (Ann. Intern.
Med. 1989; 111: 273-279):
dose route days flavonoid _ 200-2000 mg/m2/day Dl -or 5-50 mg/kg/day i.v.
1 h infusion paclitaxel 135 mg/m- i.v.
3 hour or 24 hour infusion the therapy comprising two of these cycles, 28 days apart (with evaluation at the end).
- for the treatment of metastatic and resistant ovarian carcinomas, the flavonoids can be added to the second choice protocol, based on topotecan:
dose route days flavonoid 200-2000 mg/m'/day i.v. D1-D;
or 5-50 mg/kg/day 1 h infusion topotecan 1.5 mg/m'/day i.v. D1-Ds 0.5 hour infusion the cure comprising two cycles, 21 days apart (with evaluation at the end) according to A. P. Kudelka et al: (J. Clin. Oncol.
' 1996; 14: 1552-1557).
3.2 Trophoblastic tumours:
- in patients at low risk, the flavonoids may be combined with the protocol described by H. Takamizawa et al. (Semin. Surg. Oncol. 1987;
36-44):
,i .I _ 29 _ dose route days flavonoid 200-2000 mg/m2/day i .v. DI-D
or 5-50 mg/kg/day s 1 h in usion methotrexate (MTX) f 20 mg/d i .m. D1-Ds r dactinomycin 0.5 mg/day i b n a i.v. D1-D
r: ; ( DACT ) olus (MTX-DATC protocol).
3.3 Cancers of the uterus:
- the flavonoids can also be combined with the CAV
(or VAC) protocol according to the- scheme below:
dose route days flavonoid 200-2000 mg/m'-/day or 5-50 mg/kg/day 1 h infusion i.v. Di-Ds cyclophosphamide X50-1200 mg/m=
in an infusion i.v. D1 doxorubicin 45-50 mg/m' in an infusion i.v. D1 vincristine 1.4 mg/m'-i,v, n, the therapy comprising the repetition of this cycle every 21 days.
- in the FAP protocol:
dose route days flavonoid 200-2000 mg/m~/day or 5-50 mg/kg/day i ,v. D,-Ds 1 h infusion fluorouracil 600 mg/m'/day i . v. D1, (5-FU) De doxorubicin 340 mg/m' i .v. D
cisplatin ~5 mg/m' i .v. D, the therapy comprising the repetition of this cycle every 21 or 28 days.
_:_ . , 4°/ Cancers of the testicle and of the rostate - the flavonoids can also be combined with protocols for cancer of the testicles:
BEP protocol:
__dose flavonoid --- route y da s 200-2000 mg/mz/day or 5-50 mg/kg/day i .v. D1_DS
1 h infusion bleomycin 30 mg/m2 in an infusion i.v. D1 etoposide 100 mg/m'/day in an infusion-i.v. D
cisplatin 20 mg/m'/day i .v, D,-DS
the therapy comprising 3 cycles, at a rate of 1 cycle every 21 days.
5°/ Cancers to the bladder - the flavonoids can be combined with the CISCA2 (also called PAC) protocol:
dose route days ~ flavonoid 200-2 0 g/m'-/day or 5-50 mg/kg/day i_v. D -DS
1 h infusion ~ cisplatin 50 mg/m~ i.v. D
~ cyclophosphamide 600 mg/m' i.v. Dy in an infusion ~ doxorubicin 75 mg/m= i,v. D
in an infusion . the cycle being repeated every 3 weeks.
- in the MVAC protocol (according to CN Sternberg et I., J. Urol. 1988; 139: 461-969):
dose rout e days flavonoid 200-2000 mg/mz/day or 5-50 mg/kg/day . v. Dis-Dia i 1 h infusion D~~-Dz methotrexate 30 mg/m2 bolus i . v. Di, Dls, Dzz vinblastine 3 mg/mz i.v. Dz or Dz. Dis.
doxorubicin 30 mg/m' bolus i.v, D., D
cisplatin 7Q-100 mg/m2 i.v. D1 or 1 h infusion ~ Dz this cycle being repeated every 4 to 5 weeks, for a minimum of 2 cycles. _ 6°/ Nasopharyngeal carcinomas/head and neck r.an~e,.~
- The flavonoids can be validly combined with the polychemotherapy protocols used in the treatment of these cancers:
6.1 Nasopharyngeal cancers:
- ABVD protocol:
dose rout _ e days flavonoid , 200-2000 mg/m'/day D~-D3 or 5-50 mg/kg/day i.v. D8-Dlo 1 h infusion or Dls-D1, doxorubicin 30 mg/m'/day i.v. D1 and De or Dls bleomycin 10 mg/m=/day i.v. D, and De or vinblastine 6 mg/m'/day i.v. Dls D1 and De or dacarbazine 200 mg/m'/day i.v. Dis D1 and D or Dls the therapy comprising 1 to 6 cycles repeated at a rate of 1 cycle every 4 weeks.
i 6.2 Head and neck cancers with metastases:
- in the Pt-FU protocol (ex: for cancers of the pharynx): according to the DVAL Study Group (New ~' 5 Engl. J. M. 1991; 324: 1685-1690):
.;_ dose ir:~ flavonoid route days 200-2000 mg/mz/day _or 5-50 mg/kg/day i . v. Dl-Ds 1 h infusion cisplatin -100 mg/m' i .v. Dy 1 hour infusion fluorouracil (5-FU) 1000 mg/mz/day i .v.
continuous infusionDi-Ds r the therapy com prising two cycles at a rate of.l cycle every 3 weeks.
'1°/ Soft tissue sarcomas - The flavonoids can be introduced into a protocol such as the CYVADIC protocol:
- according to H.M. Pinedo et al. (Cancer 1984;
53: 1825):
dose route days ~ flavonoid 200-2000 mg/mz/day D1-Ds or 5-50 mg/kg/day i . v. De-Dlo _._.
1 h infusion Das-Dl, cyclophosphamide (Cy) 500 mg/mz bolus i;v, Dz ~ vincristine (V) 1.5 mg/mz/day bolus i.v. D1, D8,Dls ~ doxorubicin (A) 50 mg/mz bolus i,v. D
z ~ dacarbazine (DIC) 250 mg/mz/day i.v. D1-Ds 15 minute infusion the therapy comprising the repetition of this cycle every 4 weeks, for 2 cycles at first.
-; , .r 8°/ Hormono-resistant rostate cancer, with metastases - in the VBL-estramustine protocol, according to G.R. Hudis et al. (J. Clin. Oncol. 1992; 10: 1754:
1761) _ dose route_ _days _ flavonoid 200-2000 mg/m'/day Di-D3, De-Dlo or 5-50 mg/kg/day i v . Dls-D17, D,z-D,4 .
1 h infusion _D_zs-D3i. D36-D3e vinblastine 4 mg/m'/da b l y i Dl, De, Dls. D22, o . D~9, D3s us v.
estramustin e 200 mg/m= tid oral each day for 6 (600 mg/m'/day) weeks a treatment 6 week cycle lasting s and being followed by free a eri d f p ks.
o o 2 wee 9°/ Germ cell cancers i) for tumours with a favorable prognosis:
- Pt-E protocol, according to G.J. Bosl et al.
(J. Clin. Oncol. 1988; 6: 1231-1238):
dose route days flavonoid 200-2000 mg/m'/day or 5-50 mg/kg/day i.v. D1-Ds 1 h infusion cisplatin 20 mg/m=/day i .v.
to 60 minute infusion . etoposide (E) 100 mg/m=/day i .v.
1 hour infusion Di_Ds I
the therapy comprising 4 cycles, at a rate of 1 20 cycle every 21 or 28 days.
ii) for tumours with metastases:
- PEB protocol, according to S.D. Williams et al.
(N. Eng. J. Med. 1987; 316: 1435-1440):
dose route days flavonoid 200-2000 mg/m'/day D1-Ds _or 5-50 mg/kg/dayi.v. D9-Dli 1 h infusion D16-Dla cisplatin (P) 20 mg/m2/day i.v. D1-DS
20 to 60 minute infusion etoposide (E) 100 mg/m'/day i.v. D~,D9,Dls 1 hour infusion bleomycin (B) 30U (or mg)/day i.v. D1-JS
bolus the therapy comprising 4 cycles, at a rate of 1 cycle every 21 days.
10°/ Cancers of the kidney - metastatic renal carcinoma: the flavonoids can be introduced into the protocol described by M. ,1.
Wilkinson et al. (Cancer 1993; 71: 3601-3604):
dose route days flavonoid 200-2000 mg/m'-/day D1-Ds _or 5-50 mg/kg/day i.v. D&-Dls 1 h infusion floxuridine 0.075 mg/kg/day i.v. Di-D14 continuous infusion the therapy comprising two cycles, 28 days apart.
- nephroblastoma: the flavonoids can be introduced ...__ into the DAVE protocol:
dose route days flavonoid 200-2000 mg/m2/day Di-D3 _or 5-50 mg/kg/dayi.v. De-Dzo 1 h infusion dactinomycin 0.6 mg/m'/day i.v.
doxorubicin 30 mg/m'/day i.v.
cyclophosphamide 200 mg/m-/day i.v. D;,Dd 1 hour infusion at a rate of one cycle every 3 to 4 weeks.
11/ Cancers of the di estive tract 11.1 Cancers of the oesophagus:
' 5 ==-i I i ' ' - the flavonoids can be introduced nto the FAP
protocol according to:
do route d !.' flavonoid ay s _ 200-2000 mg ay or 5-50 m k D
g/ g/day i ' D
' . v. De-Dlo 1 h infusion 5-fluorouracil (5-FU) 600 =
mg/m i.v.
_ Di. De doxorubicin 30 mg/m- i.v. D
i cisplatin 75 mg/m' D, 1.V.
i this cycle being repeated every 3 t 4 o weeks .
11.2 Stomach cancers - in gastric carcinomas which are advanced and/or with metastases:
- EAP protocol (according to P. Preusser et al., J. Clin. Oncol. 1989; 7: 1310):
dose route days flavonoid 200-2000 ' mg/m ___ /day or 5-50 mg/kg/day i . v. D:-D~, D6-D
;o 1 h infusion etoposide 120 mg/m=/day i . v. D3. D~, D~ or 1 hour infusion Dq-DE
doxorubicin 20 mg/m=/day bolus i .v. Di,D-cisplatin 40 mg/m-/day i .v.
1 hour infusion at a rate of 1 cycle every 28 days.
- F~tx protocol: according to J.A. Wils et al.
(J. Clin. Oncol. 1991; 89: 827):
-:
i the therapy comprising rst two cycles at 28 fi days apart. _ , ' i - in certain diseases, or it this protocol s variant (epirubicin replacing doxorubicin) may be used according o t the following scheme:
flavonoid I
I
fluorouracil (5-FU) doxorubicin (A) or epirubicin (A) methotrexate ' (to be infused before the 5-FU) --~
leucovorin 12°/ Colorectal cancers - the flavonoids can be introduced into the protocol for FU-Levamisole adjuvant treatment of colorectal cancer (according to C.G. Moertel et al., N. Eng. J. Med. 1990; 322: 352):
dose ro t u days flavonoid 200-2000 mg/m2/daye or 5-50 mg/kg/day-i.v. D1-D3 1 h infusion fluorouracil (5-FU) 1500 mg/m2 bolus i.v.
D, (F) 1 hour after the methotrexate doxorubicin (A) 30 mg/m~ bolus i .v. Des methotrexate (Mtx) 1500 mg/m2 i.v. D, 30 minute infusion i dose route days flavonoid ' 200-2000 mg/m /day D1-Ds or 5-50 mg/kg/day i.v.
1 h infusio n i i 5-fluorouracil 450 mg/m'/day bolusi .v. D1-Ds 5-fluorouracil 450 mg/mz bolus i_v , D,, levamisole 50 ma tid oral 3 d ays/week one week out ,I of two the 5-FU bolus treatment being repeated each week after the D1-DS induction phase, for 52 weeks; the treatment with a flavonoid being repeated in the same rhythm, on the day of the 5-FU bolus and then on the following 2 days.
- for the treatment of colorectal cancer, with i0 metastases, which is resistant to treatment with 5-fluorouracil (5-FU) - according to M.L. Rothenberg et al. (J. Clin.
i Oncol. 1996; 14: 1128-1135):
dose route days ~ flavonoid 200-2000 mg/m~/day Di-D;, D~-D=~, or 5-50 mg/kg/day i . v. D:s-D1,, D=~-D~9 1 h infusion ~ irinotecan 125 mg/my/day ~i.v.~ D,, DH,Dls.- D_;
the therapy comprising two cycles, 42 days apart.
13°/ Kaposi's sarcomas - the flavonoids can be combined with the two protocols which use anthracyclines formulated in liposomes:
i) protocol described by P.S. Gill et al., (J, Clin. Oncol. 1995; 13: 996-1003) and C.A. Presant et al. (Lancet 1993; 341: 1242-1243):
i _ 38 _ dose route d flavonoid 200-2000 mg/m-'/day DmD3 or 5-50 mg/kg/day i and .v.
D~s-Di, 1 h infusion liposomal daunorubicin 20 mg/m'-/day i .v. D D, 1. .s 1 hour Infusion the thera PY comprising two cycles repeated 28 days r.
apart, before evaluating the ff e ects.
a 5 ii) protocol of M. Harrison et al.
Clin.
Oncol. 1995; 13: 914-920):
dose route days flavonoid 200-2000 mg/m=/day I
D1-D:
or 5-50 mg/kg/day i .v.
1 h infusion liposomal doxorubicin 20 mg/m=
i.v. Di 30 minute infusion the cure comprising two cycles r epeated 2 8 days apart, before evaluati ng the effects.
14°/ Metastatic melanomas - the flavonoids can also be incorporated into combined protocols fcr treatment of metastatic malignant melanomas:
- DTIC/TAM protocol: according to G. Cocconi et al . (N. Eng. ~ . Med. 1992; 327 : 516) , the thera PY
comprising the repetition of 4 cycles, at a rate of 1 cycle every 21 days, according to the scheme below:
i ---dose i I flavonoid route days 200-2000 m -----g/m-/da y I or 5-50 mg/kg/day i . v. D;-Ds bazine 1 h infusion d (DTIC 250 mg/m=/day ) infusion [15 to 30 min, if central catheter]
i.v. D,-D
or [30 min. if peripheral i nfusion in 250 ml]
tamoxifen (TAM) 20 mg/m'/day oral ... D;_D
.
~
i com risi ::;
the therapy p n g cycle every cycles at a rate 21 days. ~ of 1 15/ Neuroendocri ne carcinoma I
i - flavonoids can be combined with the described by p-otocol C.G. Moertl et al. (Cance 227) ; r 1991; 68:
- Pt-E protocol:
flavonoid _ dose rout e d s 20C-2000 mg/m=/da y D,-or 5-50 mg/kg/day 1.V.
etoposide i h infusion 130 mg/m-/day i . v. D_-D3 cisplatin 1 hour infusion i 45 mg/m=/day i.v. D_. D3 1 hour infusion the therapy comprisin g two cycles repeated every 28 days.
16°/ Cancer of the n -------. r an crea s - advanced stage pancreatic adenocarci noma: the flavonoids can be combined with the gemcitab' me treatment, according to the protocol of M. Moor a i I
j et al. (Proc. Am. Soc. Clin. Oncol. 1995; 14:
473) i dose route days ~ flavonoid 200-2000 mg/m2/day D1-D,, D~-Dio, Dls.
or 5-50 mg/kg/day i.v.
i 1 h infusion ~ gemcitabine 1000 mg/m= ~. v _ D1, D~, D, 5, D_=, D=~, i 0. 5 hour infusion Dss. D4z, then D;,, then once/week for i 3 weeks, and then l 1 week of rest and evaluation B. Oncohaematolo y 1°/ Adult acute leukeamias 1.1 Acute lymphoblastic leukaemia:
i0 1.1.1 Linker protocol The flavonoids can be added to Linker protocols - induction chemotherapy and consolidation chemotherapy -.(see C.A. Linker et al. Blood 1987; 69: 1242-1248 and C.A. Linker et al.
Blood 1991; 78: 2814-2822) according to the following schemes:
i) induction chemotherapy:
dose route days fl avonoid 200-2000 mg/m=/day D1-D;, or 5-50 mg/kg/day i.v. D8-Di~,D.J-Diy 1 h infusio n daunorubicin 50 mg/m' bolus every 24 hours (30 mg/m-' i.v. Di,D_,D3 in patients more than years old) vincristine 2 mg bolus i . D;, D~, prednison e v. D<<., D~_, ~ 60 mg/mv/day oral D:-D
L-asparaginase 6000 U/m- i.m. D,_ ii) consolidation chemotherapy (treatment A):
i dose route days flavonoid 200-2000 mg/m'/day D,-D5, D3-D;
I
; j _or 5-50 mg/kg/day i.v.
1 h infusion daunorubicin 50 mg/m' bolus i.v. D1,D
every 24 hours vincristine 2 mg bolus i,v, prednisone 60 mg/m~/day oral D1-D-:a divided into 3 doses L-asparaginase 12000 U/mv i .m. D~, Ds, D,, Dq and D1~
'~i consolidation consecutive therapy A
comprises cycles as the one described -above=.cycles such 1, 3, and 7.
iii) consolidation chemotherapy (treatments B
and C ) The therapies described below correspond to consolidation cycles 2, 4, 6 and 8 (therapy B) and 9 (therapy C), described by C.A. Linker et al.:
therapy B: dose route days flavonoid 200-2000 mg/m=/day D1-D~, D~-D1_ _or 5-50 mg/kg/day i.v.
1 h infusion Ara-C 300 mg/m- i .v. D,, D4, DP, Dl 2 hour infusion teniposide 165 mg/mv i .v. D;, D~, Dq, Dl 2 hour infusion (4 cycles) I, therapy C: dose route days flavonoid 200-2000 m g/m'/day Di-Ds or 5-50 mg/kg/day i.v.
1 h infusion methotreXate 690 mg/m' i.v. D,-D
42 hour continuous -infusion leucovorin 15 mg/m= oral D~_DS
every 6 hours 1.1.2 Hoelzer protocol The flavonoids the cytotoxic may be added protocol (D.
to 4: 38-4~~
agents of this 71: 123-131) polychemotherapy Hoelzer et al., Blood 1989; 6 Hoelzer et al., Blcod 1988;
according to the following scheme:
i) induction chemotherapy/phase 1:
,' dose route days flavonoid 200-2000 mg/mv/day D_,-D, Db-D1=, or 5-50 mg/kg/day i.v. D=
daunorubicin 1 h infusion 25 mg/m- i . v. D,, D", D1~, D
vincristine 1 . 5 mg/m- i . v. D, , D", D=5, D
(maximum 2 mg) -' prednisone 60 mg/m= oral Di-Die L-asparaginase 5000 U/m- i.m. Di-Dly (maximum 2 mg) ii) induction emotherapy/Phase 2:
ch Phase 2 of the rried out as induction may be ca follows:
dose y flavonoid 200-2000 mg/ route p'9-pdap 6-pao, j m /day i , Da3-Da, _or 5-50 mg/kg/day v.
1 h infusion cyclophosphamide i , D,9, D9;, 650 mg/m'- v. ps~
(maximum 1000 i mg) i . DsmD39, p;~-D91 cytarabine 75 v.
mg/m'/day 1 hour infusion oral Dm. Dse. Das.
mercaptopurine Ds, 60 mg/m- i.v.
methotrexate ' 10 mg/
(maximum 15 mg) iii) chemotherapy/Phase l:
reinduction I
dose route days flavonoid 200-2000 mg/m=/day Di-D;, DR-Di~, D i.v. ,5-D14~ D-__p~s or 5-50 mg/kg/day 1 h infusion --dcxorubicin 25 mg/m=/day i . D1, D~, D.:;, v. D
dexamethasone 10 mg/mv/day oral D
I
vincristine 1.5 mg/mv/day oral i ~ D, , D=8.
(maximum 2 mg) D._5 and _ D_, _ iv) reinduction chemotherapy/Phase 2:
dose route days ~ flavonoid 200-2000 mg/m~/day D;i-D;S, D;~-D4~
or 5=50 mg/kg/day i.v.
1 h infusion ~ cyclophosphamide 650 mg/m= i,v_ (maximum: 1000 mg) ~ cytarabine 75 mg/mv/day i.v.
~ thioguanine 60 mg/mv l oral p_ 1.2 Acute myeloid leukaemias:
1.2.1. Treatment of adults of any age The flavonoids can be added, according to the scheme below, to the treatment which incorporates the standard dose of cytarabine previously described by R.O. Dilleman et al. (Blood, 1991; 78: 2520-2526), Z.A. Arlin et al. (Leukemia 1990; 4: 177-183) and P.H. Wiernik et al. (Blood 1992; 79: 313-319):
dose route days flavonoid 200-2000 mg/m-/day _or 5-50 mg/kg/day i.v.
1 h infusion cytarabine 100-200 mg/m-/day i.v. D,-D, in a continuous infusion daunorubicin 45 mg/m'/day as a bolus i.v. D1-D~,or _ (30 mg/mo/day if age >_ D~-Dlo 60)-or mitoxantrone 12 mg/m- i.v. D1-D3 in a daily bolus or idarubicin 13 mg/m- i.v. D1-D3 in a daily bolus 1.2.2. Treatment of adults under the age of 60 i) induction chemotherapy:
This induction cycle incorporates the administration of cytarabine at high dose according to the following scheme:
dose route days flavonoid 200-2000 mg/mr/day DmDio _or 5-50 mg/kg/day i.v.
1 h infusion Ara-C (cytarabine) 2000 mg/m-/day i.v. Di-D6 in a 2 hour infusion, every 12 hours Daunorubicin 60 mg/m-/day i.v. DQ-D6 in a 24 hour continuous infusion O-r Cytarabine 3000 mg/m-/day i.v. D_-DE
in a 1 hour infusion, every 12 hours Daunorubicin 45 mg/m' bolus i.v. D7-D3 every 24 hours (in order to reduce the risk of C.N.S. toxicity, in the event of renal failure, adjust the cytarabine dosage to the creatinin clearance) according to L.E. Damon et al. (Leukemia 1994; 8:
535-541), G.L. Phillips et al. (Blood 1991; 77:
1429-1435) and G. Smith et al. (J. Clin. Oncol.
1997; 15: 833-839).
ii) consolidation chemotherapy:.
The cycle, described hereinafter, will be repeated 8 times, at a rate of 1 cycle every 4 to 6 weeks (according to R. J. Mayer et al . , N.
Engl J. Med. 1994; 331: 896-90-3):
dose route days flavonoid 200-2000 mg/m~/day i.v. _ D-_-D_5 _or 5-50 mg/kg/day 1 h infusion cytarabine 3000 mg/m' i.v. D1, D3, D;
in a 3 hour infusion, every 12 hours (4 cycles) then 100 mg/mv/day cytarabine every i2 hours s.c. D._-D=.
daunorubicin 45 mg/m- bolus y.v. D
(4 cycles) iii) consolidation chemotherapy (with high dose of cytarabine):
The cycle, described hereinafter, must be repeated twice and is adapted according to G.L. Phillips et al. (Blood 1991; 77: 1429-1435); S.N. Wolff et al. (J. Clin. Oncol. 1989;
7: 1260-1267); R.J. Mayer et al. (N. Engl J.
Med. 1994; 331: 896-903):
dose route days flavonoid 200-2000 mg/m'/day i.v.
or 5-50 mg/kg/day 1 h infusion cytarabine 3000 mg/m~ i . D.,-DE
v.
[lacuna]
1 hour every 12 hours daunorubicin 30-45 mg/m'/day bolus i.v. D;-D4 ~
once/day 1.2.3. Treatment of adults aged 60 or older The flavonoids may be added to the consolidation chemotherapy protocols hereinafter:
i) according to R.O. Dilman et al. (Blood 1991; 78;
2520-2526), Z.A. Arlin et al. (~eukemia 1990; 4:
177-183), P.H. Wiernik et al. (Blood 1992; 79:
313-319):
dose route days flavonoid 200-2000 mg/mv/day i.v.
or 5-50 mg/kg/day 1 h infusion cytarabine (Ara-C) 100-200 mg/mv i.v.
[lacuna]
24 hour continuous infusion daunorubicin 30-45 mg/m'/day bolusi.v.
o r _.. _ .-mitoxantrone 12 mg/m'/day bolus i.v. D1.D~
or idarubicin 23 mg/m-/day bolus i.v. D-, D, ii) according to R.J. Mayer et al. (N. Engl. J. Med.
194; 331: 896-903):
dose route days flavonoid 200-2000 mg/m~/day i.v.
or 5-50 mg/kg/day 1 h infusion cytarabine 100 mg/m= i . D1-D;
v.
24 hour continuous infusion (4 cycles) then . cytarabine 100 mg/m- s . D1, D_.
c .
every 12 hours daunorubicin 45 mg/m'/day bolus i.v. D.
(4 cycles) iii) according to C.A. Linker et al. -(Blood 1993; 81:
311-318), N. Chao et al. (Blood 1993; 81: 319-323) and A.M. Yeager et al. (N. Eng. J. Med. 1986; 315:
145-147):
This protocol comprises an autologous bone marrow transplant (carried out on day Do):
dose route days flavonoid 200-2000 mg/m-/day i.v. D_,-D__ or 5-5C mg/kg/day 1 h infusion busulphan 1 mg/kg qid oral D_~ to D_a (16 doses in total) etoposide ~ 60 mg/kg/day i.v. D_3 10 hour infusion or ' dose route days flavonoid 200-2000 mg/mv/day i.v. D_~-D_1 or 5-50 mg/kg/day 1 h infusion busulphan 1 mg/kg aid oral D_5 to D_6 cyclophosphamide 50 mg/kg/day i . D_; to v. D_, ~
1 hour infusion iv) in the event of HLA-compatible allogenic bone marrow transplant according to:
P.J. Tutscha et al. Blood 1987; 70: 1382--1388, F.R. Applebaum et al. Ann. Int. Med. 1984; 101:
581-588:
dose route days flavonoid 200-2000 mg/m-/day i.v. p_,-p or 5-50 mg/kg/day 1 h infusion busulphan 1 mg/kg qid oral D_, to D_s (16 doses in total) cyclophosphamide 60 mg/kg/day i.v. D_3 to D_ 1 hour infusion 2°/ Adult chronic leukaemias 2.1 Chronic myeloid leukaemia In the myeloblastic phase, the flavonoids can be added to the HU-Mith treatment described by C.A. Koller et al. (N. Engl. J. med. 1986; 315:
1433-1438):
dose route days D:-D
flavonoid 200-2000 mg/mv/dayi.v. p~-D1' _or 5-50 mg/kg/day p,;-D-_ 1 h infusion hydroxyurea 500 mg/day oral every day mithramycin 25 ~g/kg/day i.v. daily for 3 2-4 hour infusion weeks, then.
times/week 2.2 Chronic lymphocytic leukaemia 2.2.1 FCG-CLL protocol The flavonoids can be added to the "pulsed chlorambucil" combinations as described by E. Kimby et al. (Leuk. Lymphoma 1991; 5 (Suppl.) 93-96) and by FCGCLL (Blood 1990; 75:
1422-1425):
dose route days flavonoid 200-2000 mg/m'/day D1-Ds, D-~_D1'~
_or 5-50 mg/kg/dayi.v. Dis-Dz 1 h infusion chlorambucil 0.1 mg/kg/day oral once/day _or chlorambucil 0.4 mg/kg/day oral Di every 14 days and prednisone 75 mg/day oral D1-D3 2.2.2 Fludarabine-CdA protocol according to H.G. Chun et al.-(J. Clin. Oncol.
1991; 9: 175-188), M.J. Keating et al-. (Blood 1989; 74: 19-25 / J. Clin. Oncol. 1991; 9: 44 49) and A. Saven et a1. (J. Clin. Oncol. 1995;
13; 570-574):
dose route days fl avonoid 200-2000 mg/m-/day D~-Da _or 5-50 mg/kg/day i.v. (once/month 1 h infusion for 6 to cycles) fludarabine 25-30 mg/m'/day i.v. D
30 minute infusion [every 4 weeks for 6 to 12 cycles]
or cladribine 0.09 mg/kg/day i.v. D_-D-;
in a continuous infusion [1 cycle every 28 to days for 1 to 9 cycles (median: 4 cycles)]
3°/ Lymphoproliferative diseases 3.1 Hodgkin's disease The flavonoids can be incorporated into the polychemotherapy protocols conventionally used for the treatment of Hodgkin's lymphoma:
3.1.1 AVDB protocol according to G. Bonnadonna et al. (Cancer Clin.
Trials 1979; 2: 217-226) and G.P. Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484):
dose route days flavonoid 200-2000 mg/m=/day Dl-D~, _or 5-50 mg/kg/dayi.v. Dls-D1~
1 h infusion doxorubicin (A) 25 mg/mr bolus i.v. Dl,Dis bleomycin (B) 10 U/m~ bolus i.v. D1,D._s vinblastine (V) 6 mg/m' bolus i.v. D,, Dls dacarbazine (D) 375 mg/m- bolus ~ i.v.Dl,Dls the therapy comprising 6 to 8 cycles, at a rate of 1 cycle every 28 days.
3.1.2 MOPP/ABVD protocol according to G. Bonnadonna et al. (Ann. Intern.
Med. 1986; 104: 739-746) and G.P. Canellos et al. (N. ~r.gl. J. Med. 1993; 327: 1478-1484):
The MOPP protocol should be alternated with the ABVD protocol (cf. 3.1.1) every 28 days, and the therapy comprises 6 cycles:
MOPP protocol: dose route days flavcnoid 200-2000 mg/mr/day _or 5-50 mg/kg/day i.v. and D;a-D1,-- -1 h infusion mechlorethamine (M) 6 mg/mv bolus ~ i.v. D1, D8 vincristine (0) 1.4 mg/mv bolus i.v. D,, Ds (no maximum) procarbazine (P) 100 mg/m~/day oral D1-D1~
prednisone (P) 40 ma/m-/day oral 3.1.3 Stanford V protocol according to N.L. Bartlett et al. (J. Clin.
Oncol. 1995; 13; 1080-1088):
dose route days flavonoid 200-2000 mg/m'/day D~-Ds or 5-50 mg/kg/day i.v. D9-J1~
_ D,5_D~a 1 h infusion D,~-D=s doxorubicin 25 mg/m- i.v. Dl,D~s vinblastine 6 mg/m' bolus i.v. D.,, D15 (4 mg/m' during cycle 3 if age >_ 50) mechlorethamine 6 mg/m' bolus i.v. D1 (M) vincristine 1 .4 mg/m' bolus i.v. Di, D
(maximum dose: 2 mg) [1 mg/m' during cycle 3 if age >_ 50) bleomycin 5 U/mv i .v. Do, D__ etoposide 60 mg/m' oral D15, Dib prednisone 40 mg/m-/day oral once/week (weeks 1-9) the therapy comprising 3 cycles, at a rate oy 1 cycle every 28 days.
S 3.1.4 EVA protocol according to G.P. Canellos et al. (Proc. Am.
Soc. Clin. Oncol. 1991; 10: 273):
dose route days flavonoid 200-2000 mg/m-/day _or 5-50 mg/kg/dayi.v.
1 h infusion etoposide (E) 100 mg/m' oral D1, D=, . 2 hour infusion D3 vinblastine (V) 6 mg/m' bolus i.v. D1 doxorubicin (A) ~ 50 mg/mv bolus i.v. D1 the therapy comprising 6 cycles, at a rate of 1 cycle every 28 days.
3.1.5 B-CAVe protocol according to W.G. Harker et al. (Ann. Intern.
Med. 1984; 101: 440-446):
dose _route days flavonoid 200-2000 mg/mr/day D1-D
_or 5-50 mg/kg/dayi.v.
1 h infusion (B) 5 U/m' bolus i.v. D, bleomycin _ lomustine (CCNU) 100 mg/m' oral D1 doxorubicin (A) 60 mg/m- bolus i.v. D
vinblastine (Ve) ~ 5 mg/m- bolus ~ i.v. ~ D, the therapy comprising 8 cycles, at a rate of 1 cycle every 28 days.
3.2 Non-Hodgkin's lymphomas.
3.2.1. non-Hodgkin's lymphomas with -a low degree of malignancy i) - CVP protocol lp - according to C.M. Bagley et al. (Ann. Intern.
Med. 1972; 76: 227-234) and C.S. Portlock et al. (Blood 1976; 47: 747-756) dose route days flavonoid 200-2000 mg/m-/day Di-D
I _or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide (C) 300-400 mg/m-/day i.v. D,,D;
vincristine (0) 1.4 mg/m- bolus ~ i.v.D, (max: 2 mg) prednisone (P) 100 mg/mr/day oral Di-D;
This cycle is repeated every 21 days until maximum response ii) - I-COPA protocol - according to RV Smalley et al/ (N. Eng. J. Med.
1992; 327: 1336-1341) dose route days flavonoid 200-2000 mg/m'/day Di-Ds or 5-50 mg/kg/day i.v.
_ 1 h infusion clophosphamide (C) 600 mg/m'/day i.v.
c y vincristine (0) 1.2 mg/m- bolus i.v.
(max: 2 mg) prednisone (P) 100 mg/m'/day i.v. D;-D5 doxorubicin (A) 50 mg/m- bolus i.v. D
interferon-alpha (I) 6 MU/m- i.m. D~=-D_6 The therapy comprises cles, a rate 8 to 10 cy at of one cycle every days.
iii) - fludarabine-CdA protocol ~-- according to P. Solol-Celigny et al. (Blood 1994; 84 (Supp. 1): 383a), H. Hoeschster et al.; (Blood 1994; 84 (Suppl. 1): 564a and A.C. Kay (J. Clin. Oncol.
1992; 10: 371-377) dose route days . flavonoid 200-2000 mg/mr/day Dm D, _or 5-50 mg/kg/day i.v.
i h infusion fludarabine ~ 25 mg/~'~-/day ~ i.v. ~ D,_-D, 0.5 hour infusion or ~ fludarabine 20 mg/mr/day i.v D1-D
and cyclophosphamide 600-1000 mg/m-/day i.v D1 or cladribine 0 . 1 mg/m-/day i . v D~-D, ' 24 hour infusion For fiudaribine, each cycle is repeated every 28 days; for cladribine, each cycle is repeated every 35 days.
3.2.2. non-Hodgkin's lymphomas with an intermediate degree of malignancy 1992, 3.
dose route days ~ flavonoid 200-2 0 g/m'-/day or 5-50 mg/kg/day i_v. D -DS
1 h infusion ~ cisplatin 50 mg/m~ i.v. D
~ cyclophosphamide 600 mg/m' i.v. Dy in an infusion ~ doxorubicin 75 mg/m= i,v. D
in an infusion . the cycle being repeated every 3 weeks.
- in the MVAC protocol (according to CN Sternberg et I., J. Urol. 1988; 139: 461-969):
dose rout e days flavonoid 200-2000 mg/mz/day or 5-50 mg/kg/day . v. Dis-Dia i 1 h infusion D~~-Dz methotrexate 30 mg/m2 bolus i . v. Di, Dls, Dzz vinblastine 3 mg/mz i.v. Dz or Dz. Dis.
doxorubicin 30 mg/m' bolus i.v, D., D
cisplatin 7Q-100 mg/m2 i.v. D1 or 1 h infusion ~ Dz this cycle being repeated every 4 to 5 weeks, for a minimum of 2 cycles. _ 6°/ Nasopharyngeal carcinomas/head and neck r.an~e,.~
- The flavonoids can be validly combined with the polychemotherapy protocols used in the treatment of these cancers:
6.1 Nasopharyngeal cancers:
- ABVD protocol:
dose rout _ e days flavonoid , 200-2000 mg/m'/day D~-D3 or 5-50 mg/kg/day i.v. D8-Dlo 1 h infusion or Dls-D1, doxorubicin 30 mg/m'/day i.v. D1 and De or Dls bleomycin 10 mg/m=/day i.v. D, and De or vinblastine 6 mg/m'/day i.v. Dls D1 and De or dacarbazine 200 mg/m'/day i.v. Dis D1 and D or Dls the therapy comprising 1 to 6 cycles repeated at a rate of 1 cycle every 4 weeks.
i 6.2 Head and neck cancers with metastases:
- in the Pt-FU protocol (ex: for cancers of the pharynx): according to the DVAL Study Group (New ~' 5 Engl. J. M. 1991; 324: 1685-1690):
.;_ dose ir:~ flavonoid route days 200-2000 mg/mz/day _or 5-50 mg/kg/day i . v. Dl-Ds 1 h infusion cisplatin -100 mg/m' i .v. Dy 1 hour infusion fluorouracil (5-FU) 1000 mg/mz/day i .v.
continuous infusionDi-Ds r the therapy com prising two cycles at a rate of.l cycle every 3 weeks.
'1°/ Soft tissue sarcomas - The flavonoids can be introduced into a protocol such as the CYVADIC protocol:
- according to H.M. Pinedo et al. (Cancer 1984;
53: 1825):
dose route days ~ flavonoid 200-2000 mg/mz/day D1-Ds or 5-50 mg/kg/day i . v. De-Dlo _._.
1 h infusion Das-Dl, cyclophosphamide (Cy) 500 mg/mz bolus i;v, Dz ~ vincristine (V) 1.5 mg/mz/day bolus i.v. D1, D8,Dls ~ doxorubicin (A) 50 mg/mz bolus i,v. D
z ~ dacarbazine (DIC) 250 mg/mz/day i.v. D1-Ds 15 minute infusion the therapy comprising the repetition of this cycle every 4 weeks, for 2 cycles at first.
-; , .r 8°/ Hormono-resistant rostate cancer, with metastases - in the VBL-estramustine protocol, according to G.R. Hudis et al. (J. Clin. Oncol. 1992; 10: 1754:
1761) _ dose route_ _days _ flavonoid 200-2000 mg/m'/day Di-D3, De-Dlo or 5-50 mg/kg/day i v . Dls-D17, D,z-D,4 .
1 h infusion _D_zs-D3i. D36-D3e vinblastine 4 mg/m'/da b l y i Dl, De, Dls. D22, o . D~9, D3s us v.
estramustin e 200 mg/m= tid oral each day for 6 (600 mg/m'/day) weeks a treatment 6 week cycle lasting s and being followed by free a eri d f p ks.
o o 2 wee 9°/ Germ cell cancers i) for tumours with a favorable prognosis:
- Pt-E protocol, according to G.J. Bosl et al.
(J. Clin. Oncol. 1988; 6: 1231-1238):
dose route days flavonoid 200-2000 mg/m'/day or 5-50 mg/kg/day i.v. D1-Ds 1 h infusion cisplatin 20 mg/m=/day i .v.
to 60 minute infusion . etoposide (E) 100 mg/m=/day i .v.
1 hour infusion Di_Ds I
the therapy comprising 4 cycles, at a rate of 1 20 cycle every 21 or 28 days.
ii) for tumours with metastases:
- PEB protocol, according to S.D. Williams et al.
(N. Eng. J. Med. 1987; 316: 1435-1440):
dose route days flavonoid 200-2000 mg/m'/day D1-Ds _or 5-50 mg/kg/dayi.v. D9-Dli 1 h infusion D16-Dla cisplatin (P) 20 mg/m2/day i.v. D1-DS
20 to 60 minute infusion etoposide (E) 100 mg/m'/day i.v. D~,D9,Dls 1 hour infusion bleomycin (B) 30U (or mg)/day i.v. D1-JS
bolus the therapy comprising 4 cycles, at a rate of 1 cycle every 21 days.
10°/ Cancers of the kidney - metastatic renal carcinoma: the flavonoids can be introduced into the protocol described by M. ,1.
Wilkinson et al. (Cancer 1993; 71: 3601-3604):
dose route days flavonoid 200-2000 mg/m'-/day D1-Ds _or 5-50 mg/kg/day i.v. D&-Dls 1 h infusion floxuridine 0.075 mg/kg/day i.v. Di-D14 continuous infusion the therapy comprising two cycles, 28 days apart.
- nephroblastoma: the flavonoids can be introduced ...__ into the DAVE protocol:
dose route days flavonoid 200-2000 mg/m2/day Di-D3 _or 5-50 mg/kg/dayi.v. De-Dzo 1 h infusion dactinomycin 0.6 mg/m'/day i.v.
doxorubicin 30 mg/m'/day i.v.
cyclophosphamide 200 mg/m-/day i.v. D;,Dd 1 hour infusion at a rate of one cycle every 3 to 4 weeks.
11/ Cancers of the di estive tract 11.1 Cancers of the oesophagus:
' 5 ==-i I i ' ' - the flavonoids can be introduced nto the FAP
protocol according to:
do route d !.' flavonoid ay s _ 200-2000 mg ay or 5-50 m k D
g/ g/day i ' D
' . v. De-Dlo 1 h infusion 5-fluorouracil (5-FU) 600 =
mg/m i.v.
_ Di. De doxorubicin 30 mg/m- i.v. D
i cisplatin 75 mg/m' D, 1.V.
i this cycle being repeated every 3 t 4 o weeks .
11.2 Stomach cancers - in gastric carcinomas which are advanced and/or with metastases:
- EAP protocol (according to P. Preusser et al., J. Clin. Oncol. 1989; 7: 1310):
dose route days flavonoid 200-2000 ' mg/m ___ /day or 5-50 mg/kg/day i . v. D:-D~, D6-D
;o 1 h infusion etoposide 120 mg/m=/day i . v. D3. D~, D~ or 1 hour infusion Dq-DE
doxorubicin 20 mg/m=/day bolus i .v. Di,D-cisplatin 40 mg/m-/day i .v.
1 hour infusion at a rate of 1 cycle every 28 days.
- F~tx protocol: according to J.A. Wils et al.
(J. Clin. Oncol. 1991; 89: 827):
-:
i the therapy comprising rst two cycles at 28 fi days apart. _ , ' i - in certain diseases, or it this protocol s variant (epirubicin replacing doxorubicin) may be used according o t the following scheme:
flavonoid I
I
fluorouracil (5-FU) doxorubicin (A) or epirubicin (A) methotrexate ' (to be infused before the 5-FU) --~
leucovorin 12°/ Colorectal cancers - the flavonoids can be introduced into the protocol for FU-Levamisole adjuvant treatment of colorectal cancer (according to C.G. Moertel et al., N. Eng. J. Med. 1990; 322: 352):
dose ro t u days flavonoid 200-2000 mg/m2/daye or 5-50 mg/kg/day-i.v. D1-D3 1 h infusion fluorouracil (5-FU) 1500 mg/m2 bolus i.v.
D, (F) 1 hour after the methotrexate doxorubicin (A) 30 mg/m~ bolus i .v. Des methotrexate (Mtx) 1500 mg/m2 i.v. D, 30 minute infusion i dose route days flavonoid ' 200-2000 mg/m /day D1-Ds or 5-50 mg/kg/day i.v.
1 h infusio n i i 5-fluorouracil 450 mg/m'/day bolusi .v. D1-Ds 5-fluorouracil 450 mg/mz bolus i_v , D,, levamisole 50 ma tid oral 3 d ays/week one week out ,I of two the 5-FU bolus treatment being repeated each week after the D1-DS induction phase, for 52 weeks; the treatment with a flavonoid being repeated in the same rhythm, on the day of the 5-FU bolus and then on the following 2 days.
- for the treatment of colorectal cancer, with i0 metastases, which is resistant to treatment with 5-fluorouracil (5-FU) - according to M.L. Rothenberg et al. (J. Clin.
i Oncol. 1996; 14: 1128-1135):
dose route days ~ flavonoid 200-2000 mg/m~/day Di-D;, D~-D=~, or 5-50 mg/kg/day i . v. D:s-D1,, D=~-D~9 1 h infusion ~ irinotecan 125 mg/my/day ~i.v.~ D,, DH,Dls.- D_;
the therapy comprising two cycles, 42 days apart.
13°/ Kaposi's sarcomas - the flavonoids can be combined with the two protocols which use anthracyclines formulated in liposomes:
i) protocol described by P.S. Gill et al., (J, Clin. Oncol. 1995; 13: 996-1003) and C.A. Presant et al. (Lancet 1993; 341: 1242-1243):
i _ 38 _ dose route d flavonoid 200-2000 mg/m-'/day DmD3 or 5-50 mg/kg/day i and .v.
D~s-Di, 1 h infusion liposomal daunorubicin 20 mg/m'-/day i .v. D D, 1. .s 1 hour Infusion the thera PY comprising two cycles repeated 28 days r.
apart, before evaluating the ff e ects.
a 5 ii) protocol of M. Harrison et al.
Clin.
Oncol. 1995; 13: 914-920):
dose route days flavonoid 200-2000 mg/m=/day I
D1-D:
or 5-50 mg/kg/day i .v.
1 h infusion liposomal doxorubicin 20 mg/m=
i.v. Di 30 minute infusion the cure comprising two cycles r epeated 2 8 days apart, before evaluati ng the effects.
14°/ Metastatic melanomas - the flavonoids can also be incorporated into combined protocols fcr treatment of metastatic malignant melanomas:
- DTIC/TAM protocol: according to G. Cocconi et al . (N. Eng. ~ . Med. 1992; 327 : 516) , the thera PY
comprising the repetition of 4 cycles, at a rate of 1 cycle every 21 days, according to the scheme below:
i ---dose i I flavonoid route days 200-2000 m -----g/m-/da y I or 5-50 mg/kg/day i . v. D;-Ds bazine 1 h infusion d (DTIC 250 mg/m=/day ) infusion [15 to 30 min, if central catheter]
i.v. D,-D
or [30 min. if peripheral i nfusion in 250 ml]
tamoxifen (TAM) 20 mg/m'/day oral ... D;_D
.
~
i com risi ::;
the therapy p n g cycle every cycles at a rate 21 days. ~ of 1 15/ Neuroendocri ne carcinoma I
i - flavonoids can be combined with the described by p-otocol C.G. Moertl et al. (Cance 227) ; r 1991; 68:
- Pt-E protocol:
flavonoid _ dose rout e d s 20C-2000 mg/m=/da y D,-or 5-50 mg/kg/day 1.V.
etoposide i h infusion 130 mg/m-/day i . v. D_-D3 cisplatin 1 hour infusion i 45 mg/m=/day i.v. D_. D3 1 hour infusion the therapy comprisin g two cycles repeated every 28 days.
16°/ Cancer of the n -------. r an crea s - advanced stage pancreatic adenocarci noma: the flavonoids can be combined with the gemcitab' me treatment, according to the protocol of M. Moor a i I
j et al. (Proc. Am. Soc. Clin. Oncol. 1995; 14:
473) i dose route days ~ flavonoid 200-2000 mg/m2/day D1-D,, D~-Dio, Dls.
or 5-50 mg/kg/day i.v.
i 1 h infusion ~ gemcitabine 1000 mg/m= ~. v _ D1, D~, D, 5, D_=, D=~, i 0. 5 hour infusion Dss. D4z, then D;,, then once/week for i 3 weeks, and then l 1 week of rest and evaluation B. Oncohaematolo y 1°/ Adult acute leukeamias 1.1 Acute lymphoblastic leukaemia:
i0 1.1.1 Linker protocol The flavonoids can be added to Linker protocols - induction chemotherapy and consolidation chemotherapy -.(see C.A. Linker et al. Blood 1987; 69: 1242-1248 and C.A. Linker et al.
Blood 1991; 78: 2814-2822) according to the following schemes:
i) induction chemotherapy:
dose route days fl avonoid 200-2000 mg/m=/day D1-D;, or 5-50 mg/kg/day i.v. D8-Di~,D.J-Diy 1 h infusio n daunorubicin 50 mg/m' bolus every 24 hours (30 mg/m-' i.v. Di,D_,D3 in patients more than years old) vincristine 2 mg bolus i . D;, D~, prednison e v. D<<., D~_, ~ 60 mg/mv/day oral D:-D
L-asparaginase 6000 U/m- i.m. D,_ ii) consolidation chemotherapy (treatment A):
i dose route days flavonoid 200-2000 mg/m'/day D,-D5, D3-D;
I
; j _or 5-50 mg/kg/day i.v.
1 h infusion daunorubicin 50 mg/m' bolus i.v. D1,D
every 24 hours vincristine 2 mg bolus i,v, prednisone 60 mg/m~/day oral D1-D-:a divided into 3 doses L-asparaginase 12000 U/mv i .m. D~, Ds, D,, Dq and D1~
'~i consolidation consecutive therapy A
comprises cycles as the one described -above=.cycles such 1, 3, and 7.
iii) consolidation chemotherapy (treatments B
and C ) The therapies described below correspond to consolidation cycles 2, 4, 6 and 8 (therapy B) and 9 (therapy C), described by C.A. Linker et al.:
therapy B: dose route days flavonoid 200-2000 mg/m=/day D1-D~, D~-D1_ _or 5-50 mg/kg/day i.v.
1 h infusion Ara-C 300 mg/m- i .v. D,, D4, DP, Dl 2 hour infusion teniposide 165 mg/mv i .v. D;, D~, Dq, Dl 2 hour infusion (4 cycles) I, therapy C: dose route days flavonoid 200-2000 m g/m'/day Di-Ds or 5-50 mg/kg/day i.v.
1 h infusion methotreXate 690 mg/m' i.v. D,-D
42 hour continuous -infusion leucovorin 15 mg/m= oral D~_DS
every 6 hours 1.1.2 Hoelzer protocol The flavonoids the cytotoxic may be added protocol (D.
to 4: 38-4~~
agents of this 71: 123-131) polychemotherapy Hoelzer et al., Blood 1989; 6 Hoelzer et al., Blcod 1988;
according to the following scheme:
i) induction chemotherapy/phase 1:
,' dose route days flavonoid 200-2000 mg/mv/day D_,-D, Db-D1=, or 5-50 mg/kg/day i.v. D=
daunorubicin 1 h infusion 25 mg/m- i . v. D,, D", D1~, D
vincristine 1 . 5 mg/m- i . v. D, , D", D=5, D
(maximum 2 mg) -' prednisone 60 mg/m= oral Di-Die L-asparaginase 5000 U/m- i.m. Di-Dly (maximum 2 mg) ii) induction emotherapy/Phase 2:
ch Phase 2 of the rried out as induction may be ca follows:
dose y flavonoid 200-2000 mg/ route p'9-pdap 6-pao, j m /day i , Da3-Da, _or 5-50 mg/kg/day v.
1 h infusion cyclophosphamide i , D,9, D9;, 650 mg/m'- v. ps~
(maximum 1000 i mg) i . DsmD39, p;~-D91 cytarabine 75 v.
mg/m'/day 1 hour infusion oral Dm. Dse. Das.
mercaptopurine Ds, 60 mg/m- i.v.
methotrexate ' 10 mg/
(maximum 15 mg) iii) chemotherapy/Phase l:
reinduction I
dose route days flavonoid 200-2000 mg/m=/day Di-D;, DR-Di~, D i.v. ,5-D14~ D-__p~s or 5-50 mg/kg/day 1 h infusion --dcxorubicin 25 mg/m=/day i . D1, D~, D.:;, v. D
dexamethasone 10 mg/mv/day oral D
I
vincristine 1.5 mg/mv/day oral i ~ D, , D=8.
(maximum 2 mg) D._5 and _ D_, _ iv) reinduction chemotherapy/Phase 2:
dose route days ~ flavonoid 200-2000 mg/m~/day D;i-D;S, D;~-D4~
or 5=50 mg/kg/day i.v.
1 h infusion ~ cyclophosphamide 650 mg/m= i,v_ (maximum: 1000 mg) ~ cytarabine 75 mg/mv/day i.v.
~ thioguanine 60 mg/mv l oral p_ 1.2 Acute myeloid leukaemias:
1.2.1. Treatment of adults of any age The flavonoids can be added, according to the scheme below, to the treatment which incorporates the standard dose of cytarabine previously described by R.O. Dilleman et al. (Blood, 1991; 78: 2520-2526), Z.A. Arlin et al. (Leukemia 1990; 4: 177-183) and P.H. Wiernik et al. (Blood 1992; 79: 313-319):
dose route days flavonoid 200-2000 mg/m-/day _or 5-50 mg/kg/day i.v.
1 h infusion cytarabine 100-200 mg/m-/day i.v. D,-D, in a continuous infusion daunorubicin 45 mg/m'/day as a bolus i.v. D1-D~,or _ (30 mg/mo/day if age >_ D~-Dlo 60)-or mitoxantrone 12 mg/m- i.v. D1-D3 in a daily bolus or idarubicin 13 mg/m- i.v. D1-D3 in a daily bolus 1.2.2. Treatment of adults under the age of 60 i) induction chemotherapy:
This induction cycle incorporates the administration of cytarabine at high dose according to the following scheme:
dose route days flavonoid 200-2000 mg/mr/day DmDio _or 5-50 mg/kg/day i.v.
1 h infusion Ara-C (cytarabine) 2000 mg/m-/day i.v. Di-D6 in a 2 hour infusion, every 12 hours Daunorubicin 60 mg/m-/day i.v. DQ-D6 in a 24 hour continuous infusion O-r Cytarabine 3000 mg/m-/day i.v. D_-DE
in a 1 hour infusion, every 12 hours Daunorubicin 45 mg/m' bolus i.v. D7-D3 every 24 hours (in order to reduce the risk of C.N.S. toxicity, in the event of renal failure, adjust the cytarabine dosage to the creatinin clearance) according to L.E. Damon et al. (Leukemia 1994; 8:
535-541), G.L. Phillips et al. (Blood 1991; 77:
1429-1435) and G. Smith et al. (J. Clin. Oncol.
1997; 15: 833-839).
ii) consolidation chemotherapy:.
The cycle, described hereinafter, will be repeated 8 times, at a rate of 1 cycle every 4 to 6 weeks (according to R. J. Mayer et al . , N.
Engl J. Med. 1994; 331: 896-90-3):
dose route days flavonoid 200-2000 mg/m~/day i.v. _ D-_-D_5 _or 5-50 mg/kg/day 1 h infusion cytarabine 3000 mg/m' i.v. D1, D3, D;
in a 3 hour infusion, every 12 hours (4 cycles) then 100 mg/mv/day cytarabine every i2 hours s.c. D._-D=.
daunorubicin 45 mg/m- bolus y.v. D
(4 cycles) iii) consolidation chemotherapy (with high dose of cytarabine):
The cycle, described hereinafter, must be repeated twice and is adapted according to G.L. Phillips et al. (Blood 1991; 77: 1429-1435); S.N. Wolff et al. (J. Clin. Oncol. 1989;
7: 1260-1267); R.J. Mayer et al. (N. Engl J.
Med. 1994; 331: 896-903):
dose route days flavonoid 200-2000 mg/m'/day i.v.
or 5-50 mg/kg/day 1 h infusion cytarabine 3000 mg/m~ i . D.,-DE
v.
[lacuna]
1 hour every 12 hours daunorubicin 30-45 mg/m'/day bolus i.v. D;-D4 ~
once/day 1.2.3. Treatment of adults aged 60 or older The flavonoids may be added to the consolidation chemotherapy protocols hereinafter:
i) according to R.O. Dilman et al. (Blood 1991; 78;
2520-2526), Z.A. Arlin et al. (~eukemia 1990; 4:
177-183), P.H. Wiernik et al. (Blood 1992; 79:
313-319):
dose route days flavonoid 200-2000 mg/mv/day i.v.
or 5-50 mg/kg/day 1 h infusion cytarabine (Ara-C) 100-200 mg/mv i.v.
[lacuna]
24 hour continuous infusion daunorubicin 30-45 mg/m'/day bolusi.v.
o r _.. _ .-mitoxantrone 12 mg/m'/day bolus i.v. D1.D~
or idarubicin 23 mg/m-/day bolus i.v. D-, D, ii) according to R.J. Mayer et al. (N. Engl. J. Med.
194; 331: 896-903):
dose route days flavonoid 200-2000 mg/m~/day i.v.
or 5-50 mg/kg/day 1 h infusion cytarabine 100 mg/m= i . D1-D;
v.
24 hour continuous infusion (4 cycles) then . cytarabine 100 mg/m- s . D1, D_.
c .
every 12 hours daunorubicin 45 mg/m'/day bolus i.v. D.
(4 cycles) iii) according to C.A. Linker et al. -(Blood 1993; 81:
311-318), N. Chao et al. (Blood 1993; 81: 319-323) and A.M. Yeager et al. (N. Eng. J. Med. 1986; 315:
145-147):
This protocol comprises an autologous bone marrow transplant (carried out on day Do):
dose route days flavonoid 200-2000 mg/m-/day i.v. D_,-D__ or 5-5C mg/kg/day 1 h infusion busulphan 1 mg/kg qid oral D_~ to D_a (16 doses in total) etoposide ~ 60 mg/kg/day i.v. D_3 10 hour infusion or ' dose route days flavonoid 200-2000 mg/mv/day i.v. D_~-D_1 or 5-50 mg/kg/day 1 h infusion busulphan 1 mg/kg aid oral D_5 to D_6 cyclophosphamide 50 mg/kg/day i . D_; to v. D_, ~
1 hour infusion iv) in the event of HLA-compatible allogenic bone marrow transplant according to:
P.J. Tutscha et al. Blood 1987; 70: 1382--1388, F.R. Applebaum et al. Ann. Int. Med. 1984; 101:
581-588:
dose route days flavonoid 200-2000 mg/m-/day i.v. p_,-p or 5-50 mg/kg/day 1 h infusion busulphan 1 mg/kg qid oral D_, to D_s (16 doses in total) cyclophosphamide 60 mg/kg/day i.v. D_3 to D_ 1 hour infusion 2°/ Adult chronic leukaemias 2.1 Chronic myeloid leukaemia In the myeloblastic phase, the flavonoids can be added to the HU-Mith treatment described by C.A. Koller et al. (N. Engl. J. med. 1986; 315:
1433-1438):
dose route days D:-D
flavonoid 200-2000 mg/mv/dayi.v. p~-D1' _or 5-50 mg/kg/day p,;-D-_ 1 h infusion hydroxyurea 500 mg/day oral every day mithramycin 25 ~g/kg/day i.v. daily for 3 2-4 hour infusion weeks, then.
times/week 2.2 Chronic lymphocytic leukaemia 2.2.1 FCG-CLL protocol The flavonoids can be added to the "pulsed chlorambucil" combinations as described by E. Kimby et al. (Leuk. Lymphoma 1991; 5 (Suppl.) 93-96) and by FCGCLL (Blood 1990; 75:
1422-1425):
dose route days flavonoid 200-2000 mg/m'/day D1-Ds, D-~_D1'~
_or 5-50 mg/kg/dayi.v. Dis-Dz 1 h infusion chlorambucil 0.1 mg/kg/day oral once/day _or chlorambucil 0.4 mg/kg/day oral Di every 14 days and prednisone 75 mg/day oral D1-D3 2.2.2 Fludarabine-CdA protocol according to H.G. Chun et al.-(J. Clin. Oncol.
1991; 9: 175-188), M.J. Keating et al-. (Blood 1989; 74: 19-25 / J. Clin. Oncol. 1991; 9: 44 49) and A. Saven et a1. (J. Clin. Oncol. 1995;
13; 570-574):
dose route days fl avonoid 200-2000 mg/m-/day D~-Da _or 5-50 mg/kg/day i.v. (once/month 1 h infusion for 6 to cycles) fludarabine 25-30 mg/m'/day i.v. D
30 minute infusion [every 4 weeks for 6 to 12 cycles]
or cladribine 0.09 mg/kg/day i.v. D_-D-;
in a continuous infusion [1 cycle every 28 to days for 1 to 9 cycles (median: 4 cycles)]
3°/ Lymphoproliferative diseases 3.1 Hodgkin's disease The flavonoids can be incorporated into the polychemotherapy protocols conventionally used for the treatment of Hodgkin's lymphoma:
3.1.1 AVDB protocol according to G. Bonnadonna et al. (Cancer Clin.
Trials 1979; 2: 217-226) and G.P. Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484):
dose route days flavonoid 200-2000 mg/m=/day Dl-D~, _or 5-50 mg/kg/dayi.v. Dls-D1~
1 h infusion doxorubicin (A) 25 mg/mr bolus i.v. Dl,Dis bleomycin (B) 10 U/m~ bolus i.v. D1,D._s vinblastine (V) 6 mg/m' bolus i.v. D,, Dls dacarbazine (D) 375 mg/m- bolus ~ i.v.Dl,Dls the therapy comprising 6 to 8 cycles, at a rate of 1 cycle every 28 days.
3.1.2 MOPP/ABVD protocol according to G. Bonnadonna et al. (Ann. Intern.
Med. 1986; 104: 739-746) and G.P. Canellos et al. (N. ~r.gl. J. Med. 1993; 327: 1478-1484):
The MOPP protocol should be alternated with the ABVD protocol (cf. 3.1.1) every 28 days, and the therapy comprises 6 cycles:
MOPP protocol: dose route days flavcnoid 200-2000 mg/mr/day _or 5-50 mg/kg/day i.v. and D;a-D1,-- -1 h infusion mechlorethamine (M) 6 mg/mv bolus ~ i.v. D1, D8 vincristine (0) 1.4 mg/mv bolus i.v. D,, Ds (no maximum) procarbazine (P) 100 mg/m~/day oral D1-D1~
prednisone (P) 40 ma/m-/day oral 3.1.3 Stanford V protocol according to N.L. Bartlett et al. (J. Clin.
Oncol. 1995; 13; 1080-1088):
dose route days flavonoid 200-2000 mg/m'/day D~-Ds or 5-50 mg/kg/day i.v. D9-J1~
_ D,5_D~a 1 h infusion D,~-D=s doxorubicin 25 mg/m- i.v. Dl,D~s vinblastine 6 mg/m' bolus i.v. D.,, D15 (4 mg/m' during cycle 3 if age >_ 50) mechlorethamine 6 mg/m' bolus i.v. D1 (M) vincristine 1 .4 mg/m' bolus i.v. Di, D
(maximum dose: 2 mg) [1 mg/m' during cycle 3 if age >_ 50) bleomycin 5 U/mv i .v. Do, D__ etoposide 60 mg/m' oral D15, Dib prednisone 40 mg/m-/day oral once/week (weeks 1-9) the therapy comprising 3 cycles, at a rate oy 1 cycle every 28 days.
S 3.1.4 EVA protocol according to G.P. Canellos et al. (Proc. Am.
Soc. Clin. Oncol. 1991; 10: 273):
dose route days flavonoid 200-2000 mg/m-/day _or 5-50 mg/kg/dayi.v.
1 h infusion etoposide (E) 100 mg/m' oral D1, D=, . 2 hour infusion D3 vinblastine (V) 6 mg/m' bolus i.v. D1 doxorubicin (A) ~ 50 mg/mv bolus i.v. D1 the therapy comprising 6 cycles, at a rate of 1 cycle every 28 days.
3.1.5 B-CAVe protocol according to W.G. Harker et al. (Ann. Intern.
Med. 1984; 101: 440-446):
dose _route days flavonoid 200-2000 mg/mr/day D1-D
_or 5-50 mg/kg/dayi.v.
1 h infusion (B) 5 U/m' bolus i.v. D, bleomycin _ lomustine (CCNU) 100 mg/m' oral D1 doxorubicin (A) 60 mg/m- bolus i.v. D
vinblastine (Ve) ~ 5 mg/m- bolus ~ i.v. ~ D, the therapy comprising 8 cycles, at a rate of 1 cycle every 28 days.
3.2 Non-Hodgkin's lymphomas.
3.2.1. non-Hodgkin's lymphomas with -a low degree of malignancy i) - CVP protocol lp - according to C.M. Bagley et al. (Ann. Intern.
Med. 1972; 76: 227-234) and C.S. Portlock et al. (Blood 1976; 47: 747-756) dose route days flavonoid 200-2000 mg/m-/day Di-D
I _or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide (C) 300-400 mg/m-/day i.v. D,,D;
vincristine (0) 1.4 mg/m- bolus ~ i.v.D, (max: 2 mg) prednisone (P) 100 mg/mr/day oral Di-D;
This cycle is repeated every 21 days until maximum response ii) - I-COPA protocol - according to RV Smalley et al/ (N. Eng. J. Med.
1992; 327: 1336-1341) dose route days flavonoid 200-2000 mg/m'/day Di-Ds or 5-50 mg/kg/day i.v.
_ 1 h infusion clophosphamide (C) 600 mg/m'/day i.v.
c y vincristine (0) 1.2 mg/m- bolus i.v.
(max: 2 mg) prednisone (P) 100 mg/m'/day i.v. D;-D5 doxorubicin (A) 50 mg/m- bolus i.v. D
interferon-alpha (I) 6 MU/m- i.m. D~=-D_6 The therapy comprises cles, a rate 8 to 10 cy at of one cycle every days.
iii) - fludarabine-CdA protocol ~-- according to P. Solol-Celigny et al. (Blood 1994; 84 (Supp. 1): 383a), H. Hoeschster et al.; (Blood 1994; 84 (Suppl. 1): 564a and A.C. Kay (J. Clin. Oncol.
1992; 10: 371-377) dose route days . flavonoid 200-2000 mg/mr/day Dm D, _or 5-50 mg/kg/day i.v.
i h infusion fludarabine ~ 25 mg/~'~-/day ~ i.v. ~ D,_-D, 0.5 hour infusion or ~ fludarabine 20 mg/mr/day i.v D1-D
and cyclophosphamide 600-1000 mg/m-/day i.v D1 or cladribine 0 . 1 mg/m-/day i . v D~-D, ' 24 hour infusion For fiudaribine, each cycle is repeated every 28 days; for cladribine, each cycle is repeated every 35 days.
3.2.2. non-Hodgkin's lymphomas with an intermediate degree of malignancy 1992, 3.
9) dose route days flavonoid 200-2000 mg/m~/day D1-D;
_or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide (C) 750 mg/m-/day i.v. D, doxorubicin (H) ~ 50 mg/m' bolus i.v. D1 vincristine (0) 1.4 mg/m' bolus i.v. Dl (max: 2 mg) prednisone (P) 100 mg/m'/day _ ~ oral~ D,-DS
~
(in 1 dose/day) for the CHOP protocol Mitoxantrone (N) can be used to replace (CNOP
protocol) doxorubicin in patients over 60 years of age (dose: 12 mg/m2 as an i.v. bolus on day D1 of each cycle).
The therapy using the CHOP or CNOP protocol comprises 6 to 8 cycles, at a rate of 1 cycle every 21 days.
ii) - MACOP-B protocol - according to P. Klimo et a1. (Ann. Intern. Med.
1985; 102: 596-602) and I.A. Cooper et al. (J. Clin.
Oncol. 1994; 12: 769-778) i) - CHOP or CNOP protocol - according to E.M. McKelvey et al. (Cancer 1976;
38: 1484-1493), J.O. Armitage et al. (J. Clin. Oncol.
1984; 2: 898-902), S. Paulovsky et al. (Ann. Oncol.
dose route days _ _ Da-Ds ~ Do-D1~
flavonoid 200-2000 mg/m'/dayi.v. Dls-DZ~,D~g-D33 _or 5-50 mg/kg/day D93-D4,, Ds,-D61 1 h infusion D~1-D,s methotrexate (M) 100 mg/m' bolus i . D~, D36, D64 v.
then 300 mg/m' 4 hour infusion leucovorin 15 mg qid oral D9, D3,, D6s doxorubicin (A) 50 mg/m- bolus i . D1, Dls, D,4, v. D~;;, Ds~. D,1 cyclophosphamide 350 mg/mv bolus i . D, , Ds, D_q, v. Da;, (c) - Ds,. D,1 vincristine (0) 1.4 mg/m' bolus i.v. Ds,D~~,D;o, (max: 2 mg) Dso ~ D6a ~
Din prednisone (P) 75 mg/day oral Each day for 12 weeks bleomycin (B) 10 U/m- bolus i.v. D=~, Ds~, D,~
This treatment protocol spreads out over 12 weeks and corresponds to 1 cycle.
iii) - VACOP-B protocol - according J.M. Connors et al. (Proc. Am.
Soc. Clin. Oncol. 1990; 9: 254):
dose route days D1-Ds, D8-D1~
flavonoid 200-2000 mg/mz/dayi.v. Dls-D, D=9-D;a or 5-50 mg/kg/day Da3-Da,~ Ds-r-Ds=
_ D?,-D,s 1 h infusion etoposide (V) 50 mg/m' i.v. Dls, D43, D,i etoposide 100 mg/m' oral Di6, D1~, D9a, Dq5 D,~. D,3 doxorubicin (A) 50 mg/m~ bolus i .v. D1, D.ys, D_9, D~3, D~.,, D~, cyclophosphamide 350 mg/m-/day i . De, D~~, DBE, v.
(c) bolus Dso~ Dsa~ D~a vincristine (0) 1.2 mg/m~ bolus ~ i.v.Ds,D=_,D36, _ Dso ~ D6a ~
Die prednisone (P) 45 mg/m'/day ora 1/day for 1 l week, then 4/day for the following 11 weeks Each cycle lasting 12 weeks.
iv) - m-BACOD/M-BACOD protocol - according to M.A. Shipp et al. (Ann. Int.
Med. 1986; 140: 757-765) and A.T. Skarin et ai. (J.
Clin. Oncol. 1983; l: 91-98) dose route days flavonoid 200-2000 mg/m-/dayi.v. D1-D5, D3-D1~
or 5-50 mg/kg/dayD~s-D:9 _ 1 h infusion methotrexate (m) 200 mg/m' i.v. DB,D, 4 hour infusion or or 3000 mg/m2 i.v. D1~
4 hour infusion leucovorin 10 mg/m~ qid oral D9, D,_6 or Dls (6 doses in total)I
(B) 4 U/mr bolus i.v. D, bleomycin -doxorubicin (A) 45 mg/m' bolus i.v. D:
cyclophosphamide 600 mg/m- bolus i.v. . D, -(C) vincristine (0) 1 mg/m- bolus i.v.
ne (D) 6 mg/m-/day oral D:-D
th aso dexame The therapy comprising 10 cycles, at a rate of 1 cycle every 21 days.
.. _ 58 _ v) - ProMACE/CytaBOM protocol - according to D.L. Longo et al. (J. Clin.
Oncol. 1991; 9: 25-38):
dose route days flavonoid 200-2000 mg/mr/day i.v. D,-D~,D~-D1=
_or 5-50 mg/kg/day _ 1 h infusion cyclophosphamide 650 mg/m- i.v. D1 (C) 0.5 hour infusion doxorubicin (A) 25 mg/m' bolus i.v. D1 etoposide 120 mg/m- i.v. D1 1 hour infusion prednisone (P) 60 mg/day i.v. D;, D1~
cytarabine 300 mg/m' bolus -. DB
i .
v.
bleomycin (B) 5 U/m' bolus i.v. De vincristine (0) 1.4 mg/m- bolus i.v. DR
methotrexate 120 mg/m- bolus i.v. D
leucovorin 25 mg/m- qid oral D4 (4 doses in total) -The therapy comprising 6 to 8 cycles, at a rate of 1 cycle every 14 days.
3.2.3. non-Hodgkin's lymphomas with a low or intermediate degree of malignancy i) - ESHAP rescue protocol - in the event of recurrence or in the event of failure of the first-line treatment, according to W.S. Velasquez et al. (J. Clin. Onccl. 1994; i2:
1169-1176) dose route days flavonoid 200-2000 i.v. D1-DS
mg/mz/day or 5-50 mg/kg/day _ I h infusion etoposide (E) 40 mg/mv i.v. D1-D4 2 hour infusion methylprednisolone (S) 500 mg/day i.v. D1,D4 15 minute infusion cytarabine (HA) 2000 mg/m- i.v. D;
3 hour infusion cisplatin (P) 25 mg/m-/day bolusi.v. D1-Dy 24 hour continuous infusion The treatment comprising 6 cycles, at a rate of 1 cycle every 28 days.
ii) - MINE rescue protocol - in the event of recurrence or in the event of failure of the first-line treatment, according to F. Cabanillas et al. (Semin. Oncol. 1990; 17 (Suppl. 10): 28-33) dose route days flavonoid '200-2000 mg/mv/day i.v. D,-D
or 5-50 mg/kg/day _ 1 h infusion ifosfamide (I) 1330 mg/m- i.v. D1-D
1 hour infusion sna (M) 1330 mg/m' i.v. Di-D3 me in the ifosfamide infusion, then 266 mg/m-bolus 4 and 8 hours after each dose of ifosfamide mitoxantrone (M) 8 mg/m- i.v.
15 minute infusion etoposide (E) 65 mg/m'/day i.v. D1-D;
1 hour infusion This cycle being repeated every ~1 aays.
3.3 Non-Hodgkin's lymphomas: Burkitt's lymphoma, small cell lymphoma, lymphoblastic lymphoma.
3.3.1 Magrath protocol - The flavonoids may be combined with the Magrath protocols according to the following schemes:
i) - cycle 1 - according to I.T. Magrath et al. (Blood 1984; 63: 1102-1111) dose route days flavonoid 200-2000 mg/m'/dayi.v. D1-DS
_or 5-50 mg/kg/day Dq-D1_ 1 h infusion cytarabine 30 mg/m- intra- Di, D=, D;, D, thecal cyclophosphamide 1200 mg/mv bolus i.v. D1 ~
methotrexate 12.5 mg/m' Intra-(max 12.5 mg) thecal methotrexate 300 mg/m'/day i.v. D,o-D,_ -1 hour infusion then 60 mg/mv/h 41 hour infusion leucovorin 15 mg/m- bolus i.v. To begin 42 (8 successive hours after doses) the start of the ad-ministration of methotrexate ii) - cycles 2 to 15 - according to I.T. Magrath et al. (1984) as well:
dose route days flavonoid 200-2000 mg/m'/ i.v.
day Dio-Dil _or 5-50 mg/kg/
day 1 h infusion cytarabine 45 mg/m2 Intra- D1,D
thecal (cycles 2 and 3) (cycles 4 and 6) cyclophosphamide 1200 mg/m- bolusi.v. Di (C) doxorubicin 40 mg/m' bolus i.v.
vincristine 1.4 mg/m' bolus i.v. D, (max 2 mg) methotrexate 12 . 5 mg/m' Intra- D;, Dlo (max 12.5 mg) thecal (cycles 2 and 3) Dio (cycles 4,5,6) methotrexate 300 mg/mv i .
v.
I, Dic.
Dm l.hour infusion ~ (cycles 2 and then D-,4, Dls 60 mg/mv ~ (cycles 7-15) 41 hour continuous infusion leucovorin 15 mg/mv bolus j i.v. To begin at the qid ~ 42nd hour of the (8 consecutive treatment with doses) ~ methotrexate the therapy comprising 14 cycles, at a rate of one cycle every 28 days.
3.4 Waldenstrom macroglobulinaemia 3.4.1 CVP protocol according to the CVP protocol described by M.A. Dimopoulous et al. (Blood 1994; 83: 1452-1459) and C.S. Portlock et al. (Blood 1976; 47: 747-756):
15 - according to I.T. Magrath et al. (1984) as well:
dose route days flavonoid 200-2000 mg/m'/dayi.v. D1-DS
_or 5-50 mg/kg/day 1 h infusion cyclophosphamide (C) 300-400 mg/m'/day oral D1-DS
vincristine (V) 1.4 mg/mv/day bolusi.v. D
(max: 2 mg) (P) 100 mg./m'/day oral D,-DS
prednisone -the therapy being continued indefinitely (1 cycle every 21 days).
3.4.2 Fludarabine-CdA protocol -_ according to H.M. Kantarjian et al.. (Blood 1990; 75: 1928-1931) and M.A. Dinopoulous et al. (Ann.
Intern. Med. 1993; 118: 195-198):
dose ~ route days flavonoid 200-2000 mg/m-/dayi.v. D._-DS
_cr 5-5C mg/kg/day 1 h infusion fludarabine 25-30 mg/m' i.v. Di-DS
0.5 hour infusion or dose route days flavonoid 200-2000 mg/m'/dayi.v. Di-D~
_or 5-50 mg/kg/day 1 h infusion cladribine (CdA) 0.09 mg/mv/day ( i.v. ~ D-:-D, continuous infusion the therapy comprising 6 to 12 cycles 28 days apart in the case of fludarabine, and 2 cycles 28 days apart also, in the case of cladribine.
3.5 Multiple myeloma 3.5.1 MP protocol according to R. Alexanian et al. (JAMA 1969;
208: 1680-1685), A. Belch et al. (Br. J. Cancer 1988;
57: 94-99) and F. Mandelli et al. (N. Engl. J. med.
1990; 322: 1430-1434):
dose route days flavonoid 200-2000 mg/m'/dayi . D~-DS
_or 5-50 mg/kg/dayv.
1 h infusion melphalan (M) 0.25 mg/kg/day oral Di-D9 prednisone (P) 100 mg/day oral D;-Dq or dose _' route days flavonoid 200-2000 mg/m=/day i.v. D1-DS
_or 5-50 mg/kg/day 1 h infusion melphalan (M) 9 mg/m-'/day oral D1-D9 prednisone (P) 100 mg/day oral D;-Dq the therapy comprising at least 12 cycles, at a rate of 1 cycle every 4 to 6 weeks.
3.5.2 VAD protocol according to B. Barlogie et al. (N. Engl. J.
Med. 1984; 310: 1353-1356):
dose route days flavoroid 200-2000 mg/m-/day i.v. Di-DS
_or 5-50 mg/kg/day 1 h infusion -- vincristine (V) 0.4 mg/day i.v. D1-Da 24 hour continuous infusion doxorubicin (A) 9 mg/mv/day i.v. D~-Da 24 hour continuous infusion dexamethasone (D) 40 mg/day i.v. D1-Dq,DS-D1~, ~ D~ ~-Do 3.5.3 MP/interferon-a protocol according to 0. Osterborg et al. (Blood 1993;
81: 1428-1434):
dose route days flavonoid 200-2000 mg/m'/day i . D-y-Ds or 5-50 mg/kg/day v.
1 h infusion melphalan (M) 0.25 mg/kg/day oral prednisone (P) 2 mg/kg/day oral D1-Da interferon-alpha 7 MU/mv/day s.c. Di-D; and D=_-Das I
the therapy comprising the indefinite repetition of this cycle, at a rate of 1 cycle every 42 days.
3.5.4 VCAP or VBAP protocol according to S.E. Salmon et al. (J. Clin.
Oncol. 1983; l: 453-461):
protocol VCAP:
dose route days flavonoid 200-2000 mg/mr/day i.v. Di-DJ
or 5-50 mg/kg/day 1 h infusion vincristine (V) 1 mg/m' bolus i.v. Di (max: 1.5 mg) doxorubicin (A) 30 mg/m- bolus i.v.
prednisone (P) 60 mg/m-/day oral i-Da D
cyclophosphamide 125 mg/m- oral D1-Da (C) VBAP protocol: cyclophosphamide is replaced with carmustine (BCNU), the rest being identical:
dose route days carmustine 30 mg/mv i.v. D, 1 hour infusion _ 65 _ C. CHILDHOOD TUMOURS - Paediatric oncology i The flavonoids can also be incorr~rated into polychemotherapy protocols for treatment of paediatric tumours, in order to improve the antitumour :; effectiveness while at the same time reducing the severity of the side effects due to the action on the recruitment and mobilization of the clonogenic cells, and to the possibility of decreasing the active doses.
'r 1°/ Ewing's sarcoma/primitive neuroectodermal tumour The flavonoids can be introduced into -the VCR-Doxo-CY-Ifos-Mesna-E protocol (E.D. Bergert et al., J.
Clin. Oncol. 1990; 8: 1514-1524; W.H. Meyer et al., J.
Clin. Oncol. 1992; 10: 1737-1742):
dose route days flavonoi d 100-200 D;-D; and D~
m g/mv/day ~-D~
_ ;
or 2-50 mg/kg/day i . ar~d D~3-D9&
v. and 1 hour infusion vincristine 2 mg/m- bolus i .v. . D:, D"_;, Dy;, D~
~ (maximum dose =
2 mg) doxorubicin 30 mg/m-/day ~ i D1-D,, .
v.
in a 24 hour infusion D~,-D~5 cyclo- 2 . 2 g/m- i . D1, Da, v .
phosphamide in a 0.5 hour infusion ifosfamide 1800 mg/mr/day i.v.
in a 1 hour infusion Dr3-D6~
mesna 360 mg/m~ i.v. administered with in a 15 minute cyclophosphamide infusion, at a rate and ifosfamide of 5 doses every 3 hours etoposide 100 mg/m- i . p~~-D>6 v.
in a 1 hour infusion p5~_Df, the therapy comprises 6 to 10 of these cycles depending on the initial severity of the sarcoma and on the amplitude of the response.
2°/ Childhood acute lymphoblastic leukaemia 2.1. Induction chemotherapy (days D,_-D_3o).
The flavonoids can be added to the recommended protocols (P. S. Gaynon et al., J. Clin. Oncol., 1993, 11, 2234-2242; J. Pollen et al., J. Clin.
Oncol. 1993; 11: 2234-2242; J. Pollen et al., J.
Clin. Oncol. 1993; 11: 839-849; V.J. Land et al., J. Clin. Oncol. 1994; 12: 1939-1945):
dose - route days flavonoid 100-200 mg/m=/day Dl-Ds.
or 2-50 mg/kg/day i.v.
1 hour infusion vincristine 1. S mg/mv bolus i . D-;, D~, v. Dl~, D, (maximum dose = 2 mg) L-asparaginase 6000 IU/m- -i:m. 3 times/week for 3 weeks prednisone 60 mg/m- oral Dl to D~~
as 3 doses/day daunorubicin 25 mg/m'/day i.v. Dl, De, D15 and in a 15 minute infusion D_~
methotrexate depending on age intra- D
thecal cytarabine depending on age intra- Di thecal depending on the result of the examination of the bone marrow, entry into the ccnsolidation phase takes place on day D2~ of the treatment protocol.
2.2 Consolidation/maintenance chemotherapy The flavonoids can be introduced into the maintenance protocol (P. S. Gaynon et al., J. Clin.
Oncol. 1993; 11: 2234-2242; J. Pollen et al., J. Clin.
Oncol. 1993; 11: 839-849; V.J. Land et al., J. Clin.
Oncol. 1994; 12: 1939-1945) according to the following scheme:
-- dose route days flavonoid 100-200 mg/m-/day Dl-D5, D15-Duo and or 2-50 mg/kg/dayi.v. D54-DS~, Dloi-Dvos.
1 hour infusion Dlo~-D1,3, Dl~=-D,_=-, cyclo- 1000 mg/m' i.v. D;, D:S, Di phosphamide in a 0.5 hour infusion L- 6000 U/m- i.m. 3 times/week asparaginase between D4, and D1=
cytarabine 75 mg/m'/day i.v./s.c.a sequence of in a 15 minute days starting on infusion D_, Dq, D.yb, D=3, D,_3, D, doxorubicin 25 mg/m-/day i . v. Dq~, D_ol, Dloe in a 15 minute infusion mercapto- 60 mg/mv/day oral D~-D43,D1~3 to end of purine treatment methotrexate 20 mg/mv/day oral once/week between D;n and D,~, and between. D,a3 and the end of the treatment prednisone 40 mg/m-/day oral 5 consecutive days (divided into per month between doses/day) D_,4~ and the end of the treatment thioguanine 60 mg/mr/day oral D,=_-D~3, vincristine 1 . 5 mg/m' bolusi .v. D~,q, Dlo;, Dloe, then (maximum dose once/month between = 2 mg) D~3 and the end of the treatment methotrexate dependi ng on intra- D,~, DN, D;~, age D~~, D1=~, Dl3o thecal then once/3 months be tween D;93 and the end of the treatment i 3/ Childhood acute myeloid leukaemia The flavonoids the induction are added and to consolidation/maintenance according protocols to the :, following schemes:
.-., 5 3.1. Induction chemotherapy According to et al., J. Clin.
Y. Ravindranath Oncol. 1991; J. Clin.
9: 572-580;
M.E. Nesbit et al., -i Oncol. 1994; et al., J. Clin.
12: 127-135;
RJ Wells -;
Oncol. 1994;
12: 2367-2377:
ri v _ dose route days flavonoid 100-200 mg/mr/day ~ Dl-D~, D,~-D13 j or 2-50 mg/kg/day i.v.
1 hour infusion i cytarabine according to age infra- D_.
thecal daunorubicin 20 mg/mr/day i . v. D~-D,, D1~-Dls in a 24 hour infusior_ cytarabine 200 mg/m-/day i . v. D_,-D~, Dlo-D"
in a 24 hour infusion thioguanine 100 mg/mv/day oral Di-D~, D~_;,-D~:3 divided into 2 doses/day etoposide 100 mg/mr/day i.v. D.
-D~
D, -D
~ _ in a 24 hour infusion , ~
;
dexamethasone 6 mg/m- i.v. Dl-D~, Dl~a-D, /oral 3 divided into 3 doses/day _ this cycle being repeated from D~e.
3.2. Consolidation/maintenance chemotherapy According to Y. Ravidranath et al., J. Clin.
Oncol. 1991; 9: 572-580; M.E. Nesbit et al., J. Clin.
Oncol. 1994; 12: 127-135; R.J. Wells et al., J. Clin.
Oncol. 1994; 12: 2367-2377:
dose route days cytarabine according to age intra- Di, D-_,e, D,6 thecal flavonoid 100-200 mg/m'/day i.v. D~-DS,Da-Dl;
or 2-50 mg/kg/day D~a-D33, Ds6-Dsl 1 hour infusion DF~-Dq~
cytarabine 3000 mg/m' i . v. Dl-D
in a 3 hour infusion and D6-D9 every 12 hours 1-asparaginase 6000 IU/m- i.m. D=, D
3 hours after the cytarabine Vincristine 1.5/m' bolus i.v. D
(maximum dose = 2 mg) -Thioguanine 75 mg/m-/day oral D,~-DH~
Cytarabine 75 mg/mv/day bolus i.v. D_s-D~1,D~~-DSQ
Cyclo- 75 mg/mv/day i.v. D_F-D
phosphamide in a 0.5 hour infusion Cytarabine 25 mg/m-/day bolus sc/i.v. Dq4-D~3 Thioguanine 50 mg/mv/day oral ~~4-D43 Etoposide 100 mg/mv/day i.v. Des, Dq_ in a 1 hour infusion Dexamethasone 2 mg/mr/day cral D;4-Dq Daunorubicin 30 mg/m- ~.v. D"_~_, in a 15 minute infusion 4°/ Childhood Hodgkin's disease The flavonoids can be added to the MOPP-ABVD
protocol according to EA Gehan et al. (Cancer 1990; 65:
1429-1437), SP Hunger et al. (J. Clin. Oncol. 1994; 12:
2160-2166) and MM Hudson et al. (.J. Clin. Oncol. 1993;
11: 100-108):
dose days route flavonoid 100-200 i.v. Dl-Ds mg/m'/day or and 2-50 D~-D:
mg/kg/day hour infusion mechlorethamine (M) i Dl, Do 6 .
mg/m' v.
bolus vincristine (0) 1.5 i.v. Dl,D~
mg/m' bolus (maximum mg) rocarbazine (P) 100 oral D;-Dla mg/m-/day p prednisone (P) 40 oral D;-Dla mg/m'/day (divided into doses/d) doxorubicin (A) 25 i.v. D~9,D_q3 mg/m-/day in a minute infusion (B) bleomyci 10 i.v. D~o,Da3 U/m-ri in a minute infusion (V) 6 i.v. D~4,Da;
vinblastin mg/m-bolus e (maximum mg) dicarbazine (D) 375 mg/m' i.v. D=4,Da3 in a 15 minute infusion This cycle should be repeated times, at a rate of 1 cycle every weeks, the therapy comprising cycles.
If an autologous bone marrow transplant (autograft) is prescribed, the CVB protocol described by R. Chopra et al. (Blood 1993; 81: 1137-1145), C. Wheeler et al. (J.
Clin. 0ncol. 1990; 8: 648-656) and R.J Jones et al. (J.
Clin. Oncol. 1990; 8: 527-537) may be used according to the following scheme (the allograft taking place on day Do) ' dose routedays flavonoid 100-200 mg/m-/day or 2-50 mg/kg/day i.v.
1 hour infusion cyclophosphamide 1800 mg/m'/day i.v. D_,,D_E
in 2 1 hour infus ions D-~ ~
D-a carmustine (BCNU) 112 mg/mr/day i.v. D_-,,D-G
in a 0 . 5 hour infusion D-s~ D-a 500 mg/m-/day i.v. D-,,D-d I
etoposide , 2 1 hour infusions ~ ~ D-=~
i D-a n 5°/ Childhood lymphoblasic lymphoma The flavonoids may also be combined with induction chemotherapy (A. T. Meadows et al., J. Clin. Oncol.
1989: 7: 92-99 - C. Patte et al., Med. Ped. Oncol.
1992; 20: 105-113 and A. Reiter et al., J. Clin. Oncol.
1995; 13: 359-372) and maintenance chemotherapy protocols:
5.1 Induction chemotherapy dose route days flavonoid 100-200 mg/mr/day i.v. Dl-D;, 50 mg/kg/day - D;,-D,=, or 2- D=~-D~9 - -1 hour infusion cyclo- 1200 mg/m' i.v. D1 phosphamide in a 0.5 hour infusion cytarabine according to age ~ intra- D1 thecal vincristine 1 . 5 mg/m' bolus ~ i.v. D, D;o, D1,, D~.
' (maximum 2 mg) prednisone 60 mg/m-/day oral D;-D=~
divided into 3 doses/day daunorubicin 60 mg/mr i.v. D~, in a 15 minute infusion L-asparaginase 6000 U/m-/day im D1,-D
in a 15 minute infusion 3 times/week Methotrexat e accordi ng to age intra- D,~, D_;, thecal 5.2 Maintenance chemotherapy according to the following scheme:
dose route days ', Flavonoid 100-200 mg/m'/day i.v. Dl-Ds,DlS-Duo i D or 2-50 mg/kg/day =9-D3a 1 hour infusion Cyclophosphamide 1000 mg/m' i.v.
in a 0.5 hour infusion Vincristine 1. 5 mg/m-' bolus oral Dl, Ds.
(maximum 2 mg) (of cycles to 10) Methotrexate 300 mg/mv/day i.v.
(60% in a 15 minute :a infusion and 40o in a 4 hour infusion) a Leucovorin 10 mg/m'/every oral p,s 4 h Daunorubicin 30 mg/mr i.v.
in a 0.5 hour ! infusion Methotrexate according to age intro- Di, De, D.s y thecal (cycle 1) then once/month i ! (cycles 2 i to 10) the therapy comprising 10 cycles 6°/ Paediatric neuroblastoma The recommended Doxo-E-Cy-Pt polychemotherapy protocol is adapted from R.P. Castleberry et al. (J.
Clin. Oncol. 1992; 10: 1299-1304), A. Garaventa et al.
(J. Clin. Gncol. 1993; 11: 1770-1779) and D.C. West et al. (J. Clin. Oncol. 1992; 11: 84-9C):
dose route days flavonoid 100-200 mg/m-'/day i.v. Dl-Ds.
or 2-50 mg/kg/day D~e-D3s~
1 hour infusion D5a-DES
doxorubici n 25 mg/m'/day i.v. D~_,D3o,Dsa in a 15 minute infusion etoposide 100 mg/mz oral/ D=, D4, D3o, D33, in a 1 hour infusion naso- Dsa. Ds;
gastric cyclophos- 1000 mg/m' i , v. D;, Dy, D3i, D,=, phamid e in a 0 . 5 hour Dsa. Dso infusion cisplatin 60 mg/m2 i.v. Dl, DAB, Ds6 in a 6 hour infusion The evaluation of the therapeutic response is carried out after 9 weeks in order to decide upon the approach: surgical resection, radiotherapy or new chemotherapy.
7°/ Paediatric osteosarcoma The flavonoids can be added to the Doxo-Pt-Mtx-Lcv protocol as is described by M. Hudson et a1. (J.
Clin. Oncol. 1990; 8: 1988-1997), PA Meyers (J.
Clin. Oncol. 1992; 10: 5-15), and V.H.C. Bramwell et al., (J. Clin. Oncol. 1992; 10: 1579-1591):
dose route days flavonoid 100-200 mg/m'/day i.v. Dl-D;,D~1-D_~s, or 2-50 mg/kg/day D~e-D~3 - 1 hour infusion doxcrubicin 25 mg/m'/day i.v. Dl_D
in a 24 hour infusion cisplatin 120 mg/m- i,v, D, in a 6 hour infusion methotrexate 12 mg/m'/day i . v. D_,1, D=a in a 1 hour infusion leucovorin 100 mg/m' oral D
every 6 hours 8°/ Childhood rhabdomyosarcoma The Vcr-Dact-CY-Mesna protocol (H. Maurer et al., Cancer 1993; 71 : 1904-1922 and LR Mandell et al . , Oncology 1993 7~ 71-83) can 1 d lnc a a the i.v.
infusion of the flavonoids according to the following scheme:
i i dose route days flavonoid 100-200 mg/m-/day i.v. D~_DS,DB_Dl~~
or 2-50 mg/kg/day ~ D_=-D~;
D
-D
, 1 hour infusion , a;
~
vincristine 1.5 mg/m'/day _ i D,, Da, D,s, .v. D~=
, bolus maximum 2 mg D~9, D3s~
Dq3.
Dso. Ds~
dactinomycin 0.015 mg/kg bolus i.v. Di-Ds.
i (max daily dose: 0. D_~_~-D_~,, 5 mg) Dq3-D4, cyclo- 2.2 mg/m' i.v. D;, D=_, phosphamide in a 1 hour infusion mesna 360 mg/m- i.v. D1, D==.
i n a 1 hour infusion every 3 hours for 5 doses At the end of the 9th week of treatment, the effectiveness should be evaluated to decide upon the subsequent measures (surgery, radiotherapy, continuation of the chemotherapy).
9°/ Wilms' tumour in children In the Vcr-Dact protocol as is described by GJ D'Angio et al. (Cancer, 1989; 64: 349-360) and DM Green et al. (J. Clin. Oncol. 1993; 11: 91-95):
dose route days flavonoid 100-200 mg/m-/day i . v. DI-Ds, Da-Di., or 2-50 mg/kg/day then each week 1 hour infusion vincristine 2 mg/m- bolus i.v.
(max dose: 2 mg) then each week dactinomycin 0.045 mg/kg bolus i.v. D
then e 1, very (P S 30 kg) 3 weeks 1.35 mg/m' (P>30 kg) (max dose: 3 mg) :i _ ~5 _ This protocol being started after surgical I resection.
In the event of autologous bone marrow transplant (autograft) according to A. Garaventar et al.
(Med. Pediatr. Oncol. 1994; 22: 11-14), the E-Thio-Cy protocol may be modified as follows:
_, dose -. route days flavonoid 100-200 mg/mv/day i.v. D_~-D_i or 2-50 mg/kg/day 1 hour infusion etoposide 1800 mg/m~ i.v.
24 hour infusion thiotepa 300 mg/m'/day i.v. D_7,D_E,D_5 i in a 2 hour infusion cyclophosphamide 50 mg/kg/day i.v. D_9, D_;, D__~, ~ D_1 in a 1 hour infusion the bone mar row transplant taking e on Do.
plac
_or 5-50 mg/kg/day i.v.
1 h infusion cyclophosphamide (C) 750 mg/m-/day i.v. D, doxorubicin (H) ~ 50 mg/m' bolus i.v. D1 vincristine (0) 1.4 mg/m' bolus i.v. Dl (max: 2 mg) prednisone (P) 100 mg/m'/day _ ~ oral~ D,-DS
~
(in 1 dose/day) for the CHOP protocol Mitoxantrone (N) can be used to replace (CNOP
protocol) doxorubicin in patients over 60 years of age (dose: 12 mg/m2 as an i.v. bolus on day D1 of each cycle).
The therapy using the CHOP or CNOP protocol comprises 6 to 8 cycles, at a rate of 1 cycle every 21 days.
ii) - MACOP-B protocol - according to P. Klimo et a1. (Ann. Intern. Med.
1985; 102: 596-602) and I.A. Cooper et al. (J. Clin.
Oncol. 1994; 12: 769-778) i) - CHOP or CNOP protocol - according to E.M. McKelvey et al. (Cancer 1976;
38: 1484-1493), J.O. Armitage et al. (J. Clin. Oncol.
1984; 2: 898-902), S. Paulovsky et al. (Ann. Oncol.
dose route days _ _ Da-Ds ~ Do-D1~
flavonoid 200-2000 mg/m'/dayi.v. Dls-DZ~,D~g-D33 _or 5-50 mg/kg/day D93-D4,, Ds,-D61 1 h infusion D~1-D,s methotrexate (M) 100 mg/m' bolus i . D~, D36, D64 v.
then 300 mg/m' 4 hour infusion leucovorin 15 mg qid oral D9, D3,, D6s doxorubicin (A) 50 mg/m- bolus i . D1, Dls, D,4, v. D~;;, Ds~. D,1 cyclophosphamide 350 mg/mv bolus i . D, , Ds, D_q, v. Da;, (c) - Ds,. D,1 vincristine (0) 1.4 mg/m' bolus i.v. Ds,D~~,D;o, (max: 2 mg) Dso ~ D6a ~
Din prednisone (P) 75 mg/day oral Each day for 12 weeks bleomycin (B) 10 U/m- bolus i.v. D=~, Ds~, D,~
This treatment protocol spreads out over 12 weeks and corresponds to 1 cycle.
iii) - VACOP-B protocol - according J.M. Connors et al. (Proc. Am.
Soc. Clin. Oncol. 1990; 9: 254):
dose route days D1-Ds, D8-D1~
flavonoid 200-2000 mg/mz/dayi.v. Dls-D, D=9-D;a or 5-50 mg/kg/day Da3-Da,~ Ds-r-Ds=
_ D?,-D,s 1 h infusion etoposide (V) 50 mg/m' i.v. Dls, D43, D,i etoposide 100 mg/m' oral Di6, D1~, D9a, Dq5 D,~. D,3 doxorubicin (A) 50 mg/m~ bolus i .v. D1, D.ys, D_9, D~3, D~.,, D~, cyclophosphamide 350 mg/m-/day i . De, D~~, DBE, v.
(c) bolus Dso~ Dsa~ D~a vincristine (0) 1.2 mg/m~ bolus ~ i.v.Ds,D=_,D36, _ Dso ~ D6a ~
Die prednisone (P) 45 mg/m'/day ora 1/day for 1 l week, then 4/day for the following 11 weeks Each cycle lasting 12 weeks.
iv) - m-BACOD/M-BACOD protocol - according to M.A. Shipp et al. (Ann. Int.
Med. 1986; 140: 757-765) and A.T. Skarin et ai. (J.
Clin. Oncol. 1983; l: 91-98) dose route days flavonoid 200-2000 mg/m-/dayi.v. D1-D5, D3-D1~
or 5-50 mg/kg/dayD~s-D:9 _ 1 h infusion methotrexate (m) 200 mg/m' i.v. DB,D, 4 hour infusion or or 3000 mg/m2 i.v. D1~
4 hour infusion leucovorin 10 mg/m~ qid oral D9, D,_6 or Dls (6 doses in total)I
(B) 4 U/mr bolus i.v. D, bleomycin -doxorubicin (A) 45 mg/m' bolus i.v. D:
cyclophosphamide 600 mg/m- bolus i.v. . D, -(C) vincristine (0) 1 mg/m- bolus i.v.
ne (D) 6 mg/m-/day oral D:-D
th aso dexame The therapy comprising 10 cycles, at a rate of 1 cycle every 21 days.
.. _ 58 _ v) - ProMACE/CytaBOM protocol - according to D.L. Longo et al. (J. Clin.
Oncol. 1991; 9: 25-38):
dose route days flavonoid 200-2000 mg/mr/day i.v. D,-D~,D~-D1=
_or 5-50 mg/kg/day _ 1 h infusion cyclophosphamide 650 mg/m- i.v. D1 (C) 0.5 hour infusion doxorubicin (A) 25 mg/m' bolus i.v. D1 etoposide 120 mg/m- i.v. D1 1 hour infusion prednisone (P) 60 mg/day i.v. D;, D1~
cytarabine 300 mg/m' bolus -. DB
i .
v.
bleomycin (B) 5 U/m' bolus i.v. De vincristine (0) 1.4 mg/m- bolus i.v. DR
methotrexate 120 mg/m- bolus i.v. D
leucovorin 25 mg/m- qid oral D4 (4 doses in total) -The therapy comprising 6 to 8 cycles, at a rate of 1 cycle every 14 days.
3.2.3. non-Hodgkin's lymphomas with a low or intermediate degree of malignancy i) - ESHAP rescue protocol - in the event of recurrence or in the event of failure of the first-line treatment, according to W.S. Velasquez et al. (J. Clin. Onccl. 1994; i2:
1169-1176) dose route days flavonoid 200-2000 i.v. D1-DS
mg/mz/day or 5-50 mg/kg/day _ I h infusion etoposide (E) 40 mg/mv i.v. D1-D4 2 hour infusion methylprednisolone (S) 500 mg/day i.v. D1,D4 15 minute infusion cytarabine (HA) 2000 mg/m- i.v. D;
3 hour infusion cisplatin (P) 25 mg/m-/day bolusi.v. D1-Dy 24 hour continuous infusion The treatment comprising 6 cycles, at a rate of 1 cycle every 28 days.
ii) - MINE rescue protocol - in the event of recurrence or in the event of failure of the first-line treatment, according to F. Cabanillas et al. (Semin. Oncol. 1990; 17 (Suppl. 10): 28-33) dose route days flavonoid '200-2000 mg/mv/day i.v. D,-D
or 5-50 mg/kg/day _ 1 h infusion ifosfamide (I) 1330 mg/m- i.v. D1-D
1 hour infusion sna (M) 1330 mg/m' i.v. Di-D3 me in the ifosfamide infusion, then 266 mg/m-bolus 4 and 8 hours after each dose of ifosfamide mitoxantrone (M) 8 mg/m- i.v.
15 minute infusion etoposide (E) 65 mg/m'/day i.v. D1-D;
1 hour infusion This cycle being repeated every ~1 aays.
3.3 Non-Hodgkin's lymphomas: Burkitt's lymphoma, small cell lymphoma, lymphoblastic lymphoma.
3.3.1 Magrath protocol - The flavonoids may be combined with the Magrath protocols according to the following schemes:
i) - cycle 1 - according to I.T. Magrath et al. (Blood 1984; 63: 1102-1111) dose route days flavonoid 200-2000 mg/m'/dayi.v. D1-DS
_or 5-50 mg/kg/day Dq-D1_ 1 h infusion cytarabine 30 mg/m- intra- Di, D=, D;, D, thecal cyclophosphamide 1200 mg/mv bolus i.v. D1 ~
methotrexate 12.5 mg/m' Intra-(max 12.5 mg) thecal methotrexate 300 mg/m'/day i.v. D,o-D,_ -1 hour infusion then 60 mg/mv/h 41 hour infusion leucovorin 15 mg/m- bolus i.v. To begin 42 (8 successive hours after doses) the start of the ad-ministration of methotrexate ii) - cycles 2 to 15 - according to I.T. Magrath et al. (1984) as well:
dose route days flavonoid 200-2000 mg/m'/ i.v.
day Dio-Dil _or 5-50 mg/kg/
day 1 h infusion cytarabine 45 mg/m2 Intra- D1,D
thecal (cycles 2 and 3) (cycles 4 and 6) cyclophosphamide 1200 mg/m- bolusi.v. Di (C) doxorubicin 40 mg/m' bolus i.v.
vincristine 1.4 mg/m' bolus i.v. D, (max 2 mg) methotrexate 12 . 5 mg/m' Intra- D;, Dlo (max 12.5 mg) thecal (cycles 2 and 3) Dio (cycles 4,5,6) methotrexate 300 mg/mv i .
v.
I, Dic.
Dm l.hour infusion ~ (cycles 2 and then D-,4, Dls 60 mg/mv ~ (cycles 7-15) 41 hour continuous infusion leucovorin 15 mg/mv bolus j i.v. To begin at the qid ~ 42nd hour of the (8 consecutive treatment with doses) ~ methotrexate the therapy comprising 14 cycles, at a rate of one cycle every 28 days.
3.4 Waldenstrom macroglobulinaemia 3.4.1 CVP protocol according to the CVP protocol described by M.A. Dimopoulous et al. (Blood 1994; 83: 1452-1459) and C.S. Portlock et al. (Blood 1976; 47: 747-756):
15 - according to I.T. Magrath et al. (1984) as well:
dose route days flavonoid 200-2000 mg/m'/dayi.v. D1-DS
_or 5-50 mg/kg/day 1 h infusion cyclophosphamide (C) 300-400 mg/m'/day oral D1-DS
vincristine (V) 1.4 mg/mv/day bolusi.v. D
(max: 2 mg) (P) 100 mg./m'/day oral D,-DS
prednisone -the therapy being continued indefinitely (1 cycle every 21 days).
3.4.2 Fludarabine-CdA protocol -_ according to H.M. Kantarjian et al.. (Blood 1990; 75: 1928-1931) and M.A. Dinopoulous et al. (Ann.
Intern. Med. 1993; 118: 195-198):
dose ~ route days flavonoid 200-2000 mg/m-/dayi.v. D._-DS
_cr 5-5C mg/kg/day 1 h infusion fludarabine 25-30 mg/m' i.v. Di-DS
0.5 hour infusion or dose route days flavonoid 200-2000 mg/m'/dayi.v. Di-D~
_or 5-50 mg/kg/day 1 h infusion cladribine (CdA) 0.09 mg/mv/day ( i.v. ~ D-:-D, continuous infusion the therapy comprising 6 to 12 cycles 28 days apart in the case of fludarabine, and 2 cycles 28 days apart also, in the case of cladribine.
3.5 Multiple myeloma 3.5.1 MP protocol according to R. Alexanian et al. (JAMA 1969;
208: 1680-1685), A. Belch et al. (Br. J. Cancer 1988;
57: 94-99) and F. Mandelli et al. (N. Engl. J. med.
1990; 322: 1430-1434):
dose route days flavonoid 200-2000 mg/m'/dayi . D~-DS
_or 5-50 mg/kg/dayv.
1 h infusion melphalan (M) 0.25 mg/kg/day oral Di-D9 prednisone (P) 100 mg/day oral D;-Dq or dose _' route days flavonoid 200-2000 mg/m=/day i.v. D1-DS
_or 5-50 mg/kg/day 1 h infusion melphalan (M) 9 mg/m-'/day oral D1-D9 prednisone (P) 100 mg/day oral D;-Dq the therapy comprising at least 12 cycles, at a rate of 1 cycle every 4 to 6 weeks.
3.5.2 VAD protocol according to B. Barlogie et al. (N. Engl. J.
Med. 1984; 310: 1353-1356):
dose route days flavoroid 200-2000 mg/m-/day i.v. Di-DS
_or 5-50 mg/kg/day 1 h infusion -- vincristine (V) 0.4 mg/day i.v. D1-Da 24 hour continuous infusion doxorubicin (A) 9 mg/mv/day i.v. D~-Da 24 hour continuous infusion dexamethasone (D) 40 mg/day i.v. D1-Dq,DS-D1~, ~ D~ ~-Do 3.5.3 MP/interferon-a protocol according to 0. Osterborg et al. (Blood 1993;
81: 1428-1434):
dose route days flavonoid 200-2000 mg/m'/day i . D-y-Ds or 5-50 mg/kg/day v.
1 h infusion melphalan (M) 0.25 mg/kg/day oral prednisone (P) 2 mg/kg/day oral D1-Da interferon-alpha 7 MU/mv/day s.c. Di-D; and D=_-Das I
the therapy comprising the indefinite repetition of this cycle, at a rate of 1 cycle every 42 days.
3.5.4 VCAP or VBAP protocol according to S.E. Salmon et al. (J. Clin.
Oncol. 1983; l: 453-461):
protocol VCAP:
dose route days flavonoid 200-2000 mg/mr/day i.v. Di-DJ
or 5-50 mg/kg/day 1 h infusion vincristine (V) 1 mg/m' bolus i.v. Di (max: 1.5 mg) doxorubicin (A) 30 mg/m- bolus i.v.
prednisone (P) 60 mg/m-/day oral i-Da D
cyclophosphamide 125 mg/m- oral D1-Da (C) VBAP protocol: cyclophosphamide is replaced with carmustine (BCNU), the rest being identical:
dose route days carmustine 30 mg/mv i.v. D, 1 hour infusion _ 65 _ C. CHILDHOOD TUMOURS - Paediatric oncology i The flavonoids can also be incorr~rated into polychemotherapy protocols for treatment of paediatric tumours, in order to improve the antitumour :; effectiveness while at the same time reducing the severity of the side effects due to the action on the recruitment and mobilization of the clonogenic cells, and to the possibility of decreasing the active doses.
'r 1°/ Ewing's sarcoma/primitive neuroectodermal tumour The flavonoids can be introduced into -the VCR-Doxo-CY-Ifos-Mesna-E protocol (E.D. Bergert et al., J.
Clin. Oncol. 1990; 8: 1514-1524; W.H. Meyer et al., J.
Clin. Oncol. 1992; 10: 1737-1742):
dose route days flavonoi d 100-200 D;-D; and D~
m g/mv/day ~-D~
_ ;
or 2-50 mg/kg/day i . ar~d D~3-D9&
v. and 1 hour infusion vincristine 2 mg/m- bolus i .v. . D:, D"_;, Dy;, D~
~ (maximum dose =
2 mg) doxorubicin 30 mg/m-/day ~ i D1-D,, .
v.
in a 24 hour infusion D~,-D~5 cyclo- 2 . 2 g/m- i . D1, Da, v .
phosphamide in a 0.5 hour infusion ifosfamide 1800 mg/mr/day i.v.
in a 1 hour infusion Dr3-D6~
mesna 360 mg/m~ i.v. administered with in a 15 minute cyclophosphamide infusion, at a rate and ifosfamide of 5 doses every 3 hours etoposide 100 mg/m- i . p~~-D>6 v.
in a 1 hour infusion p5~_Df, the therapy comprises 6 to 10 of these cycles depending on the initial severity of the sarcoma and on the amplitude of the response.
2°/ Childhood acute lymphoblastic leukaemia 2.1. Induction chemotherapy (days D,_-D_3o).
The flavonoids can be added to the recommended protocols (P. S. Gaynon et al., J. Clin. Oncol., 1993, 11, 2234-2242; J. Pollen et al., J. Clin.
Oncol. 1993; 11: 2234-2242; J. Pollen et al., J.
Clin. Oncol. 1993; 11: 839-849; V.J. Land et al., J. Clin. Oncol. 1994; 12: 1939-1945):
dose - route days flavonoid 100-200 mg/m=/day Dl-Ds.
or 2-50 mg/kg/day i.v.
1 hour infusion vincristine 1. S mg/mv bolus i . D-;, D~, v. Dl~, D, (maximum dose = 2 mg) L-asparaginase 6000 IU/m- -i:m. 3 times/week for 3 weeks prednisone 60 mg/m- oral Dl to D~~
as 3 doses/day daunorubicin 25 mg/m'/day i.v. Dl, De, D15 and in a 15 minute infusion D_~
methotrexate depending on age intra- D
thecal cytarabine depending on age intra- Di thecal depending on the result of the examination of the bone marrow, entry into the ccnsolidation phase takes place on day D2~ of the treatment protocol.
2.2 Consolidation/maintenance chemotherapy The flavonoids can be introduced into the maintenance protocol (P. S. Gaynon et al., J. Clin.
Oncol. 1993; 11: 2234-2242; J. Pollen et al., J. Clin.
Oncol. 1993; 11: 839-849; V.J. Land et al., J. Clin.
Oncol. 1994; 12: 1939-1945) according to the following scheme:
-- dose route days flavonoid 100-200 mg/m-/day Dl-D5, D15-Duo and or 2-50 mg/kg/dayi.v. D54-DS~, Dloi-Dvos.
1 hour infusion Dlo~-D1,3, Dl~=-D,_=-, cyclo- 1000 mg/m' i.v. D;, D:S, Di phosphamide in a 0.5 hour infusion L- 6000 U/m- i.m. 3 times/week asparaginase between D4, and D1=
cytarabine 75 mg/m'/day i.v./s.c.a sequence of in a 15 minute days starting on infusion D_, Dq, D.yb, D=3, D,_3, D, doxorubicin 25 mg/m-/day i . v. Dq~, D_ol, Dloe in a 15 minute infusion mercapto- 60 mg/mv/day oral D~-D43,D1~3 to end of purine treatment methotrexate 20 mg/mv/day oral once/week between D;n and D,~, and between. D,a3 and the end of the treatment prednisone 40 mg/m-/day oral 5 consecutive days (divided into per month between doses/day) D_,4~ and the end of the treatment thioguanine 60 mg/mr/day oral D,=_-D~3, vincristine 1 . 5 mg/m' bolusi .v. D~,q, Dlo;, Dloe, then (maximum dose once/month between = 2 mg) D~3 and the end of the treatment methotrexate dependi ng on intra- D,~, DN, D;~, age D~~, D1=~, Dl3o thecal then once/3 months be tween D;93 and the end of the treatment i 3/ Childhood acute myeloid leukaemia The flavonoids the induction are added and to consolidation/maintenance according protocols to the :, following schemes:
.-., 5 3.1. Induction chemotherapy According to et al., J. Clin.
Y. Ravindranath Oncol. 1991; J. Clin.
9: 572-580;
M.E. Nesbit et al., -i Oncol. 1994; et al., J. Clin.
12: 127-135;
RJ Wells -;
Oncol. 1994;
12: 2367-2377:
ri v _ dose route days flavonoid 100-200 mg/mr/day ~ Dl-D~, D,~-D13 j or 2-50 mg/kg/day i.v.
1 hour infusion i cytarabine according to age infra- D_.
thecal daunorubicin 20 mg/mr/day i . v. D~-D,, D1~-Dls in a 24 hour infusior_ cytarabine 200 mg/m-/day i . v. D_,-D~, Dlo-D"
in a 24 hour infusion thioguanine 100 mg/mv/day oral Di-D~, D~_;,-D~:3 divided into 2 doses/day etoposide 100 mg/mr/day i.v. D.
-D~
D, -D
~ _ in a 24 hour infusion , ~
;
dexamethasone 6 mg/m- i.v. Dl-D~, Dl~a-D, /oral 3 divided into 3 doses/day _ this cycle being repeated from D~e.
3.2. Consolidation/maintenance chemotherapy According to Y. Ravidranath et al., J. Clin.
Oncol. 1991; 9: 572-580; M.E. Nesbit et al., J. Clin.
Oncol. 1994; 12: 127-135; R.J. Wells et al., J. Clin.
Oncol. 1994; 12: 2367-2377:
dose route days cytarabine according to age intra- Di, D-_,e, D,6 thecal flavonoid 100-200 mg/m'/day i.v. D~-DS,Da-Dl;
or 2-50 mg/kg/day D~a-D33, Ds6-Dsl 1 hour infusion DF~-Dq~
cytarabine 3000 mg/m' i . v. Dl-D
in a 3 hour infusion and D6-D9 every 12 hours 1-asparaginase 6000 IU/m- i.m. D=, D
3 hours after the cytarabine Vincristine 1.5/m' bolus i.v. D
(maximum dose = 2 mg) -Thioguanine 75 mg/m-/day oral D,~-DH~
Cytarabine 75 mg/mv/day bolus i.v. D_s-D~1,D~~-DSQ
Cyclo- 75 mg/mv/day i.v. D_F-D
phosphamide in a 0.5 hour infusion Cytarabine 25 mg/m-/day bolus sc/i.v. Dq4-D~3 Thioguanine 50 mg/mv/day oral ~~4-D43 Etoposide 100 mg/mv/day i.v. Des, Dq_ in a 1 hour infusion Dexamethasone 2 mg/mr/day cral D;4-Dq Daunorubicin 30 mg/m- ~.v. D"_~_, in a 15 minute infusion 4°/ Childhood Hodgkin's disease The flavonoids can be added to the MOPP-ABVD
protocol according to EA Gehan et al. (Cancer 1990; 65:
1429-1437), SP Hunger et al. (J. Clin. Oncol. 1994; 12:
2160-2166) and MM Hudson et al. (.J. Clin. Oncol. 1993;
11: 100-108):
dose days route flavonoid 100-200 i.v. Dl-Ds mg/m'/day or and 2-50 D~-D:
mg/kg/day hour infusion mechlorethamine (M) i Dl, Do 6 .
mg/m' v.
bolus vincristine (0) 1.5 i.v. Dl,D~
mg/m' bolus (maximum mg) rocarbazine (P) 100 oral D;-Dla mg/m-/day p prednisone (P) 40 oral D;-Dla mg/m'/day (divided into doses/d) doxorubicin (A) 25 i.v. D~9,D_q3 mg/m-/day in a minute infusion (B) bleomyci 10 i.v. D~o,Da3 U/m-ri in a minute infusion (V) 6 i.v. D~4,Da;
vinblastin mg/m-bolus e (maximum mg) dicarbazine (D) 375 mg/m' i.v. D=4,Da3 in a 15 minute infusion This cycle should be repeated times, at a rate of 1 cycle every weeks, the therapy comprising cycles.
If an autologous bone marrow transplant (autograft) is prescribed, the CVB protocol described by R. Chopra et al. (Blood 1993; 81: 1137-1145), C. Wheeler et al. (J.
Clin. 0ncol. 1990; 8: 648-656) and R.J Jones et al. (J.
Clin. Oncol. 1990; 8: 527-537) may be used according to the following scheme (the allograft taking place on day Do) ' dose routedays flavonoid 100-200 mg/m-/day or 2-50 mg/kg/day i.v.
1 hour infusion cyclophosphamide 1800 mg/m'/day i.v. D_,,D_E
in 2 1 hour infus ions D-~ ~
D-a carmustine (BCNU) 112 mg/mr/day i.v. D_-,,D-G
in a 0 . 5 hour infusion D-s~ D-a 500 mg/m-/day i.v. D-,,D-d I
etoposide , 2 1 hour infusions ~ ~ D-=~
i D-a n 5°/ Childhood lymphoblasic lymphoma The flavonoids may also be combined with induction chemotherapy (A. T. Meadows et al., J. Clin. Oncol.
1989: 7: 92-99 - C. Patte et al., Med. Ped. Oncol.
1992; 20: 105-113 and A. Reiter et al., J. Clin. Oncol.
1995; 13: 359-372) and maintenance chemotherapy protocols:
5.1 Induction chemotherapy dose route days flavonoid 100-200 mg/mr/day i.v. Dl-D;, 50 mg/kg/day - D;,-D,=, or 2- D=~-D~9 - -1 hour infusion cyclo- 1200 mg/m' i.v. D1 phosphamide in a 0.5 hour infusion cytarabine according to age ~ intra- D1 thecal vincristine 1 . 5 mg/m' bolus ~ i.v. D, D;o, D1,, D~.
' (maximum 2 mg) prednisone 60 mg/m-/day oral D;-D=~
divided into 3 doses/day daunorubicin 60 mg/mr i.v. D~, in a 15 minute infusion L-asparaginase 6000 U/m-/day im D1,-D
in a 15 minute infusion 3 times/week Methotrexat e accordi ng to age intra- D,~, D_;, thecal 5.2 Maintenance chemotherapy according to the following scheme:
dose route days ', Flavonoid 100-200 mg/m'/day i.v. Dl-Ds,DlS-Duo i D or 2-50 mg/kg/day =9-D3a 1 hour infusion Cyclophosphamide 1000 mg/m' i.v.
in a 0.5 hour infusion Vincristine 1. 5 mg/m-' bolus oral Dl, Ds.
(maximum 2 mg) (of cycles to 10) Methotrexate 300 mg/mv/day i.v.
(60% in a 15 minute :a infusion and 40o in a 4 hour infusion) a Leucovorin 10 mg/m'/every oral p,s 4 h Daunorubicin 30 mg/mr i.v.
in a 0.5 hour ! infusion Methotrexate according to age intro- Di, De, D.s y thecal (cycle 1) then once/month i ! (cycles 2 i to 10) the therapy comprising 10 cycles 6°/ Paediatric neuroblastoma The recommended Doxo-E-Cy-Pt polychemotherapy protocol is adapted from R.P. Castleberry et al. (J.
Clin. Oncol. 1992; 10: 1299-1304), A. Garaventa et al.
(J. Clin. Gncol. 1993; 11: 1770-1779) and D.C. West et al. (J. Clin. Oncol. 1992; 11: 84-9C):
dose route days flavonoid 100-200 mg/m-'/day i.v. Dl-Ds.
or 2-50 mg/kg/day D~e-D3s~
1 hour infusion D5a-DES
doxorubici n 25 mg/m'/day i.v. D~_,D3o,Dsa in a 15 minute infusion etoposide 100 mg/mz oral/ D=, D4, D3o, D33, in a 1 hour infusion naso- Dsa. Ds;
gastric cyclophos- 1000 mg/m' i , v. D;, Dy, D3i, D,=, phamid e in a 0 . 5 hour Dsa. Dso infusion cisplatin 60 mg/m2 i.v. Dl, DAB, Ds6 in a 6 hour infusion The evaluation of the therapeutic response is carried out after 9 weeks in order to decide upon the approach: surgical resection, radiotherapy or new chemotherapy.
7°/ Paediatric osteosarcoma The flavonoids can be added to the Doxo-Pt-Mtx-Lcv protocol as is described by M. Hudson et a1. (J.
Clin. Oncol. 1990; 8: 1988-1997), PA Meyers (J.
Clin. Oncol. 1992; 10: 5-15), and V.H.C. Bramwell et al., (J. Clin. Oncol. 1992; 10: 1579-1591):
dose route days flavonoid 100-200 mg/m'/day i.v. Dl-D;,D~1-D_~s, or 2-50 mg/kg/day D~e-D~3 - 1 hour infusion doxcrubicin 25 mg/m'/day i.v. Dl_D
in a 24 hour infusion cisplatin 120 mg/m- i,v, D, in a 6 hour infusion methotrexate 12 mg/m'/day i . v. D_,1, D=a in a 1 hour infusion leucovorin 100 mg/m' oral D
every 6 hours 8°/ Childhood rhabdomyosarcoma The Vcr-Dact-CY-Mesna protocol (H. Maurer et al., Cancer 1993; 71 : 1904-1922 and LR Mandell et al . , Oncology 1993 7~ 71-83) can 1 d lnc a a the i.v.
infusion of the flavonoids according to the following scheme:
i i dose route days flavonoid 100-200 mg/m-/day i.v. D~_DS,DB_Dl~~
or 2-50 mg/kg/day ~ D_=-D~;
D
-D
, 1 hour infusion , a;
~
vincristine 1.5 mg/m'/day _ i D,, Da, D,s, .v. D~=
, bolus maximum 2 mg D~9, D3s~
Dq3.
Dso. Ds~
dactinomycin 0.015 mg/kg bolus i.v. Di-Ds.
i (max daily dose: 0. D_~_~-D_~,, 5 mg) Dq3-D4, cyclo- 2.2 mg/m' i.v. D;, D=_, phosphamide in a 1 hour infusion mesna 360 mg/m- i.v. D1, D==.
i n a 1 hour infusion every 3 hours for 5 doses At the end of the 9th week of treatment, the effectiveness should be evaluated to decide upon the subsequent measures (surgery, radiotherapy, continuation of the chemotherapy).
9°/ Wilms' tumour in children In the Vcr-Dact protocol as is described by GJ D'Angio et al. (Cancer, 1989; 64: 349-360) and DM Green et al. (J. Clin. Oncol. 1993; 11: 91-95):
dose route days flavonoid 100-200 mg/m-/day i . v. DI-Ds, Da-Di., or 2-50 mg/kg/day then each week 1 hour infusion vincristine 2 mg/m- bolus i.v.
(max dose: 2 mg) then each week dactinomycin 0.045 mg/kg bolus i.v. D
then e 1, very (P S 30 kg) 3 weeks 1.35 mg/m' (P>30 kg) (max dose: 3 mg) :i _ ~5 _ This protocol being started after surgical I resection.
In the event of autologous bone marrow transplant (autograft) according to A. Garaventar et al.
(Med. Pediatr. Oncol. 1994; 22: 11-14), the E-Thio-Cy protocol may be modified as follows:
_, dose -. route days flavonoid 100-200 mg/mv/day i.v. D_~-D_i or 2-50 mg/kg/day 1 hour infusion etoposide 1800 mg/m~ i.v.
24 hour infusion thiotepa 300 mg/m'/day i.v. D_7,D_E,D_5 i in a 2 hour infusion cyclophosphamide 50 mg/kg/day i.v. D_9, D_;, D__~, ~ D_1 in a 1 hour infusion the bone mar row transplant taking e on Do.
plac
Claims (10)
1. Composition which has activity on the proliferation of clonogenic cells in tumours and which comprises a therapeutically effective amount of a flavonoid, naringenin being excluded.
2. Composition which has activity on the proliferation of clonogenic cells in tumours and which comprises a therapeutically effective amount of a compound chosen from the compounds of formula:
this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkoxy group and an -OCOR7 group, R7 being a C1-C4 alkyl group, at least one of the substituents R1, R2, R3 or R4 being other than H, and R2 and R3 possibly forming together a methylenedioxy group, - R5 is chosen from H, OH, a C1-C4 alkoxy group and an O-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups chosen from H, OH and a C1-C4 alkoxy group, - and designates either a double bond or a single bond, naringenin being excluded.
this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkoxy group and an -OCOR7 group, R7 being a C1-C4 alkyl group, at least one of the substituents R1, R2, R3 or R4 being other than H, and R2 and R3 possibly forming together a methylenedioxy group, - R5 is chosen from H, OH, a C1-C4 alkoxy group and an O-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups chosen from H, OH and a C1-C4 alkoxy group, - and designates either a double bond or a single bond, naringenin being excluded.
3. Composition according to Claim 2, in which the flavonoid is a flavone.
4. Composition according to Claim 1, in which the flavonoid is quercetin.
5. Use of a flavonoid, naringenin being excluded, for manufacturing a medicine intended to interfere with the generation of clonogenic cells in tumours during treatment of these tumours with at least one cytotoxic agent.
6. Use of a compound chosen from the compounds of formula this being a formula in which:
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkoxy group and an -OCOR7 group, R7 being a C1-C4 alkyl group, at least one of the substituents R1, R2, R3 or R4 being other than H, and R2 and R3 possibly forming together a methylenedioxy group, - R5 is chosen from H, OH, a C1-C4 alkoxy group and an O-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups chosen from H, OH and a C1-C4 alkoxy group, - and designates either a double bond or a single bond, naringenin being excluded, for manufacturing a medicine intended to interfere with the generation of clonogenic cells in tumours during treatment of these tumours with at least one cytotoxic agent
- R1, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkoxy group and an -OCOR7 group, R7 being a C1-C4 alkyl group, at least one of the substituents R1, R2, R3 or R4 being other than H, and R2 and R3 possibly forming together a methylenedioxy group, - R5 is chosen from H, OH, a C1-C4 alkoxy group and an O-glycosyl group, - R6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group substituted 1 to 3 times with groups chosen from H, OH and a C1-C4 alkoxy group, - and designates either a double bond or a single bond, naringenin being excluded, for manufacturing a medicine intended to interfere with the generation of clonogenic cells in tumours during treatment of these tumours with at least one cytotoxic agent
7. Use according to Claim 6, in which the flavonoid is a flavone.
8. Use according to Claim 5, in which the compound of formula I is quercetin.
9. Method for chemotherapeutic treatment of a tumour, in a patient, with at least one cytotoxic agent, which comprises the administration, during the treatment with the cytotoxic agent, of a therapeutically effective amount of a flavonoid, naringenin being excluded.
10. Method according to Claim 9, in which the flavonoid is administered at the start of the chemotherapeutic treatment and at the start of each cycle of chemotherapeutic treatment.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR98/09058 | 1998-07-15 | ||
| FR9809058A FR2781153B1 (en) | 1998-07-15 | 1998-07-15 | FLAVONOID-BASED THERAPEUTIC COMPOSITION FOR USE IN THE TREATMENT OF TUMORS WITH CYTOTOXIC AGENTS |
| PCT/FR1999/001714 WO2000003706A1 (en) | 1998-07-15 | 1999-07-13 | Therapeutic composition based on flavonoids for use in the treatment of tumours with cytotoxic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2337179A1 true CA2337179A1 (en) | 2000-01-27 |
Family
ID=9528648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002337179A Abandoned CA2337179A1 (en) | 1998-07-15 | 1999-07-13 | Therapeutic composition based on flavonoids, intended to be used in the treatment of tomours by cytotoxic |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP1096930A1 (en) |
| JP (1) | JP2002520356A (en) |
| KR (1) | KR20020003349A (en) |
| CN (1) | CN1139384C (en) |
| AU (1) | AU4789099A (en) |
| BR (1) | BR9912816A (en) |
| CA (1) | CA2337179A1 (en) |
| EA (1) | EA200100140A1 (en) |
| FR (1) | FR2781153B1 (en) |
| IL (1) | IL140588A0 (en) |
| WO (1) | WO2000003706A1 (en) |
| ZA (1) | ZA200100239B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170027900A1 (en) * | 2015-07-29 | 2017-02-02 | Macau University Of Science And Technology | Use of tangeretin in cancer treatment |
| US20170027901A1 (en) * | 2015-07-29 | 2017-02-02 | Macau University Of Science And Technology | Use of nobiletin in cancer treatment |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002069949A2 (en) * | 2001-03-06 | 2002-09-12 | Prendergast Patrick T | Combination therapy for reduction of toxycity of chemotherapeutic agents |
| EP1808172A3 (en) * | 2002-03-06 | 2010-05-26 | Activephyto Technologies Limited | Botanical extract compositions and methods of use |
| AU2003217982A1 (en) * | 2002-03-06 | 2003-09-22 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising wogonin, isoliquiritigenin and/or coumestrol |
| US20030229136A1 (en) | 2002-04-18 | 2003-12-11 | Nurulain Zaveri | Novel flavanoids as chemotherapeutic, chemopreventive, and antiangiogenic agents |
| CN1679539A (en) * | 2005-01-20 | 2005-10-12 | 吴一心 | Synergic medicinal composition for preventing from tumor |
| CA2600797A1 (en) * | 2005-03-11 | 2006-09-21 | The Regents Of The University Of Michigan | Chromen-4-one inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
| GB0808974D0 (en) * | 2008-05-16 | 2008-06-25 | Veritron Ltd | Plant extract and its therapeutic use |
| JP6775226B2 (en) * | 2016-06-30 | 2020-10-28 | 国立大学法人広島大学 | Anti-cancer drug action enhancer and anti-cancer drug kit equipped with it |
| CN106562954A (en) * | 2016-11-11 | 2017-04-19 | 黄冈师范学院 | Application of (demethylated) polymethoxylated flavones and paclitaxel drugs in preparation of drugs for treating non-small cell lung cancer |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0617304B2 (en) * | 1982-09-09 | 1994-03-09 | 理化学研究所 | Anti-cancer drug |
| JPS5959627A (en) * | 1982-09-27 | 1984-04-05 | Tatsuo Miyoshi | Carcinostatic agent |
| JPS60199817A (en) * | 1984-03-23 | 1985-10-09 | Rikagaku Kenkyusho | Carcinostatic agent |
| JPS632925A (en) * | 1986-06-23 | 1988-01-07 | Nippon Kayaku Co Ltd | C-kinase inhibitor and anti-tumor agent |
| FR2633182B1 (en) * | 1988-06-23 | 1993-07-23 | Beljanski Mirko | ANTI-CANCER PHARMACEUTICAL COMPOSITION AND METHOD OF USING THE INVENTION |
| JPH04103532A (en) * | 1990-08-24 | 1992-04-06 | Tatsuo Miyoshi | Carcinostatic agent |
| JPH04103529A (en) * | 1990-08-24 | 1992-04-06 | Tatsuo Miyoshi | Carcinostatic agent |
| JP2514500B2 (en) * | 1991-09-14 | 1996-07-10 | 呉羽化学工業株式会社 | Multidrug resistance inhibitor and expression inhibitor |
| EP0642793A4 (en) * | 1992-05-11 | 1995-03-29 | Tsumura & Co. | Apoptosis inducer. |
| WO1996031206A2 (en) * | 1995-04-07 | 1996-10-10 | Warner-Lambert Company | Flavones and coumarins as agents for the treatment of atherosclerosis |
| DE29719198U1 (en) * | 1997-10-29 | 1998-04-23 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke, 14558 Bergholz-Rehbrücke | Flavono / flavonoid preparation |
-
1998
- 1998-07-15 FR FR9809058A patent/FR2781153B1/en not_active Expired - Fee Related
-
1999
- 1999-07-13 KR KR1020017000478A patent/KR20020003349A/en not_active Application Discontinuation
- 1999-07-13 AU AU47890/99A patent/AU4789099A/en not_active Abandoned
- 1999-07-13 CA CA002337179A patent/CA2337179A1/en not_active Abandoned
- 1999-07-13 JP JP2000559841A patent/JP2002520356A/en active Pending
- 1999-07-13 BR BR9912816-0A patent/BR9912816A/en not_active IP Right Cessation
- 1999-07-13 EA EA200100140A patent/EA200100140A1/en unknown
- 1999-07-13 EP EP99931342A patent/EP1096930A1/en not_active Withdrawn
- 1999-07-13 WO PCT/FR1999/001714 patent/WO2000003706A1/en not_active Application Discontinuation
- 1999-07-13 CN CNB998098353A patent/CN1139384C/en not_active Expired - Fee Related
- 1999-07-13 IL IL14058899A patent/IL140588A0/en unknown
-
2001
- 2001-01-09 ZA ZA200100239A patent/ZA200100239B/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170027900A1 (en) * | 2015-07-29 | 2017-02-02 | Macau University Of Science And Technology | Use of tangeretin in cancer treatment |
| US20170027901A1 (en) * | 2015-07-29 | 2017-02-02 | Macau University Of Science And Technology | Use of nobiletin in cancer treatment |
| US9808439B2 (en) * | 2015-07-29 | 2017-11-07 | Macau University Of Science And Technology | Use of tangeretin in cancer treatment |
| US9808477B2 (en) * | 2015-07-29 | 2017-11-07 | Macau University Of Science And Technology | Use of nobiletin in cancer treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| AU4789099A (en) | 2000-02-07 |
| JP2002520356A (en) | 2002-07-09 |
| CN1139384C (en) | 2004-02-25 |
| EA200100140A1 (en) | 2001-06-25 |
| FR2781153B1 (en) | 2001-08-03 |
| ZA200100239B (en) | 2002-01-09 |
| IL140588A0 (en) | 2002-02-10 |
| KR20020003349A (en) | 2002-01-12 |
| CN1313765A (en) | 2001-09-19 |
| WO2000003706A1 (en) | 2000-01-27 |
| EP1096930A1 (en) | 2001-05-09 |
| BR9912816A (en) | 2001-05-08 |
| FR2781153A1 (en) | 2000-01-21 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |