EP1096929A1 - Therapeutische zusammensetzung auf isoflavonoidbasis zur verwendung bei der behandlung von tumoren mit zytotoxischen mitteln - Google Patents

Therapeutische zusammensetzung auf isoflavonoidbasis zur verwendung bei der behandlung von tumoren mit zytotoxischen mitteln

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Publication number
EP1096929A1
EP1096929A1 EP99929481A EP99929481A EP1096929A1 EP 1096929 A1 EP1096929 A1 EP 1096929A1 EP 99929481 A EP99929481 A EP 99929481A EP 99929481 A EP99929481 A EP 99929481A EP 1096929 A1 EP1096929 A1 EP 1096929A1
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Prior art keywords
group
treatment
protocol
chosen
oncol
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French (fr)
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Francis Univ. de Bruxelles Fac.Médecine DARRO
Robert Univ. de Bruxelles Fac. Médicine KISS
Armand Frydman
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Cephalon France SAS
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Laboratoire L Lafon SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of isoflavonoid type compounds in the treatment of cancers with cytotoxic agents.
  • Cancer is a disorder of the somatic genes in which genetic dysfunctions are amplified as the tumor process progresses from the precancerous lesion to that of malignant transformation, the cancerous tumor becoming metastatic and often resistant to drugs. cytotoxic.
  • the inventors are interested in a different approach.
  • the objective sought was to make the population of tumor cells more sensitive to the benchmark anticancer treatments in order to achieve a double benefit: 1) increase the cytotoxic activity therefore the efficiency and
  • a subject of the present invention is therefore the use in the treatment of cancers with at least one antitumor chosen from cytotoxic agents, of a compound having an activity on the proliferation of clonogenic cells, chosen from isoflavonoids and analogous compounds of the type chromone and in particular the compounds of formula:
  • - RR 2 , R 3 and R 4 are chosen independently of one another from H, OH, an aikoxy group in C ⁇ C, a group -OCOR 7 , R 7 being an alkyl group in 0, -0 4 , at least one of the substituents R 1 ( R 2 , R 3 or R 4 being other than H and R 2 and R 3 which can together form a methylenedioxy group, R 5 is chosen from H, OH, a C r C 4 aikoxy group, an O-glycosyl group, and a cyclohexyl group,
  • R 6 is chosen from a cyclohexyl group, a phenyl group and a phenyl group 1 to 3 times substituted by groups chosen from H, OH and an aikoxy group at 0, -0 4 , - and denotes either a double bond, or a simple bond.
  • a preferred class of compounds of formula I are those in which R ⁇ is chosen from the phenyl, 4-hydroxyphenyl group and the 4- (0, -0 4 alkoxy) phenyl groups.
  • Cytotoxic agents can be used at their usual dose and in this case their effectiveness is improved, or at lower doses given the increase in their anti-tumor efficacy if the objective sought is first to improve tolerance from patient to treatment.
  • the subject of the present invention is also a composition having an activity on the proliferation of clonogenic cells by interfering with the generation of clonogenic cells, either by stimulation of proliferation and recruitment, or by inhibition of proliferation, comprising a therapeutically effective amount of an isoflavonoid or an analogous compound of the chromone type, and in particular of a compound chosen from the compounds of formula:
  • - R ,, R 2 , R 3 and R 4 are chosen independently of one another from H, OH, an aikoxy group at 0, -0 4 , a group -OCOR 7 , R 7 being an alkyl group in C, -C 4l at least one of the substituents R ,, R 2 , R 3 or R 4 being other than H and R 2 and R 3 may together form a methylenedioxy group, - R s is chosen from H, OH, a C 1 -C 4 aikoxy group, an O-glycosyl group, and a cyclohexyl group,
  • - R ⁇ is chosen from a cyclohexyl group, a phenyl group and a phenyl group 1 to 3 times substituted with groups chosen from H, OH and a C 1 -C 4 aikoxy group )
  • the present invention also relates to the use of an isoflavonoid, in particular of a compound of formula I as defined above, for the manufacture of a medicament intended to interfere (by induction or inhibition) with the generation of clonogenic cells in tumors when treated with at least one cytotoxic agent.
  • isoflavonoids and in particular the compounds of formula I can be administered at the start of chemotherapeutic treatments either at once or over several days at the start of these treatments (for example for 5 to 7 days) and, depending on the chemotherapy protocol, at the start of each treatment cycle (for example for 2 to 5 days) during each course.
  • Isoflavonoids and in particular 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 / m 2 / day.
  • isoflavonoids should be administered in such a way that the tissue concentrations obtained are the highest that can be envisaged.
  • the intravenous route is to be preferred using:
  • lyocs for oral or perlingual absorption
  • instant or delayed release tablets for oral solutions, suspensions, granules, capsules, etc.
  • the compounds of formula (I) are for the majority of compounds of natural origin or are derivatives of compounds of natural origin. As examples, we can cite: - genistein,
  • Cytotoxic agents can be chosen from: i) intercalating agents, in particular doxorubicin (Adriamycin), daunorubicin, epirubicin, idarubicin, zorubicin, aclarubicin, pirarubicin, acridin, mitoxanthrone, l actinomycin D, eptilinium acetate; ii) alkylating agents chosen from platinum derivatives (cisplatin, carboplatin, oxaliplatin, etc.), iii) a compound chosen from other groups of alkylating agents:
  • BCNU carmustine
  • CCNU lamelonine
  • fotemustine fotemustine
  • streptozotocin
  • - ethyleneimines altretamine, triethylene-thiophosphoramide, iv) a compound chosen from other groups of anti-metabolic agents: - antifolics: methotrexate, raltitrexed,
  • - antipurics purinethol, thioguanine, pentostatin, cladribine
  • vinca-alkaloids disorganizing the mitotic spindle: vincristine, vinblastine, vinguerine, navelbine
  • a splitting agent, fragmenting DNA such as bleomycin, vii) one of the following compounds; plicamycin, Asparaginase, mitoguazone, dacarbazine, viii) an anti-cancer progestin steroid: medroxy-progesterone, megestrol, ix) an anti-cancer estrogenic steroid: diethylstilbestrol; tetrasodium fosfestrol, x) an anti-estrogen: tamoxifen, droloxifene, raloxifene, amino-gluthetimide, xi) a steroid antiandrogen (ex cyproterone) or a nonsteroidal antiandrogen (flutamide, nilut
  • the compounds of formula I can be combined with any treatment with major cytotoxic agents used in multidrug therapy for solid tumors such as: - doxorubicin
  • oxazophorin alkylating agents cyclophosphamide, ifosfamide, chlorambucil, melphalan
  • mitomycin C - anti-metabolites such as methotrexate, 5-FU, Ara-C, capecitabine
  • vinca alkaloids vincristine, vinblastine, vindesine, navelbine
  • taxoids paclitaxel, docetaxel
  • epipodophyllotoxin derivatives etoposide, teniposide
  • the compounds of formula I can be combined with treatment with the major cytotoxic agents used in oncohematology for the treatment of blood cancers:
  • cyclophosphamide mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;
  • methotrexate methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase;
  • a cell is considered clonogenic if it has the capacity to proliferate and to give rise to a cell colony.
  • the “human tumor stem cells” or “human tumor stem cells” are the cells which are at the origin of the neoplastic cells which constitute a given tumor. These tumor stem cells are responsible for the recurrence processes observable after surgical resection of the primary tumors and are also responsible for the formation of metastases. At the level of a tumor or of a tumor cell line, these clonogenic stem cells differ from the other cells of the tumor or of the neoplastic cell line considered, by the fact that they retain their capacity to proliferate in the absence of any solid support.
  • the tumor cells are cultured on a semi-solid support constituted by agar. Only cells which do not require solid support for their growth (ie very tumorigenic cells called “anchorage-independent cells” by Ml Dawson et al., Cancer Res. 1995; 55: 4446-4451; also called clonogenic cells with reference to “clonal growth”) are capable of growing on such an agar-based support. Indeed, on such a medium, normal cells - which are growing in "adherent mode"("anchorage-dependentcells" according to the terminology of Ml Dawson) - such as fibroblasts, do not survive.
  • the tumor cell lines studied are maintained in culture in 25 cm 2 falcon dishes. They are then trypsinized and the cells well dissociated from each other. The percentage of living cells is determined after staining with trypan blue.
  • a cell suspension at a concentration of 5.10 4 to 15.10 "cells / ml (depending on the cell type considered) is prepared in a 0.3% agar solution. Then 200 ⁇ l of this suspension are sown in petri dishes 35 mm in diameter, in which are deposited 3 ml of a base layer consisting of a 0.5% agar solution. The 200 ⁇ l of cell suspension are in turn covered with 1.8 ml of an upper layer consisting of a 0.3% agar solution.
  • the dishes are then placed in an incubator at 37 ° C, 5% CO 2 and 70% humidity until treatment. This is carried out approximately 1 to 2 hours after seeding.
  • the test compounds are prepared at a concentration 100 times greater than the desired concentration and 50 ⁇ l of these treating solutions are deposited on the upper agar layer of the corresponding boxes. the final concentration of the tested products is 10 "5 , 10 " 7 and 10 “9 M.
  • the dishes are then kept for 21 days in the incubator.
  • the dishes are treated by depositing on the upper layer 100 ⁇ l of a solution of MTT (bromide of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazoiinium) at 1 mg / ml prepared with RPMI 1640 medium for 3 h at 37 ° C. After this time, the cell colonies are fixed by adding 2 ml of formalin per dish. After 24 hours of fixation, the formalin is evaporated and the number of colored cell colonies, therefore made up of metabolically active cells, and whose surface is greater than 100 ⁇ m 2 is determined using an inverted microscope.
  • MTT bromide of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazoiinium
  • the average number of clonogenic cell clones determined for each experimental condition studied is expressed as a percentage relative to the average number of clonogenic cell clones counted in the control condition and set equal to 100%. These values, expressed as a percentage relative to the control condition, are recorded in Table I.
  • genistein can:
  • MCF7 cell line at concentrations of 10 "5 M and 10 " 7 M).
  • the principle of the MTT test is based on the mitochondrial reduction by the metabolically active living cells of the product MTT (bromide of 3- (4,5-dimethylthiazol-2- yl) -2.5 diphenyltetrazolium) yellow in color, a blue product, formazan.
  • the quantity of formazan thus obtained is directly proportional to the quantity of living cells present in the culture well (s). This quantity of formazan is measured by spectrophotometry.
  • the cell lines are maintained in monolayer culture at 37 ° C. in closed-cap culture dishes containing MEM 25 MM HEPES base medium.
  • FCS Fetal Calf Serum
  • the 12 human cancer cell lines that were used were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA). These 12 cell lines are:
  • A549 (ATCC code: CCL-185) and A-427 (ATCC code: HTB-53) which are two non-small cell lung cancers,
  • 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 in 96-well multi-well plates with a flat bottom and are incubated at 37 ° C, below atmosphere comprising 5% CO2 and 70% humidity. After 24 hours of incubation, the culture medium is replaced by 100 ⁇ l of fresh medium containing either the various compounds to be tested at concentrations varying from 10 -5 to 10 -10 M or the solvent used for setting solution of the products to be tested (control condition).
  • the culture medium is replaced by 100 ⁇ l of a yellowish solution of MTT dissolved at a rate of 1 mg / ml in RPMI 1640.
  • the microplates are incubated for 3 hours at 37 ° C then centrifuged for
  • the results of the average optical density expressed as a percentage relative to the average optical density measured in the control condition (posed equal to 100%), will be given in Table II, obtained with an isoflavonoid: genistein, on the 5 tumor cell lines U-87MG, J82, HCT-
  • Genistein has a weak anti-tumor power. This non-cytotoxic product induces, when this is the case, an inhibition of the overall cell proliferation of these lines only at the concentration of 10 "5 M and this inhibition does not exceed 20%. At the other concentrations tested, only a few marginal effects can be highlighted.
  • the evaluation of the maximum tolerated dose was carried out in B6D2F1 / Jico mice aged 4 to 6 weeks.
  • the compounds were administered intraperitoneally at increasing doses ranging from 2.5 to 160 mg / kg.
  • the value of the DMT (expressed in mg / kg) is determined from the observation of the survival rate of the animals over a period of 14 days after a single administration of the product considered. The weight evolution of the animals is also monitored during this period. When the value of the DMT is greater than 160 mg / kg, the value of the DMT is assimilated to 160 mg / kg by default.
  • Genistein is associated by default with a DMT equal to 160 mg / kg. This result suggests that the products of the isoflavonoid family do not exhibit any toxicity. direct and can be used at high tissue concentrations, therefore at high dosages.
  • MXT-HS - Hormone-sensitive MXT murine mammary adenocarcinoma
  • cytotoxic agents such as cyclophosphamide, etoposide, doxorubicin or vincristine.
  • the control condition is represented by a batch of 9 mice to which is administered for 5 consecutive weeks and at the rate of 5 administrations. (Monday, Tuesday, Wednesday, Thursday and Friday) per week a volume of 0.2 ml of physiological saline containing the solvent used to dissolve the various compounds of formula (I) used.
  • mice 0- the survival rate of mice.
  • This survival rate was calculated as a T / C ratio:
  • This ratio represents the average survival time of the median mouse in the batch of treated mice compared to the average survival time of the median mouse in the batch of control mice.
  • a molecule induces a significant increase (P ⁇ 0.05) in the survival of animals when the T / C index exceeds 130%.
  • it has a toxic effect when this T / C value is less than 70%.
  • ii) - Tumor growth by measuring twice a week (Monday and Friday) the surface of grafted MXT-HS and P388 tumors. This area is calculated by taking the product of the value of the two largest perpendicular axes of the tumor. The value of these axes is measured using a caliper.
  • the model of hormone-sensitive murine mammary adenocarcinoma MXT (MXT-HS) grafted on B6D2F1 / Jlco mice aged from 4 to 6 weeks is a model derived from the milk ducts of the mammary gland (Watson C. et al. Cancer Res. 1977; 37: 3344- ⁇ 8).
  • results obtained using genistein will be given either alone or in combination with cytotoxic agents.
  • Genistein is administered alone.
  • the first injection of the product is carried out on the seventh day post-transplant (D7) for four consecutive weeks at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) and at a dose of 20 mg / kg.
  • Cyclophosphamide (CPA) is given alone.
  • the first injection of the product is made on the fourteenth day post-transplant (D14) for three consecutive weeks at the rate of 3 injections per week (Monday, Wednesday and Friday) and at a dose of 10 mg / kg.
  • Vincristine (VCR) is administered alone.
  • the first injection of the product is made on the fourteenth day post-transplant (D14) for three consecutive weeks at the rate of 3 injections per week (Monday, Wednesday and Friday) and at a dose of 0.63 mg / kg.
  • ETO Etoposide
  • D14 fourteenth day post-transplant
  • Genistein is co-administered with cyclophosphamide.
  • the first injection of genistein is carried out on the seventh day post-transplant (D7) for four consecutive weeks at the rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) at a dose of 20 mg / kg and the first injection of cyclophosphamide is given on the fourteenth day post-transplant (D14) for three consecutive weeks at the rate of 3 injections per week (Monday, Wednesday and Friday) at a dose of 10 mg / kg.
  • Genistein is co-administered with vincristine.
  • the first injection of genistein is carried out on the seventh day post-transplant (D7) for four consecutive weeks at the rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) at a dose of 20 mg / kg and the first injection of vincristine is performed on the fourteenth day post-transplant (D14) for three consecutive weeks at the rate of 3 injections per week (Monday, Wednesday and Friday) at a dose of 0.63 mg / kg.
  • Genistein is co-administered with etoposide.
  • the first injection of genistein is carried out on the seventh day post-transplant (D7) for four consecutive weeks at the rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) at a dose of 20 mg / kg and the first injection of etoposide is given on the fourteenth day post-transplant (D14) for three consecutive weeks at the rate of 3 injections per week (Monday, Wednesday and Friday) at a dose of 10 mg / kg.
  • CDF1 mice aged 4 to 6 weeks are grafted with a piece of tumor P388 (from a tumor bank maintained in the laboratory) subcutaneously in the right flank on day D0.
  • P388 from a tumor bank maintained in the laboratory
  • Genistein is administered alone.
  • the first injection of the product is made on the fifth day post-transplant (D5) at the rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks and at a dose of 40 mg / kg.
  • Vincristine (VCR) is administered alone.
  • the first injection of the product is made on the fifth day post-transplant (D5) at the rate of 3 injections per week (Monday, Wednesday and Friday) for three consecutive weeks and at a dose of 0.63 mg / kg.
  • Treatment 3 Genistein is co-administered with vincristine.
  • the first injection of genistein is carried out on the fifth day post-transplant (D5) at the rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks at a dose of 40 mg / kg and the first injection of vincristine is given on the fifth day post-transplant (D5) at the rate of 3 injections per week (Monday, Wednesday and Friday) for three consecutive weeks at a dose of 0.63 mg / kg.
  • each cycle is repeated every 21 days and the treatment includes 6 cycles.
  • the course of treatment may include repeating this 4-week cycle.
  • the treatment including the repetition of this cycle every 21 days.
  • each cycle is repeated every 21 days and the treatment has 4 cycles.
  • each cycle is repeated every 28 days until the diagnosis of a new progression of the disease.
  • this treatment is to be repeated every 28 days until the diagnosis of disease progression.
  • the treatment has two cycles spaced 21 days apart and then requires an evaluation.
  • Isoflavonoid infusions can also be used to treat metastatic breast cancer when a taxoid is used, for example:
  • This cycle is repeated every 21 days until a new progression of the disease is diagnosed.
  • This cycle is repeated every 21 days for a cure of 2 cycles or until the onset of disease progression.
  • this cycle is repeated every 21 to 28 days and the treatment has 8 cycles.
  • paclitaxel protocol isoflavonoids can be added to the paclitaxel protocol as described by W.P. Me Guire et al. (Ann. Intern. Med. 1989; 111: 273 - 279):
  • the treatment comprising two of these cycles, spaced 28 days apart (with evaluation at the end).
  • isoflavonoids can be added to the second-line protocol, based on topotecan:
  • the treatment comprising two cycles, spaced 21 days apart (with evaluation the outcome)
  • isoflavonoids may be associated with the protocol described by H. Takamizawa et al. (Semin. Surg. Oncol. 1987; 3: 36-44):
  • isoflavonoids can also be combined with the CAV (or VAC) protocol according to the following scheme:
  • the treatment including the repetition of this cycle every 21 days.
  • the treatment including the repetition of this cycle every 21 or 28 days.
  • the treatment comprising 3 cycles, at the rate of 1 cycle every 21 days. ° / Ca ncers of the bladder ie
  • isoflavonoids can be combined with the CISCA2 protocol (also called PAC)
  • the cure comprising 1 to 6 cycles repeated at the rate of 1 cycle every 4 weeks.
  • the treatment comprising two cycles, at the rate of 1 cycle every 3 weeks.
  • Isoflavonoids can be introduced into a protocol such as the CYVADIC protocol: - according to H. M. Pinedo et al. (Cancer 1984; 53: 1825):
  • the cure comprising 4 cycles, at the rate of 1 cycle every 21 or 28 days.
  • isoflavonoids can be introduced into the protocol described by M. J. Wilkinson et al. (Cancer 1993; 71: 3601- 3604):
  • the treatment comprising two cycles spaced 28 days apart.
  • nephroblastoma isoflavonoids can be introduced into the DAVE protocol:
  • this protocol or its variant epirubicin replacing doxorubicin may be used according to the following scheme:
  • the bolus treatment with 5-FU being repeated each week after the induction phase D, - D 5 , for .52 weeks; that by an isoflavonoid being repeated on the same rhythm, the day of the bolus of 5-FU then the 2 following days.
  • the treatment comprising two cycles, spaced 42 days apart. 3 ° / Kaposi sarcomas
  • the treatment comprising two cycles repeated 28 days apart before evaluating the effects.
  • the treatment comprising two cycles repeated 28 days apart before evaluating the effects.
  • the cure comprising 4 cycles at the rate of 1 cycle every 21 days.
  • the treatment comprising two cycles repeated every 28 days.
  • pancreatic adeno-carcinoma isoflavonoids can be associated with gemcitabine treatment, according to the protocol of M. Moore et al. (Proc. Am. Soc. Clin. Oncol. 1995; 14: 473)
  • Acute lymphoblastic leukemia 1.1. Acute lymphoblastic leukemia:
  • Isoflavonoids can be added to Linker's 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 diagrams:
  • Phase 2 of the induction can be carried out as follows
  • Isoflavonoids can be added, according to the scheme below, to the treatment incorporating 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):
  • This induction cycle incorporates the administration of high-dose cytarabine according to the following scheme:
  • the substances claimed may be added to the following consolidation chemotherapy protocols: i) according to RO Dilman et al. (Blood 1991; 78; 2520-2526), ZA Arlin et al. (Leukemia 1990; 4: 177-183), PH Wiernik et al. (Blood1992; 79: 313-319):
  • This protocol includes an autologous bone marrow transplant
  • isoflavonoids can be added to the HU-Mith treatment, described by C.A. Koller et al. (N. Engl. J. med. 1986; 315: 1433-1438):
  • Isoflavonoids can be added to the "pulsed chlorambucil" combinations as described by E. Kimby et al. (Leuk. Lymphoma 1991; 5 (SuppI.) 93-96) and by the FCGCLL (Blood 1990; 75: 1422-1425):
  • Isoflavonoids can be incorporated into the chemotherapy protocols conventionally used for the treatment of Hodgkin's lymphoma:
  • the MOPP protocol must be alternated with the ABVD protocol (see ⁇ 3.1.1) every 28 days and the treatment includes 6 cycles:
  • the treatment comprising 3 cycles at the rate of 1 cycle every 28 days.
  • the treatment comprising 6 cycles, at the rate of 1 cycle every 28 days.
  • the treatment includes 8 to 10 cycles, one cycle every 28 days.
  • each cycle is repeated every 28 days; for cladribine, each cycle is repeated every 35 days. .2.2. intermediate malignancy grade
  • Mitoxantrone can be used to replace (CNOP protocol) doxorubicin in patients over 60 years of age (dose: 12 mg / m 2 bolus i; v. On day D1 of each cycle).
  • the cure by the CHOP or CNOP protocol includes 6 to 8 cycles at the rate of 1 cycle every 21 days.
  • This treatment protocol is spread over 12 weeks and corresponds to 1 cycle.
  • the treatment comprising 10 cycles, at the rate of 1 cycle every 21 days.
  • the cure comprising 6 to 8 cycles, at the rate of 1 cycle every 14 days.
  • the treatment comprising 6 cycles, at the rate of 1 cycle every 28 days.
  • Non-Hodgkin's lymphomas Burkitt's lymphoma, small cell lymphoma, iymphobiastic lymphoma.
  • the treatment comprising 14 cycles, one cycle every 28 days.
  • the treatment comprising 6 to 12 cycles spaced 28 days apart in the case of fludarabine and 2 cycles spaced 28 days apart also in the case of the cladribine.
  • VCAP or VBAP protocol according to SE Salmon et al. (J. Clin. Oncol. 1983; 1: 453-461) VCAP protocol:
  • VBAP protocol cyclophosphamide is replaced by carmustine (BCNU), the rest being identical:
  • Isoflavonoids can also be incorporated into polychemotherapy protocols for the treatment of pediatric tumors in order to improve antitumor efficacy while reducing the severity of side effects thanks to the action on the recruitment and mobilization of clonogenic cells and the possibility of reducing active doses.
  • Ewing's sarcoma Primary neuroectodermal tumor
  • Isoflavonoids can be introduced into the VCR-Doxo-CY-1fos-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 treatment includes 6 to 10 of these cycles depending on the initial severity of the sarcoma and the amplitude of the response.
  • Isoflavonoids can be added to the recommended protocols (PS Gaynon et al., J. Clin. Oncol., 1993, 11, 2234-2242; J. Pullen et al., J. Clin. Oncol. 1993; 11: 2234-2242 ; J. Pullen et al., J. Clin. Oncol. 1993; 11: 839 -849; VJ Land at al., J. Clin. Oncol. 1994; 12: 1939-1945)
  • the transition to the consolidation phase takes place on day D 28 of the treatment protocol.
  • Isoflavonoids can be introduced into the maintenance protocol (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: 37 Acute myeloid leukemia in children
  • Isoflavonoids are added to the induction and consolidation / maintenance protocols according to the following schedules:
  • Isoflavonoids 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 must be repeated 6 times at the rate of 1 cycle every 8 weeks, the treatment comprising 6 cycles.
  • Isoflavonoids may also be associated with induction chemotherapy protocols (AT 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:
  • the evaluation of the therapeutic response is made after 9 weeks in order to decide on the attitude: surgical resection, radiotherapy or new chemotherapy.
  • Isoflavonoids can be added to the Doxo-Pt-Mtx-Lcv protocol as described by M. Hudson et al. (J. Clin. Oncol. 1990; 8: 1988 - 1997), PA Meyers (J. Clin. Oncol. 1992; 10: 5 - 15), and HCV Bramwell et al. (J. Clin. Oncol. 1992; 10: 1579-1591):
  • Vcr-Dact-CY-Mesna protocol H. Maurer et al., Cancer 1993; 71: 1904 - 1922 and LR Mandell et al., Oncology 1993; 7: 71 - 83
  • the Vcr-Dact-CY-Mesna protocol may include the iv infusion of isoflavonoids depending on the following diagram:

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EP99929481A 1998-07-15 1999-07-13 Therapeutische zusammensetzung auf isoflavonoidbasis zur verwendung bei der behandlung von tumoren mit zytotoxischen mitteln Withdrawn EP1096929A1 (de)

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FR9809059 1998-07-15
FR9809059A FR2781154B1 (fr) 1998-07-15 1998-07-15 Composition therapeutique a base d'isoflavonoides destinee a etre utilisee dans le traitement des tumeurs par des agents cytotoxiques
PCT/FR1999/001715 WO2000003707A1 (fr) 1998-07-15 1999-07-13 Composition therapeutique a base d'isoflavonoïdes destinee a etre utilisee dans le traitement des tumeurs par des agents cytotoxiques

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US6146668A (en) 1997-04-28 2000-11-14 Novogen, Inc. Preparation of isoflavones from legumes
AUPP260798A0 (en) 1998-03-26 1998-04-23 Novogen Research Pty Ltd Treatment of medical related conditions with isoflavone containing extracts of clover
AUPQ266199A0 (en) * 1999-09-06 1999-09-30 Novogen Research Pty Ltd Compositions and therapeutic methods involving isoflavones and analogues thereof
PL205635B1 (pl) * 2001-04-09 2010-05-31 Inst Farmaceutyczny Nowe pochodne genisteiny i zawierające je środki farmaceutyczne
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
AU2002951833A0 (en) 2002-10-02 2002-10-24 Novogen Research Pty Ltd Compositions and therapeutic methods invloving platinum complexes
DE10337863A1 (de) 2003-08-18 2005-03-17 Merck Patent Gmbh Verwendung von Chromen-4-on-Derivaten
CA2590048C (en) 2007-05-23 2013-07-16 Institut National De La Recherche Scientifique Cytosine nucleoside analogs and isoflavones and uses thereof
CN106265669A (zh) * 2016-08-04 2017-01-04 大连理工大学 大豆苷元与10‑羟基喜树碱的药物组合及其应用
CN113842387A (zh) * 2021-11-19 2021-12-28 大连理工大学盘锦产业技术研究院 10-羟基喜树碱与鹰嘴豆芽素a的药物组合物及其应用

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JPH0617304B2 (ja) * 1982-09-09 1994-03-09 理化学研究所 制癌剤
US5506211A (en) * 1994-05-09 1996-04-09 The Uab Research Foundation Genistein for use in inhibiting osteroclasts
US5824702A (en) * 1996-06-07 1998-10-20 Mount Sinai School Of Medicine Of The City University Of New York Genistein as a preventive against ultraviolet induced skin photodamage and cancer
AUPO203996A0 (en) * 1996-08-30 1996-09-26 Novogen Research Pty Ltd Therapeutic uses
JP2829387B2 (ja) * 1996-09-13 1998-11-25 農林水産省四国農業試験場長 脂肪細胞における脂肪分解促進用組成物
GB9621757D0 (en) * 1996-10-18 1996-12-11 Ciba Geigy Ag Phenyl-substituted bicyclic heterocyclyl derivatives and their use
US5733926A (en) * 1996-12-13 1998-03-31 Gorbach; Sherwood L. Isoflavonoids for treatment and prevention of alzheimer dementia and reduced cognitive functions

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AU761417B2 (en) 2003-06-05
FR2781154B1 (fr) 2001-09-07
CN1312712A (zh) 2001-09-12
WO2000003707A1 (fr) 2000-01-27
CN1139383C (zh) 2004-02-25
KR20020006510A (ko) 2002-01-19
EA200100141A1 (ru) 2001-06-25
IL140580A0 (en) 2002-02-10
FR2781154A1 (fr) 2000-01-21
BR9912817A (pt) 2001-05-08
JP2002520357A (ja) 2002-07-09
CA2337256A1 (en) 2000-01-27
AU4628299A (en) 2000-02-07

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