MXPA01000387A - Therapeutic composition based on flavonoids for use in the treatment of tumours with cytotoxic agents - Google Patents

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

THERAPEUTIC COMPOSITIONS BASED ON FLAVONOIDS, INTENDED FOR USE IN THE TREATMENT OF TUMORS THROUGH AGENTS CYTOTOXS.

The present invention relates to the use of compounds of the flavonoid type, in the treatment of cancers, by cytotoxic agents.

A cancer is a disorder of the somatic genes, in the course of which, the genetic dysfunctions worsen when the tumor progresses from the state of precancerous lesion to that of malignant transformation, the cancerous tumor becomes metastatic and frequently resistant to cytotoxic medicines.

Despite very considerable efforts directed in all developed countries, particularly through clinical and experimental research programs, the mortality due to various cancers (solid tumors and hematological neoplasms) remains unacceptably high. In many countries, cancer is the second place, only after cardiovascular diseases, as a cause of mortality.

No. Ref.: 126341 In terms of cancers recently diagnosed, the distribution between solid tumors and hematological neoplasms (of the bone marrow, blood, lymphatic system) shows that 9 cancers out of 10 are solid tumors. Unlike what is observed in the hematological oncology, (therapeutic success of 40 to 90% of cancers of blood cells), only a small number of advanced or disseminated solid tumors respond to chemotherapy alone. It is partly for this reason that total mortality due to cancer increased in the USA. between 1973 and 1992.

It is untrue, unfortunately, that this trend can only be reversed by the appearance, together with the establishment of a chemotherapeutic arsenal, of new anti-tumor drugs, such as taxanes (paclitaxol and docetaxol), which interfere with the formation of microtubules (WP McGuire et al., Am. Intern, Med., 1989), topoisomerase I inhibitors derived from camptothecin (topotecan and irinotecan), vinorelbine (new alkaloid derived from periwinkle vinca), gemcitabine (new cytotoxic anti-metabolic agent), raltitrexed (inhibitor of thymidylate cystetase) or miltefosine (first representative of the alkylphosphocholine family). These treatments are added, any, as a first choice or as a second choice, to medicines for which, the specific activity is not well recognized at this time, such as doxorubicin, cisplatin, vincristine, methotrexate, and 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 the established cytotoxic substances. More commonly, this situation results from the existence of multi-resistance genes or the frequency of genetic mutations in certain types of tumors. Thus, the treatment of cancers requires new approaches, which are complementary to those currently implemented, and which are intended to combat more successfully the extension and heterogeneity of tumor burden, and the acquisition of resistance to "multi-toxic drugs". .

Among these new approaches, some are already promising. This is the case of the induction of apoptosis, and the inhibition of tumor angiogenesis and metastatic processes, not to mention gene therapy or immunotherapy.

The inventors were interested in a different approach. The objective was to make the population of tumor cells, more sensitive to anticancer treatments of reference, to achieve a double benefit: 1) increase cytotoxic activity and therefore effectiveness, and 2) decrease the frequency and severity of certain side effects, due to the reduction in dosage that could follow the induction of the increase in antitumor effectiveness.

It is this strategy, which is behind the discovery of an original mechanism caused by substances - that have a weak antitumor power, or are lacking this power - but that are capable of inducing a very significant increase in the cytotoxic activity of medicines anticancer drugs tested. This original mechanism arises from the possibility that these substances, any, stimulate the re-establishment of the clonogenic cells within the tumor, make them more sensitive to conventional treatment with cytotoxic agents, or inhibit the proliferation of clonogenic cells, thus contributing to the regression of the tumor.

An objective of the present invention is, the use in the treatment of cancers, with at least one antitumor agent selected from the cytotoxic agents, of a compound having activity on the proliferation of clonogenic cells, chosen from the flavonoids and in in particular the compounds of the formula: this, which is a formula in which: ~ Ri / R? R3 and R4 are chosen, independently from one another from, H, OH, a C? -C alkoxy group and a group -OCOR7, R7 which is an alkyl group of C? -C4, at least one of the substituents Ri, R2, R3 or R4 which is different from H, and R2 and R3 possibly forming together a methylenedioxy group, - R5 is selected from H, OH, a C? ~C alkoxy group and an O-glycosyl group, - R6 is selected from a cyclohexyl group, a phenyl group and a substituted phenyl group 1 to 3 times with group selected from H, OH and a C 1 -C 4 alkoxy group, and designates, any, a double bond or a single bond.

The cytotoxic agents can be used in their conventional doses, and in this case, their effectiveness is improved or at lower doses they give an increase in their antitumor effectiveness.

An object 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 proliferation and restoration, or by inhibiting proliferation, which comprises a therapeutically effective amount of a flavonoid and in particular of a compound of formula I, chosen from the compounds of the formula: (I) this, which is a formula in which: -Ri, R2, R3 and R4 are chosen, independently of one another from, H, OH, an alkoxy group of C? -C4 and a group -OCOR- ?,? R7 which is an alkyl group of C? ~ C4, at least one of the substituents Ri, R2 R3 or R4, which is different from H, and R2 and R3 possibly forming together a methylenedioxy group, -R5 is chosen from H, OH, an alkoxy group of C? ~ C4 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 an alkoxy group of C? ~ C4, - and designates any, a double bond or a single bond.

An objective of the present invention is also the use of a flavonoid and in particular of a compound of the formula I as defined above, for the manufacture of a medicine intended to interfere (by induction or inhibition), with the generation of clonogenic cells in tumors, during treatment with at least one cytotoxic agent.

In the chemotherapeutic treatment of the cancers, the cytotoxic agents, flavonoids, and in particular the compounds of formula I, can be administered at the start of the chemotherapeutic treatment, any, in the taking of a single dose or for several days at the beginning of these treatments. (for example, for 5 to 7 days) and, depending on the chemotherapeutic protocol, at the beginning of each treatment cycle (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) in doses of 5 to 50 mg / kg / day or 200 to 2000 mg / m2 / day.

To obtain a maximum effect on the production of clonogenic cells, the flavonoids should be administered so that the tissue concentrations obtained are as high as possible conceivable concentrations.

For the treatment protocols in the acute phases of the therapies, the intravenous route is favored using: -supplement infusions ready to be used (bags, bottles, etc.) intended to be administered without modification by intravenous infusion, using an infusion line and according to the recommended flow rate: -liofilized, to be resuspended for intravenous infusion, using pharmaceutical solutes known to those skilled in the art; -for maintenance treatments, it is also possible to conceive the oral route when treatment by chemotherapy favors the oral administration of cytostatic agents. For this purpose, oral lyophilisates (for oral or perlingual absorption), immediate or delayed release tablets, oral solutions, suspensions, granules, capsules, etc. can 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: - cuercetin, - 4-hydroxyflavone, - ß-hydroxyflavone, - 7-hydroxyflavone, -5-methoxyflavone, -6-methoxyflavone, -7-methoxyflavone, -2-cyclohexyl -5-hydroxychromone, 2-cyclohexyl-β-hydroxychromone, 2-cyclohexyl-7-hydroxychromone, ogonin or 5,7-dihydroxy-8-methoxyflavone, - acacetin or 5,7-dihydroxy-1-methoxyflavone, - pedalitin or 5, ß, 3 ',' -tetrahydroxy-7-methoxyflavone, - apigenin or 5, 7, 4 '-trihydroxyflavone, - luteolin or 5, 7, 3', 4'-tetrahydroxyflavone, - baicaleine or 5,6,7-trihydroxyflavone, - escuterarein or 5, β, 7, 4 '- tetrahydroxyflavone, - fisetin or 7, 3 ',' -trihydroxyflavonol, - robinetine or 7, 3 ', 4', 5 '- tetrahydroxyflavonol, - caempferol or 5, 7, 4' - trihydroxyflavonol, -, - caempferide 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: - aromadendrine or 5, 7, 4 '-trihydroxiflavanolol, -fustine or 7, 3', 4 '-trihydroxiflavanolol, -hydroxyirobinetine or 7, 3', 4 ', 5' -tetrahydroxiflavanolol, - taxifolin or 5, 7, 3 ', 4' - trihydroxyiflavonolol, 3) flavanones such as: - naringenin or 5, 6, 4 '- trihydroxyflavonone, - 7, 4' - dihydroxyflavonone - eriodictyol or 5, 7, 3 ', '-tetrahydroxyflavonone, - hesperetin or 5, 7, 3' -trihydroxyflavonone.

Flavones are the preferred compounds.

The cytotoxic agents can be chosen from: i) intercalating agents, in particular daunorubicin, epirubin, idarubicin, zorubicin, aclarubicin, pirarubicin, acridine, mitoxantrone, actinomycin D, eptilinium acetate; (ii) to alkylating agents chosen from platinum derivatives (cisplatin, carboplatin, oxaliplatin); (iii) a compound chosen from the different groups of alkylating agents: cyclophosphamide, ifosfamide, chlormethrin, melphalan, chlorambucil, estramustine, busulfan, mitomycin C, nitrosoureas: BCNU (carmustine), CCNU (lomustine), fotemustine, streptozotocin, triazines or derivatives: procarbazine, decarbazine pipobroman, - ethylene imines: altretamine, triethylene-thiophosphoramide, _ ^^^ ii _ ^^ Éfc_ ^ Éi ^ __ iv) a compound chosen from the different groups of antimetabolic agents: - antifolates: methotrexate, raltitrexed, - antipyrimidines: 5-fluorouracil (5-FU), cytarabine (Ara- C), - hydroxyurea, antipurins: purinetol, thioguanine, pentostatin, cladribine - inducers of the synthesis of the cytotoxic nucleoside: gemcitabine, v) a compound selected from the different groups of agents with affinity for tubulin: - vinca-alkaloids which disorganize the mitotic axis: vincristine, vinblastine, vindesine, navelbine - agents that block the depolymerization of the mitotic axis: paclitaxol, docetaxol agents that induce the break in the DNA by the inhibition of topoisomerase II: etoposide, teniposide topoisomerase inhibitors I that induce the unfolding of DNA: totpotecan, irinotecan, vi) a disintegrating agent, which fragments DNA, such as bleomycin, vii) one of the following compounds; plicamycin, L asparaginase, mitoguazone, descarbazine, viii) a progestative anticancer spheroid: medroxyprogesterone, megestrol, ix) an oestrogenic anticancer spheroid: diethylstilbestrol, tetrasodium fosfestrol, x) an anti-estrogen: tamixofen, droloxifen, raloxifen, aminoglutethimide, xi) an anti steroidal androgen (ex cyproterone) or a non-steroidal anti-androgen (flutamide, nilutamide).

In particular, the compounds of formula I can be combined with all treatments with the main cytotoxic agents used in polychemotherapies for solid tumors, such as: alkylating agents: oxazoforins (cyclophosphamide, ifosfamide, chlorambucil, melphalan) - nitroureas - mitomycin C antimetabolites , such as, methotrexate, 5-FU, Ara-C, capacitabine - agents that interfere with tubulin: vinca alkaloids (vincristine, vinblastine, vindesine, navelbine), taxoids (paclitaxol, docetaxol), epipodophyllotoxin derivatives (etoposide, teniposide) - bleomycin - inhibitors of topoisomerase I; topotecan, irinotecan.

Similarly, the compounds of the formula I can be combined with treatments with the main cytotoxic agents used in oncohematology for the treatment of blood cancers: Hodgkin's disease: cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin; - Acute leukemias: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase; - malignant non-Hodgkin lymphomas: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristira, etoposide, doxorubicin, daunorubicin, carmustine, lomustine, cisplatin; - chronic lymphoid leukemias: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.

The results of the pharmacological tests demonstrating the properties of the compounds of the formula (I) used alone or in combination with the cytotoxic agents will be given hereinafter.

BÍa | ij ^ | W, 1- Interaction (stimulation or inhibition of proliferation) with the generation of clonogenic cells (clonogenic assay) The test 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 ability to proliferate and to give rise to a cell colony. The cell clusters of human tumors are the cells behind the neoplastic cells, which constitute a given tumor. These tumor cell clusters are responsible for the recurrence processes, which can be observed after a surgical recession of primary tumors, and are also responsible for the formation of metastases. In a tumor or a cell line of a tumor, these clones of clonogenic cells differ from the other cells of the tumor or of the neoplastic cell line under consideration, in the fact that they retain their ability to proliferate in the absence of any solid support.

In this assay, the tumor cells are grown on a semi-solid support consisting of agar. Only cells that do not require a solid support for their growth (i.e., highly tumorigenic cells called "anchorage-independent cells" by MI Dawson et al., Cancer Res. 1995; 55: 4446-4451; also called clonogenic cells with respect to to "clonal growth") are able to develop in such agar-based support. Specifically, normal cells - which grow in an "adherent mode" ("anchorage-dependent" cells according to the terminology of M.I. Dawson) - such as, for example, fibroblasts do not survive on such a medium. Within a population of tumor cells, grown on such a support, are these clonogenic cells (associated with an unlimited number of cell divisions, and the proliferation of which, was called "growth [clonic] independent of anchorage" by MI Dawson), those that are capable of growing. The percentage of these clonogenic cells within a tumor or a cell line varies between 0.1% and 0.001%. non-clonogenic cells (associated with a limited number of cell divisions) are not developed in this assay, since they require a solid support for their growth, which must take place in an "adherent mode" ("adherent growth" dependent on the anchoring ", according to MI Dawson et al., Cancer Res. 1995; 55: 4446-51.

The influence of the compounds of formula (I) on the growth of the cell colonies obtained by culture was measured on the culture medium known as "soft agar", for example, the mammary cell lines MCF7 and MXT, and the colorectal line HT -29. On such a medium, only clonogenic cells called by M.I. survive and develop. Dawson, "cells (clonic) independent of the anchorage". The growth of these cells in such a "non-adherent" manner indicates their degree of tumorigenecity. The inhibition of the growth of the size of a tumor in which a larger number of clonogenic cells has developed then becomes the sign of enhanced cytotoxic activity.

Conversely, this assay can also reveal that a compound is capable of inhibiting the generation / proliferation of clonogenic cells, which makes the tumor less capable of developing, and therefore decreases the population of tumor cells.

The tumor cell lines studied are kept in culture in 25 cm2 falcon dishes. They are then synthesized, and the cells dissociate well from each other. The percentage of living cells is determined after dyeing with trypan blue. A suspension of cells at the concentration of 5 × 10 4 at 15 × 10 4 cells / mL (depending on the type of cells under consorption) is prepared in a 0.3% agar solution. Next, 200 μl of this suspension is seeded in petri dishes of 35 mm diameter, inside which 3 mL of a base layer consisting of a 0.5% agar solution is placed. The 200 μl of cell suspension is covered with 1.8 mL of an upper layer consisting of a 0.3% agar solution. The plates are then placed in a 37 ° C incubator, 5% C02 and 70% humidity, until treatment. The latter is carried out approximately 1 to 2 hours after planting. The compounds to be tested are prepared at a concentration 100 times greater than the desired concentration, and 50 μl of these treating solutions are deposited on the upper agar layer of the corresponding dishes. In the present study, the final concentration of the products tested is 10"5, 10 ~ 7 and 10" 9 M. The dishes are then kept for 21 days in an incubator. On day 21, the dishes are treated by deposition on the upper layer of 100 μl of a solution of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolyl bromide) to 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 the addition of 2 mL of formalin per dish. After fixation for 24 hours, the formaldehyde is evaporated and determined using a reverse microscope, the number of stained cell colonies, and therefore consisting of cells that are metabolically active and having a surface area greater than 100mm2.

The average number of clonogenic cell clones, determined for each experimental condition studied, is expressed as a percentage with respect to the average number of clonogenic cell clones counted in the control condition and considered equal to 100%. These values, expressed as a percentage with respect to the control condition, are given in Table I, for the corcetin.

TABLE I - The results given in this table represent the average values ± the standard error of the average (SEM) established on at least 6 domes -Control condition = 100% - (NS: p> 0.05; *: p <0.05: ** p < 0.01; **: p < 0.001).

On the three cell lines MCF7, HT-29 and MXT, the corcetin is able to partially inhibit the proliferation of the clonogenic cells within the tumor, that is, to induce a significant decrease in the number of colonies of these cells with respect to that obtained in the control condition (from 20% to 50%), and therefore contributes to making the tumors from which they are derived, more sensitive to conventional treatment with cytotoxic agents. .á ^ Mfa ^^^ u ^^ ytu-fc. 2- Cytotoxic activity on non-clonogenic cells: "MTT assay" The influence of the compounds of formula (I) on non-clonogenic cells was evaluated using the MTT colorimetric assay.

The principle of the MTT test is based on the mitochondrial reduction, by means of active metabolically active cells, of the MTT yellow product (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) in a product of blue color, formazan. The amount of formazan obtained in this way is directly proportional to the amount of living cells present in the culture well (s). The amount of formazan is measured by spectrophotometry.

The cell lines are maintained in a monolayer culture at 37 ° C in closed dishes containing basic medium MEM 25 MM HEPES (Minimum Essential Medium). This medium is suitable for the growth of a range of varied diploids or primary mammalian cells. This medium is then supplemented with: an amount of 5% FSC (fetal calf serum) decomplemented at 56 ° C for 1 hour, - with 0.6 mg / mL L-glutamine, - with 200 IU / ml penicillin, - with 200 μg / mL of streptomycin, - with 0.1 mg / mL of gentamicin.

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: CRL-1435), which is a prostate cancer.

In experimental terms: lOOμl of a cell suspension, containing 20,000 to 50,000, is seeded -kJ-tt-kMÉÉllJ (depending on the type of cell used) cells / mL of culture medium, in 96-well flat-bottomed multi-well plates, and incubated at 37 ° C under an atmosphere comprising 5% C02 and 70% humidity After 24 hours of incubation, the culture medium is replaced with 100 μl of medium, which contains any of the various compounds to be tested, at concentrations ranging from 10 ~ 5 to 10 ~ 10 M, or the solvent that is used 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 μl of a yellow solution of dissolved MTT, at a rate of 1 mg / mL, in RPMI 1640. The microplates are reincubated for 3 hours at 37 ° C, and then centrifuged for 10 minutes at 400 g. The yellowish solution of MTT is removed and the blue crystals of formazan that are formed at the cellular level, are dissolved in 100 μl of DMSO. The microplates are then stirred for 5 minutes. The intensity of the blue coloration resulting, therefore, from the transformation of the yellow MTT product to blue formazan using the cells that still live at the end of the experiment is quantified by spectrophotometry using a DYNATECH IMMUNOASSAY SYSTEM type machine, at wavelengths of 579 nm and 630 nm corresponding, respectively, to the wavelengths of maximum absorbance of formazan and ~ khgjj £ yj &? antecedent noise. The set of programs integrated within the spectrophotometer calculates the average values of the optical density, and the standard derivation (Std. Dev.) And the standard error of the values (SEM) average.

By way of example, the results of the average optical density, expressed as a percentage with respect to the optical density measured in the control condition (taken as equal to 100%), obtained - by way of non-limiting example - with a flavonoid: cuertcetin, in the 5 tumor cell lines U-373MG, T24, LoVo, MCF7 and A549, will be given in Table II.

Concentrations expressed in mol.l 1 xx ± yy = average value ± standard error of the average - Control conditions = 100% - (NS / p> 0.05; *: p <0.05; **: p <0.01; p < 0.001).

These results show that the corcetin has a weak anti-tumor power. This product, which is non-cytotoxic, induces the inhibition of the total cell proliferation of these lines only at the concentration of 10"5 M, and this inhibition does not exceed 20% In the other tested concentration only a few can be detected minor effects. 3. - Determination of the maximum tolerated dose (MTD): The evaluation of the maximum tolerated dose was carried out in B6D2Fl / Jico mice from 4 to 6 weeks of age. The compounds were administered via the intraperitoneal route in increasing doses ranging from 2.5 to 160 mg / kg. The BAT value (expressed in mg / mk) is determined based on the observation of the ratio of surviving animals during 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 BAT value is greater than 160 mg / kg ^ the BAT value is assimilated to 160 mg / kg by default.

The corcetin is associated by default with a BAT equal to 160 mg / kg. This result emphasizes that the products belonging to the flavonoid family do not have a 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 mono or polychemotherapy protocols with cytotoxic agents will be given hereafter. A. Solid tumors 1 ° / Cancers of lung 1. 1 non-small cell lung cancers (advanced state): added to the recommended protocol (T. Le Chevalier et al., J. Clin Oncol 1994, 12: 360-367) are intravenous infusions of a compound of formula I: This therapy is repeated 8 times. 1. 2 cancers of small cell lung (advanced stage): - in addition to the recommended CAV or VAC protocols (B. J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291) are the flavonoid infusions: This therapy is repeated 6 times every 21 days. '- > - * »- in addition to the recommended protocol Pt-E (B.J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291) are the flavonoid infusions: 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 ^^ B t-áj UÉlriMMriu therapy possibly involves the repetition of this 4 week cycle. • gemcitabine / cisplatin combination: The therapy includes the repetition of this cycle every 21 days. 2 ° / Chest cancers - CMF protocol as an auxiliary treatment of 0 operable breast cancer (G. Bonnadonna et al., N. Engl. J. Med., 1976; 294: 405-410): -üá-áa- ^ HUi-a-á 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 auxiliary treatment: Each cycle is repeated every 21 days, and the therapy comprises 4 cycles. -. 10 - breast cancer with metastasis - in the FAC protocol (A.U. Buzdar et al., cancer 1981; 47: 2537-2542) and its multiple adaptations, the flavonoid infusions are added according to the following scheme (not limiting): ^^ 3 * Each cycle is repeated every 3 days until a new progression of the disease is diagnosed. - in the CAF protocol (G. Falkson et al., Cancer 1985; 56: 219-224): Each cycle is repeated every 28 days until a new progression of the disease is diagnosed. - in the CMF protocol: This cycle is repeated every 3 to 5 weeks and the therapy comprises 6 cycles. - in the CMF-VP protocol: This therapy is repeated every 4 weeks - in the FEC protocol: ^^ This therapy is repeated every 3 weeks. in the MMC-VBC protocol (C. Brambilla et al., Tumori, 1989; 75: 141-144): This therapy is repeated every 28 days until a new progression of the disease is diagnosed. - in the NFL protocol (S.E. Jones et al.

J. Clin. Oncol. 1991; 9: 1736-1739): the therapy comprises two separate cycles 21 days, and then requires an evaluation.

Infusions of flavonoids can also be combined with the treatment of breast cancer with metastasis, when a taxoid is used, for example: - with paclitaxol (FA Holmes et al., J. Nati. Cancer Inst. 1991; 83: 1797-1805 ) in the treatment of forms with metastasis possibly resistant to anthracyclines: A i i t «mui a 'i i This cycle is repeated every 21 days until a new progression of the disease is diagnosed. - with docetaxol (CA Hundis et al., J. Clin. Oncol. 1996; 14: 58-65), in locally advanced or metastatic breast cancer, which is resistant or relapsing after cytotoxic chemotherapy (which includes a anthracycline), or in relapses during an auxiliary treatment: This cycle is repeated every 21 days by a two-cycle therapy, or until the onset of a progression of the disease. - in increasing dose protocols, which combine the transplantation of medullary antigen cells and cells of the peripheral blood cluster, as reinforcement for the first treatment chosen, for example: - CPB Protocol (W.P. Peters et al, J. Clin. Oncol., 1993; 11: 132-1143), in which the i.v infusion of the cell cluster takes place on the days D_ ?, Do and Di: - CTCb protocol (K. Antman et al, J. Clin Oncol 1992, 10: 102-110), in which the i.v. of the stem cells takes place in the D0: - CTM protocol (L.E. Damon et al., J. Clin Oncol 1989, 7: 560-571 and I.C. Henderson et al., J. Cellular Biochem, 1994 (Sup 18B): 95) in which the infusion i.v. of hematopoietic stem cells takes place in the Do: 3o / Gynecological cancers 3.1 Ovarian cancer: For the treatment of ovarian carcinomas, particularly metastatic ovarian carcinomas: i) PAC protocol (G. A. Omura et al, J. Clin, Oncol 1989, 7: 457-465): the flavonoid infusions are administered according to the following scheme: 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): The therapy comprises two cycles, separated by 28 days. ii) paclitaxol protocol: flavonoids can be added to the paclitaxoí protocol as described by W.P. McGuire et al., (Ann, Intern. Med. 1989; 111: 273-279): The therapy comprises two of these cycles, separated by 28 days (with evaluation at the end).

For the treatment of metastatic and resistant ovarian carcinomas, flavonoids can be added to the second selected protocol, based on topotecan: The cure comprises two cycles, separated by 21 days (with evaluation at the end) according to A. P. Kudelka et al., (J. Clin. Oncol., 1996; 14: 1552-1557). 3. 2 Trophoblastic tumors in low-risk patients, flavonoids can be combined with the protocol described by H. Takamizawa et al. (Semin. Surg. Oncol., 1987; 36-44): (MTX-DATC protocol). 3. 3 Cancers of the uterus: - the flavonoids can also be combined with the CAV protocol (or VAC) according to the diagram below: The therapy includes the repetition of this cycle every 21 days. - in the FAP protocol: The therapy includes the repetition of this cycle every 21 or 28 days. 4o / Cancers of the testicle and the prostate - flavonoids can also be combined with the protocols for testicular cancer: BEP protocol: The therapy comprises 3 cycles, at a ratio of one cycle every 21 days. 5th / Cancers of the bladder - the flavonoids can be combined with the CISCA2 protocol (also called PAC): The cycle is repeated every 3 weeks. - in the MVAC protocol (according to CN Eternberg et I., J. Urol. 1988; 139: 461-469): This cycle, repeated every 4 to 5 weeks, for a minimum of 2 cycles. 6o / Nasopharyngeal carcinomas / cancers of the head and neck - Flavonoids can be validly combined with the polychemotherapeutic protocols used in the treatment of these cancers: 6. 1 Nasopharyngeal cancers: - ABVD protocol: The therapy comprises 1 to 6 repeated cycles at a rate of 1 cycle every 4 weeks. 6. 2 Cancers of head and neck with metastasis: - in the Pt-FU protocol (eg: for cancers of the pharynx): according to the DVAL Study Group (New Ing. J. M. 1991; 324: 1685-1690): The therapy comprises two cycles at the rate of 1 cycle every 3 weeks. 7o / Sarcomas of soft tissues 5 - Flavonoids can be introduced into a protocol, such as the CYVADIC protocol: - according to H.M. Pinedo et al. (Cancer 1984; 53: 1825): The therapy includes the repetition of this cycle every 4 weeks, for two cycles at the beginning. j «, itMa ^ lii-ii-M? i-aUBA-MHfe-U 8 ° / Hormone-resistant prostate cancer, with metastasis - in the VBL-estramustine protocol, according to G.R. and collaborators (J. Clin. Oncol. 1992; 10: 1754: 1761): A treatment cycle consists of 6 weeks and is followed by a free period of 2 weeks. 9 ° / Cancers of germ cells i) for tumors with 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 D1-D5 mg / m2 / day i. V or 5-50 mg / kg / day infusion for 1 h • cisplatin 20 mg / m / day Di - D5 infusion for 20 i.v. at 60 minutes • etoposide (E) 100 mg / m / day Di - D5 infusion per 1 i.v. hour The tereipia comprises 4 cid., at a ratio of 1 cycle every 21 or 28 days. ii) for tumors with metastases: PEB Protocol, according to S.D Williams and collaborators (N. Eng. J. Med. 1987; 316: 1435-1440): The therapy comprises 4 cycles, at a ratio of 1 cycle every 21 days. 10 ° / Cancers of the kidney metastatic renal carcinoma: the flavonoids can be introduced in the protocol described by M.J. Wiikinson et al (Cancer 1993; 71: 3601-3604): The therapy comprises two cycles, separated by 28 days. Nephroblastoma: flavonoids can be introduced in the DAVE protocol: at a ratio of one cycle every 3 to 4 weeks 11 ° / Cancers of the digestive tract 11.1 Cancers of the esophagus: - Flavonoids can be introduced in the FAP protocol according to: this cycle is repeated every 3 to 4 weeks. 11. 2 stomach cancers in gastric carcinomas, which are advanced and / or metastatic: EAP protocol (according to P. Preusser et al, J. Clin. Oncol. 1989; 7: 1310): at a ratio of 1 cycle every 28 days. FAMtx protocol: according to J.A. Wils et al. (J. Clin. Oncol., 1991; 89: 827): The therapy comprises two cycles first, separated by 28 days. -in certain diseases, this protocol or its 5 variants (epirubicin replacing doxorubicin) can be used according to the following scheme: 12 ° / colorectal cancers 10-flavonoids can be introduced into the protocol for the auxiliary treatment of FU-Levamisole, h ^ n¡? m? tl »mm? ai | Mt | BH | adUia | a || jttMitABa ||| tMMaitaM | ta ^^^^ MI É of colorectal cancer (according to CG Moertel et al., N. Eng J. Med. 1990; 322: 352): The bolus treatment of 5-FU is repeated every week after the induction phase of D1-D5, for 52 weeks; the flavonoid treatment is repeated at the same rate, on the bolus day of 5-FU and then in the next two days. 10 - for the treatment of colorectal cancer, with metastasis, which is resistant to treatment with 5-fluorouracin (5-FU): -according to M.L. Rothemberg and collaborators. (J. 15 Clin Oncol 1996; 14: 1128-1135): _TO* ..'. i? úi ** ».-. ^^^^^^^^^^^^^ ^^^^^ The therapy comprises two cycles, separated by 42 days. 13 ° / Kaposi Sarcomas - flavonoids can be combined with the two protocols that use anthracyclines formulated in liposomes: i) the protocol described by P.S. Gilí et al., (J. Clin. Oncol., 1995; 13: 996-1003) and C.A. Presant and collaborators. (Lancet 1993; 341: 1242-1243): The therapy comprises two repeated cycles, separated by 28 days, before the evaluation of the effects. ii) protocol of M. Harrison et al., (J. Clin. Oncol., 1995; 13: 914-920) the cure comprises two repeated cycles, separated 28 days, before the evaluation of the effects. 14 ° / Metastatic melanomas - flavonoids can also be incorporated into the combined protocols for the treatment of malignant metastatic melanomas: - DTIC / TAM protocol: according to G. Cocconi et al. (N. Eng. J. Med 1992; 327: 516), the therapy comprises the repetition of 4 cycles, at a ratio of 1 cycle every 21 days, according to to the scheme below: The therapy comprises 4 cycles at a ratio of 1 cycle every 21 days.

° / Neuroendocrine Carcinoma - flavonoids can be combined with the protocol described by C.G. Moertl et al. (Cancer 1991; 68): 227): ... aat ^ M-MMUM - Pt-E Protocol The therapy comprises two cycles repeated every 2S days. 16 ° / Cancer of the pancreas -Advanced pancreatic adenocarcinoma: Flavonoids can be combined with the treatment of gemcitabine, according to the protocol of M. Moore et al. (Proc. Soc. Clin. Oncol. 1995; 14: 473) a jf a ^ M_Ma ^ _ ^ aM > UMMt ^^ Mfc -.-.- ^ - a-fcM-tlJ-B-.l? TlJ__dM-B M. ^ HH ^^ _? Tj? U-l < ia B. Oncohematology 1 ° / Acute leukemia in adults 1.1 Acute lymphoblastic leukemia 1. 1.1 Linker protocol Flavonoids can be added to Linker Protocols - induction chemotherapy and consolidation chemotherapy - (see CA Linker et al., Blood 1987: 69: 1242-1248 and CA Linker et al., 1991; 78: 2814-2822) to the following schemes: ri ^ MuA ^^^ tiüüaiíi i) induction chemotherapy ii) consolidation chemotherapy (treatment A) Consolidation therapy A comprises 4 consecutive cycles, such as the one described above = cycles 1, 3, 5, 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 and collaborators: B therapy: ¿^ ^ C therapy: 1. 1.2 Hoelzer protocol Flavonoids can be added to the cytotoxic agents of this polychemotherapy protocol (D. Hoelzer et al., Blood 1984; 64: 38-47, D. Hoelzer et al., Blood 1988; 71: 123-131) according to the following scheme: i) induction chemotherapy / Phase 1: ii) induction chemotherapy / Phase 2 Phase 2 of the induction can be carried out as follows: iii) reinduction chemotherapy / Phase 1 iv) reinduction chemotherapy / Phase 2: 1. 2 Acute myeloid leukemias 1. 2.1. Treatment of adults of any age Flavonoids can be added, according to the scheme below, to the treatment that 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): ¿G | ¡¡¡¡^ ^ ^ ^ ^^^^^^^ 1. 2.2. Treatment of adults under the age of 60 i) induction chemotherapy: This cycle of induction incorporates the administration of cytarabine at high doses, according to the following scheme: (To reduce the risk of CNS toxicity, in the case of renal failure, the dosage of cytarabine is adjusted to the elimination of creatinine) , according to LE 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 hereafter, will be repeated 8 times, at a ratio of 1 cycle every 4 to 6 weeks (according to RJ Mayer et al., N. Engl J. Med. 1994; 331: 896 -903): iii) consolidation chemotherapy (with high doses 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. Wolf et al (J. Oncol 1989, 7: 1260-1267); R.J. Mayer et al. (N. Engl J. Med. 1994; 331: 896-903): 1.2.3. Treatment of adults 60 years of age or older Flavonoids can be added to consolidation chemotherapy protocols from now on: i) according to R.O. Dilman et al (Blood 1991; 78; 2520-2526), Z.A. Arlin et al. (Leukemia 1990; 4: 177-183), P.H. Wiernik et al. (Blood 1992; 79: 313-319): ii) according to R.J. Mayer et al. (N, Engl. J. Med. 194; 331: 896-903): iii) according to C.A. Linker et al. (Blood 1993; 81: 311-318), N. Chao et al. (Blood . & ,. £ l sMtofcaa ^. 1993; 81: 319-323) and A.M. Yeager et al. (N. Eng. J. Med. 1986; 315: 145-147): This protocol includes a transplant of autologous bone marrow (it takes place on day D0): or iv) in the case of an allogeneic bone marrow transplant compatible with HLA according to: P.J. Tutscha et al. Blood 1987; 70: 1382-1388, F.R. Applebaum and collaborators Ann. Int. Med. 1984; 101: 581-588: 2 ° / Chronic leukemia in adults 2. 1 Chronic myeloid leukemia In the myeloblastic phase, the flavonoids can be added to the HU-Mith treatment described by C.A. Koller and collaborators. (N. Engl. J. Med. 1986; 315: 1433-1438): 2. 2 Chronic lymphocytic leukemia 2. 2.1 FCG-CLL protocol Flavonoids can be added to the combinations of "pulsed chlorambucil" as described by E. Kimby et al (Leuk, Lymphoma 1991; 5 (Suppl.) 93-96) and by FCGCLL (Blood 1990; 75: 1422-1425). : 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 Clinical Oncol 1991; 9: 44-49) and A. Saven et al. (J. Clin. Oncol. 1995; 13; 570-574): 3 ° / Lymphoproliferative diseases 3. 1 Hodkin disease Flavonoids can be incorporated into the polychemotherapy protocols conventionally used for the treatment of Hodkin lymphoma: 3. 1.1. AVDB protocol according to G. Bonnadonna et al.

(Cancer, Clin Triáis 1979; 2: 217-226) and G.F. Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484): The therapy comprises 6 to 8 cycles, at a ratio 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. Engl. J. Med. 1993; 327: 1478-1484): The MOPP protocol should be alternated with the ABVD protocol (see 3.1.1.) Every 28 days, and the therapy includes 6 cycles: MOPP Protocol: 3. 1.3 Stanford Protocol V according to N.L. Bartlett et al. '(J. Clin. Oncol., 1995; 13; 1080-1088): The therapy comprises 3 cycles, at a ratio of 1 cycle every 28 days. 3. 1.4 EVA Protocol according to G.P. Canellos et al (Proc. Am. Soc. Clin. Oncol. 1991; 10: 273): The therapy comprises 6 cycles, at a ratio of 1 cycle every 28 days. 3. 1.5 Protocol B-CAVe A ** - ~ ¿^ 'ft according to W.G. Harker and collaborators. (Ann, Intern. Med. 1984; 101: 440-446): The therapy comprises 8 cycles, at a ratio of 1 cycle every 28 days. 3. 2 Lymphomas that are not Hodkin's. 3. 2.1 Lymphomas that are not Hodkin with a low degree of malignancy i) - CVP Protocol - according to C.M. Bagley et al. (Ann Intern. Med. 1972; 76: 227-234) and C.S. Portlock and collaborators. (Blood 1976; 47: 747-756) ^ ^ ^ ^^^ 1 ^ ^ fe ^^ gß ^ This cycle is repeated every 21 days until a maximum response. ii) - I-COPA Protocol - according to RV Smalley et al / (N. Engl. J. Med. 1992; 327: 1336-1341) & l The therapy comprises 8 to 10 cycles, at a ratio of one cycle every 28 days. iii) - Fludarabine-CdA Protocol - according to P. Solol-Celigny et al.

(Blood 1994; 84 (Sup. 1): 383a), H. Hoeschster et al .; (Blood 1994; 84 (Sup.1): 564a and A.C. Kay (J. Clin. Oncol. 1992; 10: 371-377) For fludaribine, each cycle is repeated every 28 days; for cladribine, each cycle is repeated every 35 days. 3. 2.2. Non-Hodkin lymphomas with an intermediate degree of malignancy i) - CHOP or CNOP protocol according to E.M. McKelvey and collaborators. (Cancer 1976; 38: 1484-1493), J.O. Armitage et al. (J. Clin. Oncol 1984, 2: 898-902), S. Paulovsky et al. (Ann Oncol 1992, 3: 205-209) 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 a bolus i.v. on the Di day of each cycle).

The therapy that uses 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 al (Ann.Inter.Med., 1985; 102: 596-602 and I.A. Cooper et al. (J. Clin. Oncol., 1994; 12: 769-778).

This treatment protocol extends for 12 weeks and corresponds to 1 cycle. iii) -Protocol VACOP-B - according to J.M. Connors et al. (Proc. Am. Soc. Clin. Oncol. 1990; 9. 254): Each cycle lasts 12 weeks. iv) - Protocol m-BACOD / M-BACOD - according to M-A. Shipp and collaborators. 8ann. Int. Med. 1986; 140: 575-765) and A.T. Skarin et al. (J. Clin. Oncol. 1983; 1: 91-98) The therapy comprises 10 cycles, at a ratio of 1 cycle every 21 days. v) - ProMACE / CytaBOM protocol - according to D.L. Longo et al. (J. Clin Oncol 1991, 9: 25-38): The therapy comprises 6 to 8 cycles, at a ratio of 1 cycle every 14 days. 3. 2.3. Lymphomas that are not Hodkin, with a low or intermediate degree of malignancy i) - ESHAP rescue protocol - in the case of recurrence or in the case of failure of the first line treatment, according to W.S. Velásquez et al. (J. Clin. Oncol., 1994; 12: 1169-1176) The treatment comprises 6 cycles, at a ratio of 1 cycle every 28 days. ii) - MINE rescue protocol - in the case of recurrence or in the case of the failure of first-line treatment, according to F. Cabanillas et al. (Semin. Oncol., 990; 17 (Sup. 10); This cycle is repeated every 21 days. 3. 3 Non-Hodkin lymphomas: Burkitt's lymphoma, small-cell lymphoma, lymphoblastic lymphoma. 3. 3.1 Magrath Protocol - The flavonoids can 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) ii) - cycles 2 to 15 - according to I.T. Magrath et al. (1984) if as: The therapy comprises 14 cycles, at a ratio of one cycle every 28 days. 3. Waldentrom macroglobulinaemia 3. 4.1 CVP protocol according to the CVP protocol described by M.A. Diomopoulous and collaborators. (Blood 1994; 83: 1452-1459) and C.S. Portlock et al (Blood 1976; 47: 747-756): the therapy is continued indefinitely (1 cycle every 21 days). 3. 4.2 Protocol of Fludarabine-CdA according to H.M. Kantarjian and collaborators.

(Blood 1990; 75: 1928-1931) and M.A. Dinopolous et al. (Ann. Intern. Med. 1993; 118: 195-198): the therapy comprises 6 to 12 separate cycles 2 days in the case of fludarabine, and 2 cycles stopped 2 days also, in the case of cladribine. 3. 5 Multiple myeloma 3. 5.1 Protocol MP 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): The therapy comprises at least 12 cycles, at a ratio 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): 3. 5.3 Protocol of Mp / interferon-a according to O. Osterborg et al. (Blood 1993; 81: 1428-1434): The therapy includes the indefinite repetition of this cycle, at a ratio of 1 cycle every 21 days. 3. 5.4 Protocol VCAP or VBAP according to S.E. Salmon et al. (J. Clin. Oncol. 1983; 1: 453-461): VCAP protocol: VBAP protocol: cyclophosphamide is replaced with carmustine (BCNU), the rest remains identical: C. INFANTILE TUMORS - Pediatric oncology Flavonoids can also be incorporated into polychemotherapy protocols for the treatment of pediatric tumors, to improve antitumor effectiveness while at the same time reducing the severity of side effects due to the action on recrudescence and mobilization of clonogenic cells and the possibility of decreasing the active doses. 1 ° / Ewing's sarcoma / primitive neuroectodermal tumor Flavonoids can be introduced into the VCR-Doxo-CY-Ifos-Mesna-E protocol (ED Bergert et al., J. Clin Oncol 1990; 8: 1514-1524; WH Meyer et al., J. Clin. Oncol. 1992; 10: 1737-1742): ? - - The therapy comprises 6 to 10 of these cycles depending on the initial severity of the sarcoma and the amplitude of the response. 2 ° / Childhood acute lymphoblastic leukemia 2. 1 Induction chemotherapy (days D? -D_30).

Flavonoids can be added to recommended protocols (PS Gaynon et al, J. Clin Oncol., 1993 11, 2234-2242, J. Pullen et al, J. Clin. Oncol., 1993; 11: 2234-2242; Pullen et al., J. Clin. Oncol., 1993; 11; 839-849; VJ Land et al., J. Clin. Oncol., 1994; 12: 1939-1945): * ^ i ^? ^ - XI Depending on the result of the examination of the bone marrow, entry into the consolidation phase takes place on day D28 of the treatment protocol. 2. 2 Consolidation / maintenance chemotherapy Flavonoids can be introduced into maintenance protocols (PS Gaynon et al, J. Clin Oncol 1993, 11: 2234-2242, J. Pullen et al., J. Clin. Oncol., 1993; 11: 839-849. VJ Land et al., J. Clin. Oncol, 1994; 12: 1939-1945) according to the following scheme: 3 ° / Child acute myeloid leukemia The flavonoids are added to the protocols of induction and consolidation / maintenance, according to the following schemes: 3. 1. Induction chemotherapy According to Y. Ravindranath et al., J. Clin. Oncol. 1991; 9: 572-580; ME. Nesbit and collaborators, * -4Í * ^ * ?.

J. Clin. Oncol. 1994; 12: 127-135; RJ Wells et al., J. Clin. Oncol. 1994; 12: 2367-2377: This cycle is repeated from D28. 3. 2 Consolidation / maintenance chemotherapy According to Y. Ravidranath et al., J.

Clin. Oncol. 1991; 9; 572-580; ME. Nesbit and collaborators, *, ***! + - J. Clin. Oncol. 1994; 12: 127-135; R.J. Wells et al., J. Clin. Oncol. 1994; 12: 2367-2377: 4 ° / Hodgkin's disease in infants 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) This cycle should be repeated 6 times, at a ratio of 1 cycle every 8 weeks, the therapy comprises 6 cycles.

If a transplant of autologous bone marrow (autograft) is prescribed, the CVB protocol described by R. Chopra et al. (Blood 1993) may be used; 81: 1137-1145), C. Wheeler et al. (J. Clin Oncol, 1990; 8: 648-656) and R.J. Jones et al (J. Clin. Oncol. 1990; 8: 527-537), can be used according to the following scheme (the allograft takes place on day D0): ° / childhood lymphoblastic lymphoma Flavonoids can also be combined with induction chemotherapy protocols (AT Meadows et al., J. Clin. Oncol. 1989; 7: 92-99 - C. Patte et al., Med. Pd. Oncol. 1992; 20: 105-113 and A. Reiter et al., J. Clin. Oncol. 1995; 13: 359-372) and maintenance chemotherapy: . 1 Induction chemotherapy . 2 Maintenance chemotherapy according to the following scheme: • Methotrexate Depending on the D ?, D8, D? 5 age (Cycle 1) intra- after a thecal time / month (cycles 2 to 10) The therapy comprises 10 cycles. 6th / Pediatric Neuroblastoma The recommended polychemotherapy protocol Doxo-E-Cy-Pt, is adapted from R.P. Castleberry and collaborators. (J. Clin Oncol 1992, 10: 1299-1304), A. Garaventa et al. (J. Clin Oncol, 1993; 11: 1770-1779) and D.C. West et al (J. Clin. Oncol. 1992; 11: 84-90): a ^ gjjSsagjjgjg ^^ j The evaluation of the therapeutic response is carried out after 9 weeks to decide on the treatment: surgical resection, radiotherapy or new chemotherapy. 7th / Pediatric Osteosarcoma Flavonoids can be added to the protocol Doxo-Pt-Mtx-Lcv as described by M. Hudson et al. (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): ^^^ g »***? 8 ° / Childhood rhabdomyosarcoma The Vcr-Dact-CY-Mesna protocol (H. Maurer et al., Cancer 1993; 71: 1904-1922 and LR Mandel et al., Oncology 1003; 7: 71-83), may include the i.v. of the flavonoids, according to the following scheme: At the end of the 9th week of treatment, effectiveness should be evaluated to decide on subsequent measures (surgery, radiotherapy, continuation of chemotherapy). 9 ° / Wilms' tumor in children In the Vcr-Dact protocol as described by GJ D'Angio et al. (Cancer, 1989; 64: 349-360) and DM Green et al. (J. Clin. Oncol. 1993; 11: 91-95): This protocol is initiated after surgical resection.

In the case of a transplant of autologous bone marrow (autograft) according to A. Garaventar et al., (Med. Pediatr Oncol 1994, 22: 11-14), the Thio-Cy protocol can be modified as follows: The bone marrow transplant takes place in the D0.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (9)

1. A composition, which, characterized because, has activity on the proliferation of clonogenic cells in tumors and which comprises, a therapeutically effective amount of a flavonoid, excluding naringenin.

2. A composition, characterized in that it has activity on the proliferation of clonogenic cells in tumors and which comprises a therapeutically effective amount of a compound chosen from the compounds of the formula: this, which is a formula in which: Ri, R2, R3 and R are chosen, independently of one another from, H, OH, a C1-C4 alkoxy group and a group -OCOR7, R7 which is an alkyl group of C1-C4, at least one of the substituents Ri, R2, R3 or R4 which is different from H, and R2 and R3 possibly forming together a methylenedioxy group, -R5 is chosen from H, OH, an alkoxy group of C ~ C4 and an O-glycosyl group, -R6 is selected from a cyclohexyl group, a phenyl group and a substituted phenyl group from 1 to 3 times with groups selected from H, OH and a C? -C4 alkoxy group , - and designates, any, a double bond or a simple bond, excluding naringenin.

3. The composition according to claim 2, characterized in that, the flavonoid is a flavone.

4. The composition according to claim 1, characterized in that, the flavonoid is cuercetin.

5. The use of a flavonoid, excluding naringenin, for the preparation of a medicament intended to interfere with the generation of elongogenic cells in tumors during the treatment of these tumors with at least one agent eit.ot.o.xico.

6. The use of a compound chosen from the compounds' of formula this, which is a formula in which: -Ri, R2, R3 and 4 are chosen, independently of one another, from, H, OH, a C 1 -C 4 alkoxy group and a group -OCOR 7, R 7 which is a C 1 -C 4 alkyl group, at least one of the substituents R i, R 2 R 3 or R 4, which is different from H, and R 2 and R 3 possibly together forming a methylenedioxy group, -R 5 is chosen from H, OH, an alkoxy group of C? -C and an O-glycosyl group, -R6 is selected from a cyclohexy group, a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, and a alkoxy group of C1-C4, - and designates any, a double bond or a single bond, excluding naringenin for the preparation of a medicament intended to interfere with the generation of clonogenic cells in tumors during the treatment of these tumors with at least a cytotoxic agent. characterized because the flavonoid is a flavone.

7. The use according to claim 6, characterized in that the flavonoid is a flavone.

8. The use according to claim 5, characterized in that the compound of formula I is cuercetin.

9. The use according to claim 5, characterized in that the flavonoid is administered at the beginning of the chemotherapeutic treatment and at the start of each cycle of chemotherapeutic treatment. 10 fifteen twenty