KR20020006510A - Therapeutic composition based on flavonoids for use in the treatment of tumours with cytotoxic agents - Google Patents

Abstract

The present invention provides for the activity against the proliferation of clonal cells in tumors, including therapeutically effective amounts of isoflavonoids or similar chromone compounds, in particular compounds selected from compounds of formula (I). To a composition having R ₁ , R ₂ , R ₃ and R ₄ , R ₅ and R ₆ in formula (I) as defined in claim 2. The composition is intended for use in the treatment of cytotoxic substances in tumors.

Description

Therapeutic composition based on flavonoids used in the treatment of tumors using cytotoxic substances {THERAPEUTIC COMPOSITION BASED ON FLAVONOIDS FOR USE IN THE TREATMENT OF TUMOURS WITH CYTOTOXIC AGENTS}

The present invention relates to the use of isoflavonoids in treating cancer tumors with cytotoxic substances.

Cancer is a disease of somatic genes in which hereditary dysfunction expands as the tumor progresses from a precancerous lesion to a malignant state of deformation, and the cancer tumor becomes metastatic and often resistant to cytotoxic drugs. do.

Despite the many efforts made in all developed countries, especially experimental and clinical studies, mortality from various carcinomas (solid tumors and hematologic tumors) is still high. In many countries, mortality from cancer is second only to mortality from cardiovascular disease.

For newly diagnosed cancers, the distribution between solid tumors and hematologic tumors (spinal cord, blood, lymphatic system) indicates that 9 out of 10 cancers are solid tumors. In contrast to what is observed in hematological oncology (40-90% of blood cell cancers succeed in healing), only a small number of advanced or diffuse solid tumors respond to chemotherapy alone. The overall increase in cancer mortality in the United States between 1973 and 1992 is partly for the same reason.

Unfortunately, taxanes (paclitaxel and docetaxel), camptothecin that interfere with the formation of microtubules in addition to established chemotherapy (WP McGuire et al., Am. Intern. Med. 1989) Inhibitors of topoisomerases I (topotecan and irinotecan), vinorelbine (new alkaloids derived from periwinkle), gemcitabine only novel antitumor such as gemcitabine (a novel cytotoxic anti-metabolizer), raltitrexed (inhibitor of thymidylate synthetase) and miltfosine (a typical example of alkylphosphocholine family) It is clear that this trend cannot be reversed by the emergence of drugs. In addition, these therapies are the first line of treatment or next-line treatments other than drugs such as doxorubicin, cisplatin, vincristine, methotrexate, 5-fluorouracil, which are well known for their specific activity. Used.

One of the most difficult problems with current chemotherapy is due to the fact that many of the malignant cells are substantially resistant to established cytotoxics. Most often, this situation is due to the presence of multiple resistance genes or frequent genetic variations in certain types of tumors. Thus, the treatment of carcinomas requires new attempts to complement currently used methods, to better match tumor expansion and heterogeneity, and to obtain "multi-cytotoxic drug" resistance.

Some of the new attempts are already certain. Such are the cases of induction of apoptosis, inhibition of tumor angiogenesis and inhibition of metastatic progression in addition to gene therapy or immunotherapy.

We are interested in other approaches. The desired purpose is to have two beneficial effects:

1) effect of increasing efficacy by increasing cytotoxic activity, and

2) Induction of increased antitumor efficacy could then occur, making the tumor cell population more sensitive to control anticancer treatments in order to achieve the effect of reducing the dose to reduce the frequency and severity of certain side effects.

This strategy is due to the discovery of innovative mechanisms due to substances with low or no antitumor capacity, but which can induce a very significant increase in the cytotoxic activity of confirmed anticancer drugs. These innovative mechanisms can stimulate the regeneration of clonal cells within these tumors, making them more sensitive to conventional cytotoxic treatments or inhibiting the proliferation of clonal cells. This is due to the possibility of contributing to relief.

The present invention thus has an activity in the proliferation of clonal cells selected from isoflavonoids and similar compounds of chromone type, in the treatment of cancer using at least one anti-tumor agent selected from cytotoxic substances. Compounds, in particular compounds of the structure

(I)

Where:

R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, OH, a C ₁ to C ₄ alkoxy group, a -OCOR ₇ group, R ₇ is a C ₁ to C ₄ alkoxy group, R ₁ At least one of R ₂ , R ₃ and R ₄ substituents is not H, and R ₂ and R ₃ may together form a methylenedioxy group,

R ₅ is selected from H, OH, a C ₁ to C ₄ alkoxy group, an O-glycosyl group and a cyclohexyl group,

R ₆ is selected from a cyclohexyl group, a phenyl group and a phenyl group substituted one to three times with H, OH and a C ₁ to C ₄ alkoxy group,

- Also, Represents a double bond or a single bond.

Preferred groups of compounds of formula I are those wherein R ₆ is selected from phenyl group, 4-hydroxyphenyl group and 4- (C ₁ -C ₄ alkoxy) phenyl group.

Cytotoxics can be used in conventional dosages, in which case their efficacy is improved, taking into account the increase in antitumor efficacy of cytotoxics if the desired purpose is first to improve the patient's adaptability to such treatment, Small dosages may be used.

The invention also interferes with the development of clonal cells by stimulating or inhibiting proliferation and swelling, thereby having a therapeutically effective amount of isoflavonoid or chromone type analogues having activity on the proliferation of clonal cells. A compound, in particular a composition comprising a compound selected from compounds of the structure:

(I)

Where:

R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, OH, a C ₁ to C ₄ alkoxy group, a -OCOR ₇ group, R ₇ is a C ₁ to C ₄ alkyl group, R ₁ , At least one of the R ₂ , R ₃ and R ₄ substituents is not H, and R ₂ and R ₃ together may form a methylenedioxy group,

R ₅ is selected from H, OH, a C ₁ to C ₄ alkoxy group, an O-glycosyl group and a cyclohexyl group,

R ₆ is selected from a cyclohexyl group, a phenyl group and a phenyl group substituted one to three times with H, OH and a C ₁ to C ₄ alkoxy group,

- Also, Represents a double bond or a single bond.

The invention also relates to isoflavonoids, in particular as defined above, in the preparation of a medicament for interfering (by inducing or inhibiting) the development of clonal cells in tumors during treatment of the tumor with at least one cytotoxic agent. It relates to using the compound of.

In chemotherapeutic treatment of carcinomas using cytotoxic substances, the isoflavonoids, especially compounds of formula I, may be used once or over the initial days of these treatments (eg 5-7 days), and chemotherapy Different protocols may be applied at the beginning of each treatment cycle (eg 2-5 days) during each treatment.

The isoflavonoids and especially compounds of formula I are advantageously administered by infusion (generally over 1 to 3 hours) at a dosage of 5-50 mg / kg / day or 200-2000 mg / m 2 / day. Do.

In order to obtain the maximum effect on the production of cloned cells, the isoflavonoids should be applied such that the tissue concentrations obtained are the highest concentrations that can be considered.

For treatment protocols in the acute phase of treatment, venous routes using the following are preferred:

Ready-to-use injectable solutions (pouches, vials, etc.), administered at the desired flow rate as the solution is injected intravenously through the infusion line

Lyophilisates that can be resuspended in a solution for intravenous infusion with the aid of pharmaceutical solutions known to those skilled in the art

For maintenance therapy, it is also possible to consider the oral route if chemotherapy treatment preferably utilizes administration of cytostatic inhibitors by the oral route. For this purpose, oral lyophilisates (for oral or sublingual absorption), immediate release or sustained release tablets, oral solutions, suspensions, particles, gelatin capsules and the like can be used.

The compounds of formula (I) are mostly natural compounds or derivatives of natural compounds. Examples include the following:

-Genistein,

Biochanin A,

-Daidzein,

Formononetin,

7-acetylformononetine,

Glycerine,

Orobol or 5,7,3 ', 4'-tetrahydroxyisoflavones,

Irizolone or 6,7-methylenedioxy-4'-hydroxyisoflavones,

Irigenin or 3 ', 5,7-trihydroxy-4,', 5 ', 6-methoxyisoflavone,

Tectorigenin or 4 ', 5,7-trihydroxy-6-methoxyisoflavone,

2-hydroxy-8-methoxy-2,3-dihydroisoflavone,

4 ', 7-dihydroxy-5-methoxyisoflavones.

Other isoflavones that may be used are those described in Donnelly et al., Natural Products Report, 1995, 321 or may be prepared by the methods described in the report.

Cytotoxics can be selected from the following compounds:

i) intercalating agents, in particular doxorubicin (adriamycin), daunorubicin, epirubicin, epirubicin, idarubicin, zorubicin, aclarubicin (aclarubicin), pyrarubicin, acridine, mitoxanthrone, actinomycin D, eptilinium acetate;

Ii) alkylating agents selected from platinum derivatives (cisplatin, carboplatin, oxaliplatin, etc.);

Iii) a compound selected from other groups of alkylating agents:

Cyclophosphamide, ifosfamide, chlormetrin, melphalan, chlorambucil, estramustine,

Busulfan, mitomycin C

Nitrosourea: BCNU (carmustine), CCNU (lomustine), fotemustine, streptozotocin

Triazines or derivatives, procarbazine, dacarbazine,

-Pipeobroman,

Ethyleneimines: altretamine, triethylenethiophosphoamide,

Iii) a compound selected from another group of anti-metabolic substances:

Antifolic agents: methotrexate, raltitrex

Antipyrimidines: 5-fluorouracil (5-FU), cytarabine (Ara-C),

-Hydroxyurea

Antipurines: purinethol, thioguanine, pentostatin, cladribine

Inhibitors of synthesis of cytotoxic nucleosides: gemcitabine.

Iii) a compound selected from other groups of substances with a high affinity for tubules:

Vinca alkaloids that destroy mitotic spindles: vincristine, vinblastine, vindesine, navelbine

Substances that inhibit depolymerization of mitotic spindles: paclitaxel, docetaxel,

Substances that induce destruction in DNA by inhibition of topoisomerase II: etoposide, teniposide

Inhibitors of topoisomerase I that induce breakdown in DNA: topotecan, irinotecan

Iii) substances that destroy and fragment DNA, such as bleomycin,

Iii) one of the following compounds: plicamycin, L asparaginase, mitoguazone, dacarbazine,

암) anticancer progesterone steroids: medroxyprogesterone, megestrol,

Iii) anticancer agent estrogen steroids: diethylstilbestrol; Tetrasodium fosfestrol,

Antiestrogens: tamoxifen, droloxifen, raloxifen, aminogluthetimide,

xi) steroidal antiandrogens (eg cyproterone) or nonsteroidal antiandrogens (flutamide, nilutamide).

In particular, the compounds of formula I can be used in combination with all therapies using the major cytotoxics used in the multichemistry of solid tumors such as:

-Doxorubicin

Alkylating agents: oxazophorines (cyclophosphamide, ifosfamide, chlorambucil, melphalan)

-Nitrosoureas

-Mitomycin C

Antimetabolic products such as methotrexate, 5-FU, Ara-C, and capecitabine

Tubulin interferences: vinca alkaloids (vincristine, vinblastine, vindesine, navelbin), taxoids (paclitaxel, docetaxel), epipipodophyllotoxins (etopipside, teni) Fourside)

-Bleomycin

Inhibitors of topoisomerase I: topotecan, irinotecan.

Similarly, compounds of formula I can be used in combination with therapies using the major cytotoxic agents used in oncology for the treatment of hematological cancers:

Hodgkin's disease: cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;

Acute leukemias: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase;

Non-Hodgkin's malignant lymphomas: mechloretamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunorubicin, Carmustine, lomustine, cisplatin;

Chronic lymphocytic leukemias: mechloretamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.

The results of pharmacological trials describing the effects obtained will appear below.

1.- Interaction with Clonogenic Cells (Stimulation or Suppression of Proliferation) (Clonogenicity Test)

The tests used are described in Hamburger et al. (Science, 1977; 197, 461-463) and Salmon et al. (New England J. Med., 298, 1321-1327). Cells are considered to be clonal if they have a proliferative capacity and the ability to form cell colonies. "Human tumor stem cells" are cells that originate the tumor cells that make up a tumor. These tumor hepatocytes cause recurrence progression that can be observed after surgical removal of the initial tumors and also the formation of metastases. At the tumor or tumor cell line level, these clonal stem cells can be distinguished from the tumor or other cells of the tumorous cell line under consideration by the fact that they possess the ability to proliferate without any solid support.

In this test, tumor cells were cultured on a semisolid support. Cells that do not require a solid support for growth (i.e., "Dolster-Independent Cells" in MI Dawson et al., Cancer Res. 1995; 55: 4446-4451; also clonal cells involved in "growth of clones") Only highly tumorigenic cells, which are termed ROS, can develop on these agar-based supports. Indeed, normal cells, such as fibroblasts-growing in an "adherent manner" (fixture-dependent cells according to M.I. Dawson's nomenclature)-can not survive on such media. Within the cultured tumor cell population, cells that can be grown on these scaffolds (which are involved in an infinite number of cell divisions and their proliferation are termed "fixation-independent [clone] growth" according to MI Dawson) Clonogenic cells. The percentage of these clonal cells present in the tumor or cell line varies between 0.1 and 0.001%. Nonclonogenic cells (related to a limited number of cell divisions) are those that must arise in a "method of attachment" ("fixed-dependent [fixed] growth", MI Dawson et al., Cancer Res. 1995; 55: 4446-51). It does not grow in this test because it requires a solid support for growth.

As an example, the effect of compounds of formula (I) on the growth of cell colonies obtained by culturing mammalian tumor strains MCF7 and MXT and rectal colon HT-29 on a semi-liquid culture medium termed "soft agar" was measured. . On this medium, M.I. Only cloned cells, termed “fixation-independent (clonal) cells” by Dawson, survive and grow. This "non-stick" mode of growth of these cells reflects their degree of tumorigenicity. Inhibition of tumor size in which a larger number of clonal cells has grown is a control for enhanced cytotoxic activity.

On the other hand, the test can also reveal that the compound can inhibit the development / proliferation of clonal cells, thereby lowering the growth capacity of the tumor and thus reducing the population of tumor cells.

Tumor cell lines studied were cultured in 25 cm 2 falcon flasks. Then they were trypsinized and the cells were well separated from each other. The percentage of live cells after staining with trypan blue was determined. Cell suspensions of concentrations of 5 · 10 ⁴ to 15 · 10 ⁴ cells / ml (depending on the cell type considered) were prepared in 0.3% agar solution. Thereafter, 200 µl of this suspension was inoculated into a Petri dish on which 3 ml of a bottom layer containing a 0.5% agar solution of 35 mm in diameter was deposited. The 200 μl cell suspension is then covered with 1.8 mL of the top layer containing 0.3% agar solution. The dishes were then placed in an incubator at 37 ° C., 5% CO ₂ and 70% humidity conditions before being used for treatment. This was done about 1 to 2 hours after inoculation. The compounds to be tested were prepared at concentrations 100 times higher than desired, and 50 μl of these treatment solutions were placed on the agar top layer of the dishes. In this study, the final concentrations of the tested products were 10 ⁻⁵ , 10 ⁻⁷ and 10 ⁻⁹ M. The dishes were then stored for 21 days in an incubator. On day 21, MTT (2- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetra at a concentration of 1 mg / ml prepared using RPMI 1640 medium at 37 ° C. for 3 hours. The dishes were treated by adding 100 [mu] l of zolinium bromide) solution to the top layer. After this period, the cell colonies were fixed by adding 2 ml of formalin per dish. After fixation for 24 hours, formalin was evaporated and the number of stained cell colonies containing metabolically active cells, whose surface area was greater than 100 μm ^2, was measured using an inverted microscope.

The average number of clonal cell clones determined at each experimental condition studied was expressed as a percentage of the average number of clonal cell clones measured under control conditions at 100%. These values, expressed as percentages for the control conditions, are shown in Table 1.

The results summarized in the table above represent the mean value ± standard error of the mean (SEM) established for at least 6 wells.

-Control group = 100%

(NS: p> 0.05; *: p <0.05; **: p <0.01; ***: p <0.001).

Depending on the cell lines studied, genistein is:

-Can clone the clonal cells within the tumor (MXT cell lines at 10 ^-5 M and 10 ^-7 M concentrations, HT-29, 10 ^-7 M and 10 ^-9 M concentrations), ie control conditions Induces a significant increase in the number of colonies of these cells as compared to those obtained below, making these cells more sensitive to existing treatments with cytotoxics, or

-It can directly inhibit the proliferation of these clonal cells (MCF7 cell lines at concentrations of 10 ^-5 M and 10 ^-7 M).

2. Cytotoxic Activity at Concentration of Non-Clonogenic Cells: "MTT Test"

The effect of the compounds of formula (I) on nonclonogenic cells was measured using the MTT colorimetric test.

The principle of the MTT test is that the yellow MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) substance is a blue product by viable metabolically active cells. It is based on mitochondrial reduction to formazan. The amount of formazan thus obtained is directly proportional to the amount of live cells present in the culture well (s). The amount of formazan was measured with a spectrophotometer.

Cell lines were maintained in monolayer cultures at 37 ° C. in stoppered culture dishes with basal medium MEM 25MM HEPES (minimum essential nutrient medium). This medium is well suited for the growth of a wide range of mammalian diploid or primary cells. The medium was then supplemented with the following materials:

5% SVF (placental serum) decompensated over 1 hour at 56 ° C.,

0.6 mg / ml L-glutamine,

200 IU / ml penicillin,

200 μg / ml streptomycin,

0.1 mg / ml gentamicin.

The twelve human cancer cell lines used were obtained from the American Cell Sample Repository (ATCC, Rockvill, MD, USA). These twelve cell lines are:

Two glioblastomas, U-373MG (ATCC No .: HTB-17) and U-87MG (ATCC No .; HTB-14),

Astrocytoma SW1088 (ATCC No .: CCL-185),

Two non-small cell lung carcinomas A549 (ATCC No .: CCL-185) and A-427 (ATCC No .: HTB-53),

Two rectal carcinomas, HCT-15 (ATCC No .: CCL-225) and LoVo (ATCC No .: CCL-229),

Two breast carcinomas, T-47D (ATCC number: HTB-133) and MCF7 (ATCC number: HTB-22)

Two bladder carcinomas, J82 (ATCC number: HTB-1) and T24 (ATCC number: HTB-4)

PC-3 (ATCC No .: CRL-1435), a prostate cancer.

In the experimental aspect, 100 μl of a cell suspension containing 20,000 to 50,000 cells / ml of culture medium (depending on the cell type used) was inoculated into a 96-well multi-well plate and an atmosphere containing 5% CO ₂ and Incubate at 37 ° C. under 70% humidity. 24 hours after incubation, fresh medium 100 containing various compounds to be tested at a concentration that can vary between 10 ^-5 to 10 ^-10 M, or a solvent provided for dissolution of the product to be tested (control). Replace the culture medium with μl. After 72 hours of incubation under these conditions, the culture medium was replaced with 100 μl of a yellowish-colored MTT solution dissolved in RPMI 1640 at an amount of 1 mg / ml. The microplates were incubated at 37 ° C. for 3 hours and then centrifuged at 400 g for 10 minutes. The yellowish MTT solution was removed and blue formazan crystals formed in the cells were dissolved in 100 μl of DMSO. The microplates were then stirred for 5 minutes. The intensity of blue of the result, ie the degree of conversion of the yellow MTT product to blue formazan by the cells surviving to the end of the experiment, corresponds to the maximum absorption wavelength and fundamental noise of formazan, respectively, using a device of the DYNATECH IMMUNOASSAY SYSTEM type. Qualitative analysis was carried out at 570 nm and 630 nm wavelength spectrophotometrically. The software integrated in the spectrophotometer calculates average optical density values as well as standard deviation (Std. Dev.) And standard error of the mean (SEM).

As a non-limiting example, isoflavonoids: the results of mean optical density obtained using Genistein on five tumor cell lines U-87MG, J82, HCT-15, T-47D and A549, the average optical measured under control conditions It is shown in Table II as a percentage of the density (set to 100%).

xx ± yy = mean value ± standard error of the mean

Control condition = 100%

-(NS: p> 0.05; *: p <0.005; **; p <0.01; ***: p <0.001).

Genistein has low antitumor capacity. In this case, this non-toxic substance induces inhibition of the overall cell proliferation of these cell lines at a concentration of 10 ⁻⁵ M, which inhibition does not exceed 20%. At other concentrations tested, only some minor effects were seen.

3. Determination of Maximum Tolerated Dose (MTD):

The maximum tolerated dose was measured using B6D2F1 / Jico mice, 4-6 weeks old. Compounds were administered via an intraperitoneal route with increasing dose in the range of 2.5-160 mg / kg. MTD values (expressed in mg / kg) were determined by observing the ratio of surviving animals over a period of 14 days after a single administration of the material under consideration. Changes in the weight of the animals were also observed over this period. When the MTD value was greater than 160 mg / kg, the MTD value was regarded as the default value of 160 mg / kg.

Genistein is associated with MTD corresponding to 160 mg / kg by default. This result means that the substances of the isoflavonoid family do not show any direct toxicity and can be used at high concentrations, ie high doses, in tissues.

4. In vivo antitumor activity associated with cytotoxic substances

In the presence or absence of cytotoxic substances such as cyclophosphamide, etoposide, doxorubicin or vincristine,

Mammary gland adenocarcinoma MXT (HS-MXT) in hormone-sensitive rats,

The test was performed on lymphoma P 388 models.

When the MTD value for the substance was determined, its in vivo antitumor activity was characterized by the doses of MTD / 2, MTD / 4 and MTD / 8 in the rat-derived adenocarcinoma HS-MXT and lymphoma P388 models. This is the dose that showed the highest antitumor activity in these other models selected and used in connection with the treatment associated with the cytotoxic material.

In all of the examples given below, whatever model (mammary adenocarcinoma HS-MXT or lymphoma P 388), the control conditions were 0.2 ml of physiological saline containing the solvent used to dissolve the other compounds of formula (I) used. This means that a group of nine rats is administered at a dose rate of five times per week (Mon, Tue, Wed, Thu and Fri) for 5 consecutive weeks.

During these tests, the following were determined:

i) -survival rate of rats

Survival was calculated in the form of T / C ratios:

T = (50% survival time of mice in group of treated mice) +

C = (50% survival time in rats in control) +

This ratio represents the mean survival time for 50% of the rats in the treated rat group versus the mean survival time for 50% of the rats in the control rat group. Thus, when the T / C ratio is above 130%, the molecule induces a significant increase (P <0.05) in the survival of the animals. On the other hand, if the T / C value is lower than 70% indicates a toxicity.

Ii)-Tumor growth by measuring the surface area of HS-MXT and P388 tumors implanted twice a week (Monday and Friday). The surface area is calculated by taking the products with the values of the two largest vertical axes in the tumor. The values of these axes are measured using a slide scaler.

4.1. Mammary gland adenocarcinoma (HS-MXT)

Mammary gland adenocarcinoma MXT model of hormone-sensitive (HS-MXT) mice transplanted into B6D2F1 / Jico mice, 4-6 weeks old, were derived from the mammary gland's galactophorous ducts (Watson C. et al., Cancer Res. 1977; 37: 3344-48).

The results obtained by using Genistein alone or in combination with cytotoxic substances will be presented in the form of examples.

Processing 1

Genistein was administered alone. The first injection of this material was taken on day 7 post-transplantation (D7) and was performed for four consecutive weeks with 5 weekly injections (Mon, Tue, Wed, Thu and Fri) at a dose of 20 mg / kg.

Processing 2

Cyclophosphamide was administered alone. The first injection of the material was taken on day 14 post-transplantation (D14) and was performed for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 10 mg / kg.

Processing 3

Vincristine (VCR) was administered alone. The first injection of this material was taken on day 14 post-transplantation (D14) and was performed for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 0.63 mg / kg.

Processing 4

Etoposide (ETO) was administered alone. The first injection of the material was taken on day 14 post-transplantation (D14) and was performed for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 10 mg / kg.

Processing 5

Genistein was administered with cyclophosphamide. In this case, the first injection of Genistein was performed on day 7 post-transplantation (D7) and was administered for 4 consecutive weeks with 5 mg / week injections (Mon, Tue, Wed, Thu and Fri) at a dose of 20 mg / kg. The first injection of cyclophosphamide was performed on day 14 post-transplantation (D14) and was performed for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 10 mg / kg.

Processing 6

Genistein was administered with vincristine. In this case, the first injection of Genistein was performed on day 7 post-transplantation (D7) and was administered for 4 consecutive weeks with 5 mg / week injections (Mon, Tue, Wed, Thu and Fri) at a dose of 20 mg / kg. The first injection of vincristine was performed on day 14 post-transplantation (D14) and was administered for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 0.63 mg / kg.

Processing 7

Genistein was administered with etoposide. In this case, the first injection of Genistein was performed on day 7 post-transplantation (D7) and was administered for 4 consecutive weeks with 5 mg / week injections (Mon, Tue, Wed, Thu and Fri) at a dose of 20 mg / kg. The first injection of etoposide was performed on day 14 post-transplantation (D14) and was administered for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 10 mg / kg.

Results for survival obtained for Genistein (Table III) will be shown below.

These results indicate that co-administration of genistein with cytotoxic substances: cyclophosphamide, vincristine or etoposide compared to the average survival time of the average rats of the control rat group compared to the average rats of the rats of the other treated groups. Shows a significant increase in mean survival time. In addition, this increase in the average survival time for the average rats of the rats of other groups treated with this co-administration is significantly prolonged than the results obtained with treatments involving the use of genistein or these cytotoxic agents alone. will be.

Studies on tumor growth further reveal the following results. Table IV below shows other treatments 1, compared to the control group on day 28 post tumor implantation, ie 15 doses of genistein and 6 doses of cytotoxics used or 6 co-administration with Genistein. Reduction (-) or increase (+), expressed as a percentage in the surface area of HS-MXT tumors induced by 2, 3, 4, 5, 6 and 7. On day 28 after transplantation, 89% of control animals (ie 8 out of 9) were still alive.

These results indicate that co-administration of genistein and cytotoxic substances: vincristine and etoposide significantly reduces the growth of HS-MXT tumors, and this reduction is indicated by the use of Genistein alone alone (with no associated clinical effect). None) or a greater reduction than that induced by treatments involving sole use of the two cytotoxic agents alone.

4.2. Lymphoma P 388:

The 4-6 week old CDF1 mice received implants containing P388 tumor fragments (tumors obtained from the tumor and stored in the laboratory) on the right subcutaneous day at D0. In order to ensure that the situation is the same as the actual clinical situation, wait until day 5 post-transplantation (D5) before starting treatment. This is because subcutaneous P388 tumors are palpable after this period.

By way of example, the results obtained using genistein alone or in combination with vincristine are shown below.

Processing 1

Genistein was administered alone. The first injection of this material was performed on day 5 post-transplantation (D5) and was performed for five consecutive weeks with five injections per month (Mon, Tue, Wed, Thu and Fri) at a dose of 40 mg / kg.

Processing 2

Vincristine (VCR) was administered alone. The first injection of this material was done on day 5 post-transplantation (D5) and was performed for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 0.63 mg / kg.

Processing 3

Genistein was coadministered with vincristine. In this case, the first injection of Genistein was performed on day 5 (D5) after transplantation, and was administered for 5 consecutive weeks with 5 mg / week injections (Mon, Tue, Wed, Thu and Friday) at a dose of 40 mg / kg. The first injection of vincristine was performed on day 5 post-transplantation (D5) and was administered for three consecutive weeks with three injections per month (Mon, Wed and Fri) at a dose of 0.63 mg / kg.

The results obtained in treatments 1, 2 and 3 for the survival of the mice are shown in Table V below.

These results indicate that co-administration of genistein and vincristine significantly increases the average survival time for the average rats of the other groups of treated mice as compared to the average survival time for the average rats of the control rat group. In addition, this increase in mean survival time for treated average rats is very markedly high compared to the survival time for the average rats of the other groups of genistein or vincristine treated mice used alone.

Examples of the form of using the compound of Formula I in a multiple chemotherapy protocol with single- or cytotoxic agents will be shown below.

A. Solid tumors

One/ Lung carcinoma

1.1. Non-small cell type (advanced stage):

Intravenous infusions of genistein or other isoflavonoids were added to a preferred protocol (T. Le Chevalier et al., J. Clin. Oncol. 1994; 12. 360-367):

The treatment was repeated eight times.

1.2. Small cell type (advanced stage):

Isoflavonoid injections were added to the preferred CAV or VAC protocol (B.J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291):

The treatment was repeated six times every 21 days.

Genistein injections were added to the preferred Pt-E protocol (B. J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291).

Each cycle was repeated every 21 days and the treatment included six cycles.

1.3. Locally advanced or metastatic non-small cell bronchial cancer:

Monochemistry:

The treatment may comprise a four week cycle repeat.

Gemcitabine / cisplatin combination:

The treatment includes a cycle repeat every 21 days.

2/ Breast carcinoma

CMF protocol as adjuvant therapy for surgical breast cancer (G. Bonnadonna et al., N. Engl. J. Med .; 1976; 294; 405-410):

Each cycle is repeated every 28 days and the treatment comprises six cycles.

AC protocol as adjuvant therapy (B. Fisher et al., J. Clin. Oncol; 1990; 8: 1483-1496):

Each cycle is repeated every 21 days and the treatment comprises four cycles.

Breast carcinomas with metastases:

In the FAC protocol (A.U. Buzdar et al., Cancer 1981; 47: 2537-2542) and other variants thereof, isoflavin infusions were added according to the following table (but not limited to):

Each cycle was repeated every three weeks until new progress in the disease was diagnosed.

In CAF protocol (G. Falkson et al., Cancer 1985; 56: 219-224):

Each cycle was repeated every 28 days until new progress in the disease was diagnosed.

In the CMF protocol:

This cycle is repeated every 3 to 5 weeks and the treatment comprises 6 cycles.

In the CMF-VP protocol:

The treatment was repeated every four weeks.

In the FEC protocol:

The treatment was repeated every three weeks.

In the MMC-VBC protocol (C. Brambilla et al., Tumori, 1989; 75: 141-144):

Each cycle was repeated every 28 days until new progress in the disease was diagnosed.

In the NFL protocol (S.E. Jones et al., J. Clin. Oncol. 1991; 9: 1736-1739):

The treatment includes two cycles of 21 day intervals, after which an evaluation is required.

The isoflavonoid injections are also, for example:

When taxoids are used in combination with paclitaxel (FA Holmes et al., J. Natl Cancer Inst. 1991; 83; 1797-1805) in the treatment of forms with metastases that may be resistant to anthracyclines. It may be combined with the treatment of breast carcinomas, including metastases.

Each cycle was repeated every 21 days until new progress in disease was diagnosed.

Docetaxel (CA Hudis et al., J. Clin. Oncol. 1996; 14: tolerant in locally advanced or metastatic breast cancer or in relapse after cytotoxic chemotherapy (including anthracycline) or during adjuvant therapy) 58-65)

The cycle is repeated every 21 days for two cycles of treatment or until progression of the disease occurs.

In dose enhancing protocols combined with the transplantation of autologous bone marrow cells and peripheral blood cell cells as a priority treatment, for example:

CPB protocol (WP Peters et al., J. Clin. Oncol. 1993; 11: 132-1143), wherein intravenous infusion of hepatocytes was performed on D ₋₁ , D ₀ and D ₁ :

CTCb protocol (K. Antman et al., J. Clin. Oncol. 1992; 10: 102-110), wherein intravenous infusion of hepatocytes was performed at D ₀ :

- CTM protocol (..., Etc. LE Damon, J. Clin Oncol 1989; 7: 560 ~ 571 and the IC Henderson, etc., J. Cellular Biochem 1994 (Suppl 18B ): 95) intravenous infusion of hematopoietic stem cells here is D ₀ Was performed on:

3 / Gynecological Carcinoma

3.1. Ovarian Cancer:

Especially for the treatment of metastatic ovarian carcinoma:

i) PAC protocol (GA Omura et al., J. Clin. Oncol. 1989; 7: 457-465): Infusions of isoflavonoids were administered according to the following table:

This cycle was repeated every 21-28 days and treatment included eight cycles.

. Ⅱ) A. Trail Marietta al vitamin protocol (Gynecol Oncol, etc. according 1990; 36: 93 ~ 96):

This treatment includes two cycles of 28 day intervals.

Paclitaxel protocol : Isoflavonoids can be added to the paclitaxel protocol as described by WP McGuire et al. (Ann. Intern. Med. 1989; 111: 273-279):

Treatment involves two cycles of 28 day intervals (evaluation at the end).

For the treatment of metastatic and resistant ovarian carcinomas, isoflavonoids can be added to a second level protocol based on topotecan:

A.P. According to Kudelka et al. (J. Clin. Oncol. 1996: 14: 1552-1557), treatment involves two cycles, with intervals of 21 days (evaluated at the end).

3.2 Trophoblastic Tumors:

In patients at low risk, isoflavonoids can be used in combination with the protocol described in H. Takamizawa et al. (Semin. Surg. Oncol. 1987; 3: 36-44):

(MTX-DATC protocol).

3.3 Uterine Carcinomas:

The isoflavonoids can also be used in combination with the CAV (or VAC) protocol according to the table below.

Treatment involves repeating every 21 day cycle.

In the FAP protocol:

The treatment includes repeating every 21 or 28 day cycles.

4/ Testicular and prostate carcinoma

The isoflavonoids can be used in combination with testicular cancer protocols:

BEP protocol:

The treatment comprises three cycles in which every 21 days is one cycle.

5 / Bladder Carcinoma

The isoflavonoids can be used in combination with the CISCA2 (also known as PAC) protocol.

The cycle is repeated every three weeks.

In the MVAC protocol (CN Sternberg et al., J. Urol. 1988; 139: 461-469):

The cycle is repeated at least twice every four to five weeks.

6 / Nasopharyngeal Carcinomas / Head and Neck Carcinomas

The isoflavonoids can be used in legal combination with the multiple chemotherapy protocols used for the treatment of the carcinomas:

6.1 Nasopharyngeal Carcinomas:

ABVD protocol:

The treatment comprises one cycle repeated at one to six cycles, at a rate of every four weeks.

6.2 Head and Neck Carcinomas with Transitions:

According to the DVAL Research Group (New Engl. J.M. 1991; 324: 1685-1690): Pt-FU protocol (e.g. for pharyngeal cancer):

The treatment comprises two cycles, at a rate where every three weeks is one cycle.

7 / Soft tissue carcinomas

The isoflavonoids can be introduced in protocols such as the CYVADIC protocol:

-H.M. According to Pinedo et al. (Cancer 1984; 53: 1825):

The treatment involves repeating the cycle every four weeks twice.

8/ Hormone-refractory prostate cancer with metastases

-G.R. In VBL-Estramustine according to Hudis et al. (J. Clin. Oncol. 1992; 10: 1754: 1761):

Treatment cycles lasted six weeks and then spaced for two weeks.

9 / Germ Cell Carcinomas

i) for tumors with a favorable prognosis:

-G.J. Pt-E protocol according to Bosl et al. (J. Clin. Oncol. 1988: 6: 1231-1238)

The treatment includes four cycles at a rate of one cycle every 21 or 28 days.

ii) for tumors with metastases:

-S.D. PEB protocol according to Williams et al. (N. Eng. J. Med. 1987; 316: 1435-1440):

The treatment comprises four cycles, at a rate of one cycle every 21 days.

10 / Kidney Carcinoma

Metastatic Kidney Carcinoma: The isoflavonoids can be introduced in the protocol described by MJ Wilkinson et al. (Cancer 1993; 71: 3601-3604):

The treatment includes two cycles of 28 day intervals.

Nephroblastoma: The isoflavonoids can be introduced into the DAVE protocol at a rate of one cycle every three to four weeks:

11 / Gastrointestinal Carcinoma

11.1 Esophageal Carcinoma:

The isoflavonoids can be introduced in the FAP protocol according to the following:

The cycle is repeated every three to four weeks.

11.2 Gastric Carcinomas

Gastric carcinomas with advanced and / or metastases:

EAP protocol (according to P. Preusser et al., J. Clin. Oncol. 1989; 7: 1310):

Every 28 days performed at a rate.

FAMtx protocol: J.A. According to Wils et al. (J. Clin. Oncol. 1991; 89; 827):

The treatment comprises two cycles, 28 days apart.

In certain patients, the protocol or variants thereof (substituting doxorubicin for epirubicin) can be used according to the following table:

12 / Colorectal carcinoma

The isoflavonoids can be introduced into the protocol for adjuvant FU-Levamisole adjuvant treatment of colorectal cancer (according to C.G. Moertel et al., N. Eng. J. Med. 1990; 322: 352):

Treatment in which 5-FU is in the form of pills is repeated weekly after the introduction phase of D ₁ to D ₅ ; The treatment uses isoflavonoids repeated at the same rate on the day using 5-FU pills and two days thereafter.

For the treatment of treatment-resistant colorectal cancer with 5-fluorouracil (5-FU) metastases:

-M.L. According to Rothenberg et al. (J. Clin. Oncol. 1996; 14: 1128-1135):

The treatment comprises two cycles of 42 days apart.

13 / Kaposi's Breeding

The isoflavonoids can be used in combination with two protocols using antracyclines formulated in the form of liposomes:

i) P.S. Gill et al. (J. Clin. Oncol. 1995; 13: 996-1003) and C.A. Protocol described by Presant et al. (Lancet 1993; 341: 1242-1243):

The treatment comprises two cycles repeated at intervals of 28 days prior to assessing effectiveness.

ii) M. Harrison et al. (J. Clin. Oncol. 1995; 13: 914-920):

The treatment comprises two cycles repeated at intervals of 28 days prior to assessing effectiveness.

14 / Metastatic melanoma (melanomas)

The isoflavonoids can also be included in combined protocols for treating metastatic malignant melanoma:

DTIC / TAM protocol: according to G. Cocconi et al. (N. Eng. J. Med. 1992; 327: 516), the treatment comprising 4 cycles of repetition, with 1 cycle every 21 days according to the table below :

The treatment includes four cycle repetitions at a rate of one cycle every 21 days.

15 / Neuroendocrine cancer

The isoflavonoids are C.G. It can be used in combination with the protocol described by Moertel et al. (Cancer 1991; 68: 227):

Pt-E protocol:

The treatment includes two cycles, repeated every 28 days.

16 / Pancreatic cancer

Advanced-stage pancreatic adenocarcinoma : The isoflavonoids can be used in combination with treatment with gemcitabine according to the protocol of M. Moore et al. (Proc. Am. Soc. Clin. Oncol. 1995; 14: 473). :

B. Blood Tumors

One/ Acute adult leukemia

1.1 Acute Lymphoblastic Leukemia:

1.1.1. Linker Protocol

The isoflavonoids are described in Linker protocols-induced chemotherapy and fortification chemotherapy according to the following table (see CA Linker et al., Blood 1987; 69: 1242-1248 and CA Linker et al., Blood 1991; 78: 2814-2822). Can be added.

i) Induction Chemotherapy:

ii) enhanced chemotherapy (therapy A):

The augmentation therapy A comprises four consecutive cycles as described above = 1, 3, 5 and 7 cycles.

iii) enhanced chemotherapy (therapy B and C):

The therapies described below are described in C.A. Corresponds to strengthening periods 2, 4, 6 and 8 (therapy B) and 9 (therapy C), described by Linker et al .:

Therapy B:

Ect C:

1.1.2. Hoelzer Protocol

The claimed products can be added to the cytotoxic substances of the multichemotherapy protocol (D. Hoelzer et al., Blood 1984; 64: 38-47, D. Hoelzer et al., Blood 1988; 71; 123-131) according to the following table. have:

i) Induction Chemotherapy / Step 1:

ii) induction chemotherapy / step 2:

The second stage of derivation is carried out as follows:

iii) Reinduced Chemotherapy / Step 1:

iv) Reinduced Chemotherapy / Step 2:

1.2. Acute Myeloid Leukemia:

1.2.1 Treatment of Adults of Any Age

Isoflavonoids are described in R.O. Dilleman et al. (Blood, 1991; 78; 2520-2526), Z.A. Arlin et al. (Leukemia 1990; 4: 177-183) and P.H. It may be added to a treatment comprising the standard dosage of cytarabine previously described by Wiernik et al. (Blood 1992; 79: 313-319):

1.2.2. Treatment of Adults Under 60 Years Old

i) Induction Chemotherapy:

This induction cycle involves the administration of high doses of cytarabine according to the following table:

(To reduce the risk of S.N.S. toxicity, in the case of renal force, adjust the dose of cytarabine to eliminate creatinine.) L.E. Damon et al. (Leukemia 1994; 8: 535-541), G.L. According to Phillips et al. (Blood 1991; 77: 1429-1435) and G. Smith et al. (J. Clin. Oncol. 1997; 15: 833-839).

ii) Enhanced Chemotherapy:

The cycle described below will be repeated eight times, at a rate of one cycle every four to six weeks (according to R.J.Mayer et al., N. Engl J. Med. 1994; 331: 896-903):

iii) fortified chemotherapy (high dose cytarabine):

The cycle described below will be repeated twice, which is described in G.L. Phillips et al. (Blood 1991; 77: 1429-1435); S.N. Wolff et al. (J. Clin. Oncol. 1989; 7: 1260-1267); Adjusted according to R. J. Mayer et al. (N. Engl J. Med. 1994; 331: 896-903):

1.2.3. Treatment of adults 60 or older

The claimed materials can be added to the following enhanced 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. (Blood 1992; 79: 313-319):

ii) R.J. According to Mayer et al. (N. Engl. J. Med. 194; 331: 896-903):

iii ) CA Linker et al. (Blood, 1993; 81: 311-318), N. Chao et al. (Blood 1993; 81: 319-323) and AM Yeager et al. (N. Eng. J. Med. 1986; 315: 145-). According to 147):

This protocol involves autologous bone marrow transplantation (performed on day ₀ ):

or

iv ) For HLA-compatible allogeneic 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:

2/ Chronic Adult Leukemia

2.1 Chronic Myeloid Leukemia

In the myeloblastic stage, the isoflavonoids are C.A. It may be added to the HU-Mith treatment described by Koller et al. (N. Engl. J. med. 1986; 315: 1433-1438):

2.2 Chronic Lymphocytic Leukemia

2.2.1 FCG-CLL Protocol

The isoflavonoids are described as "pulsed chlorambucil" as described by E. Kimby et al. (Leuk. Lymphoma 1991; 5 (Suppl.) 93-96) and FCGCLL (Blood 1990; 75: 1422-1425). Can be added to:

2.2.2 Fludarabine-CdA Protocol

H.G. Chun et al. (J. Clin. Oncol. 1991; 9: 175-188), MJ Keating et al. (Blood 1989; 74: 19-25 / J. Clin. Oncol. 1991; 9: 44-49) and A. Saven et al. (J. Clin. Oncol. 1995; 13: 570--574):

3 / Lymphoid Proliferative Diseases

3.1 Hodgkin's disease

The isoflavonoids can be included in multiple chemotherapy protocols commonly used to treat Hodgkin's lymphoma:

3.1.1 AVDB protocol

G. Bonnadonna et al. (Cancer Clin. Trials 1979; 2: 217-226) and G.P. According to Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484)

The treatment includes 6 to 8 cycles, with a rate of 1 cycle every 28 days.

3.1.2 MOPP / ABVD Protocol

G. Bonnadonna et al. (Ann. Intern. Med. 1986; 104: 739-746) and G.P. According to Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484):

The MOPP protocol must be able to be replaced with the ABVD protocol (see § 3.3.1) every 28 days and the treatment includes six cycles:

MOPP protocol:

3.1.3 Stanford V Protocol

N.L. According to Bartlett et al. (J. Clin. Oncol. 1995; 13: 1080-1088):

The treatment comprises three cycles, at a rate where every 28 days is one cycle.

3.1.4. EVA protocol

G.P. According to Canellos et al. (Proc. Am. Soc. Clin. Oncol. 1991; 10: 273):

The treatment comprises 6 cycles, every 28 days at a rate of 1 cycle.

3.1.5. B-CAVe protocol

W.G. According to Harker et al. (Ann. Intern. Med. 1984; 101: 440-446):

The treatment comprises eight cycles, at a rate where every 28 days is one cycle.

3.2. Non-Hodgkin's Lymphomas

3.2.1. Low Grade Malignant Non-Hodgkin's Lymphomas

i)-CVP protocol

-C.M. Bagley et al. (Ann. Intern. Med. 1972; 76: 227-234) and C.S. According to Portlock et al. (Blood 1976; 47: 747-756)

The cycle is repeated every 21 days depending on the maximum response.

ii)-I-COPA protocol

According to RV Smalley et al. (N. Eng. J. Med. 1992; 327: 1336-1341)

The treatment includes 8 to 10 cycles, with a rate of 1 cycle every 28 days.

iii)-fludarabine-CdA protocol

P. Solol-Celigny et al. (Blood 1994; 84 (Supp. 1): 383a), H. Hoeschster et al .; (Blood 1994; 84 (Supple. 1): 564a and AC Kay (J. Clin. Oncol. 1992; 10: 371-377).

For fludarabine, each cycle is repeated every 28 days; For cladribine, each cycle is repeated every 35 days.

3.2.2. Medium Grade Malignant Non-Hodgkin's Lymphomas

i)-CHOP or CNOP protocol

EM Mckelvey et al. (Cancer 1976; 38: 1484-1493), J.O. According to Armitage et al. (J. Clin. Oncol. 1984; 2: 898-902) and S. Paulovsky et al. (Ann. Oncol. 1992; 3: 205-209).

For the CHOP protocol,

Mitoxantrone (N) can be used in place of doxorubicin (CNOP protocol) in patients older than 60 years (dose: 12 mg / m 2 as intravenous pill on day D1 of each cycle).

The treatment with the CHOP or CNOP protocol includes 6-8 cycles in which every 21 days is one cycle.

ii)-MACOP-B protocol

According to P. Klimo et al. (Ann. Intern. Med. 1985; 102: 596-602) and I. A. Cooper et al. (J. Clin. Oncol. 1994; 12: 769-778).

This treatment protocol lasts 12 weeks, corresponding to one cycle.

iii)-VACOP-B protocol

-J.M. According to Connors et al. (Proc. Am. Soc. Clin. Oncol. 1990; 9: 254)

Each cycle lasts 12 weeks.

Ⅳ)-m-BACOD / M-BACOD protocol

-M.A. According to Shipp et al. (Ann. Int. Med. 1986; 140: 757-765)

The treatment comprises 10 cycles, at a rate where every 21 days is 1 cycle.

v)-ProMACE / CytaBOM protocol

-D.L. According to Longo et al. (J. Clin. Oncol. 1991; 9: 25-38)

The treatment includes 6 to 8 cycles, at a rate where every 14 days is 1 cycle.

3.2.3. Low or medium grade malignant non-Hodgkin's lymphomas

i)-ESHAP Remedy Protocol

In case of relapse or failure of first-class treatment, W.S. According to Velasquez et al. (J. Clin. Oncol. 1994; 12: 1169-1176)

The treatment comprises six cycles, at a rate where every 28 days is one cycle.

ii)-MINE Remedy Protocol

In case of relapse or failure of first priority treatment according to F. Cabanillas et al. (Semin. Oncol. 1990; 17 (Suppl. 10): 28-33)

The cycle is repeated every 21 days.

3.3. Non-Hodgkin's lymphomas; Burkitt's Lymphoma, Small Cell Lymphoma, Lymphoblastic Lymphoma

3.3.1 Magrath Protocol

Claimed materials can be combined with the Maghres protocol according to the following table:

i)-cycle 1

According to I. T. Magres et al. (Blood 1984; 63: 1102-1111)

ii)-cycle 2 ~ 15

According to I. T. Magres et al. (1984)

The treatment comprises 14 cycles, at a rate where every 28 days is one cycle.

3.4 Waldenstrom macroglobulinaemia

3.4.1 CVP Protocol

M.A. Dimopoulous et al. (Blood 1994; 83: 1452-1459) and C.S. According to the CVP protocol described by Portlock et al. (Blood 1976; 47: 747-756):

The treatment continues without limitation (every 21 days is a cycle).

3.4.2 Fludarabine-CdA Protocol

H.M. Kantarjian et al. (Blood 1990; 75: 1928-1931) and M.A. According to Dinopoulous et al. (Ann. Intern. Med. 1993; 118: 195-198):

or

The treatment includes 6-12 cycles at 28-day intervals for fludarabine and 2 to 28 cycles at 28-day intervals for cladribine.

3.5 multiple myeloma

3.5.1 MP protocol

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)

or

The treatment comprises at least 12 cycles, at a rate where every 4-6 weeks is one cycle.

3.5.2 VAD Protocol

According to B. Barlogie et al. (N. Engl. J. Med. 1984; 310: 1353-1356):

3.5.3. MP-interferon α-protocol

According to O. Osterborg et al. (Blood 1993; 81: 1428-1434):

The treatment includes non-limiting repetition of this cycle at a rate where every 42 days is one cycle.

3.5.4 VCAP or VBAP protocol

S.E. According to Salmon et al. (J. Clin. Oncol. 1983; 1: 453-461):

VCAP Protocol:

VBAP protocol: cyclophosphamide is replaced with carmustine (BCNU), the rest are the same:

C. Child Tumors-Pediatric Oncology

Isoflavonoids can also reduce the severity of side effects due to the activity and activity of clonal cells and reduce the effective dose, while multi-chemotherapeutic protocols for treating pediatric tumors to improve antitumor efficacy. It may be included in these.

1 / Ewing sarcoma / primative neuroectodermal tumour

The isoflavonoids include VCR-Doxo-CY-Ifos-Mesna-E (ED Bergert et al., J. Clin. Oncol. 1990; 8: 1514-1524; WH Meyer et al., J. Clin. Oncol. 1992; 10: 1737 ~ 1742) can be introduced:

The treatment involves 6 to 10 cycles depending on the initial severity of the sarcoma and the extent of the response.

2 / Children with Acute Lymphoblastic Leukemia

2.1 Induction Chemotherapy (D ₁ to D ₃₀ days)

The isoflavonoids include preferred protocols (PS Gaynon, J. Clin. Oncol., 1993, 11, 2234-2242; J. Pullen et al., J. Clin. Oncol. 1993; 11: 2234-2224; J. Pullen et al. , J. Clin. Oncol. 1993; 11: 839-849; VJ Land et al., J. Clin. Oncol. 1994; 12: 1939-1945):

As a result of the bone marrow experiment, progression to the enrichment phase was performed on day D ₂₈ of the treatment protocol.

2.2. Fortification / Maintenance Chemotherapy

The isoflavonoids were prepared according to the following maintenance protocol (PS Gaynon et al., J. Clin. Oncol. 1993; 11: 2234-2224; J. Pullen et al., J. Clin. Oncol. 1993; 11: 839-849; VJ Land et al., J. Clin. Oncol. 1994; 12: 1939-1945.

3 / children with acute myeloid leukemia

The isoflavonoids can be added to the induction and enrichment / maintenance protocol according to the following tables:

3.1. Induction chemotherapy

Y. Ravindranath 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):

The cycle is repeated from day D ₂₈ .

3.2. Fortification / Maintenance Chemotherapy

Y. Ravindranath 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):

4 / Children's Hodgkin's Bottle

The isoflavonoids include 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) may be added to the MOPP-ABVD protocol according to:

The cycle must be repeated six times at a rate where every eight weeks is one cycle, and the treatment comprises six cycles.

When autologous bone marrow transplantation (autograft) is prescribed, R. Chopra et al. (Blood 1993; 81: 1137-1145), C. Wheeler et al. (J. Clin. Oncol. 1990; 8: 648-656) and RJ Jones et al. The CVB protocol described by (J. Clin. Oncol. 1990, 8, 527-537) is used according to the following table (autografts are performed on day D ₀ ):

5 / Child Lymphoblastic Lymphoma

The isoflavonoids are also known as 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 protocols:

5.1 Induction Chemotherapy

5.2 Maintenance Chemotherapy

According to the following table:

The treatment comprises 10 cycles.

6 / Pediatric neuroblastoma

Preferred multiple chemotherapy Doxo-E-Cy-Pt protocols are described in R.P. Castleberry et al. (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):

Evaluation of the treatment response is performed after 9 weeks to determine future treatment direction: surgical resection, radiation therapy or new chemotherapy.

7 / Pediatric Osteosarcoma

The isoflavonoids include M. Hudson et al. (J. Clin. Oncol. 1990; 8: 1988-1997), PA Meyers (J. Clin, Oncol. 1992; 10: 5-15) and V.H.C. It may be added to the Doxo-Pt-Mtx-Lcv protocol as described by Bramwell et al. (J. Clin. Oncol. 1992; 19: 1579-1591):

8 / Rhabdomyosarcoma in children

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) includes intravenous infusion of isoflavonoids according to the following table. can do:

At the end of the 9th week of treatment, efficacy should be assessed to determine future treatment (surgery, radiation therapy, maintenance 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):

The protocol started after surgical resection.

For autologous bone marrow transplantation (autograft) according to A. Garaventar et al. (Med. Pediatr. Oncol. 1994; 22: 11-14), the E-Thio-Cy protocol can be modified according to

Bone marrow transplantation was performed on day D ₀ .

Claims (8)

A composition having activity against the proliferation of clonal cells in a tumor, comprising a therapeutically effective amount of isoflavonoids or similar compounds of chromone type. The composition of claim 1, wherein the isoflavonoid is selected from compounds of the structure: (I) Where: R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, OH, a C ₁ to C ₄ alkoxy group, a -OCOR ₇ group, R ₇ is a C ₁ to C ₄ alkoxy group, R ₁ At least one of R ₂ , R ₃ and R ₄ substituents is not H, and R ₂ and R ₃ may together form a methylenedioxy group, R ₅ is selected from H, OH, a C ₁ to C ₄ alkoxy group, an O-glycosyl group and a cyclohexyl group, R ₆ is selected from a cyclohexyl group, a phenyl group and a phenyl group substituted one to three times with a group selected from H, OH and a C ₁ to C ₄ alkoxy group, - Also, Represents a double bond or a single bond. The composition of claim 2, wherein the isoflavonoid is selected from genistein, daidzein and biochanin A. A medicament for inhibiting the development of clonal cells in tumors during the treatment of tumors with at least one cytotoxic agent, prepared using isoflavonoid or chromone type analogs. A medicament for inhibiting the development of clonal cells in tumors while treating tumors with at least one cytotoxic agent, prepared using a compound selected from compounds of the following structures: (I) Where: R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, OH, a C ₁ to C ₄ alkoxy group, a -OCOR ₇ group, R ₇ is a C ₁ to C ₄ alkyl group, R ₁ , At least one of the R ₂ , R ₃ and R ₄ substituents is not H, and R ₂ and R ₃ together may form a methylenedioxy group, R ₅ is selected from H, OH, a C ₁ to C ₄ alkoxy group, an O-glycosyl group and a cyclohexyl group, R ₆ is selected from a cyclohexyl group, a phenyl group and a phenyl group substituted one to three times with a group selected from H, OH and a C ₁ to C ₄ alkoxy group, - Also, Represents a double bond or a single bond. 6. A medicament according to claim 5, wherein the compound of formula I to be used is selected from genistein, adjyne and biocaine A. A method of chemotherapy with at least one cytotoxic agent, comprising at least one cytotoxic agent, comprising administering a therapeutically effective amount of an isoflavonoid or a chromone type analogous compound during treatment with the cytotoxic agent. 8. The method of claim 7, wherein the isoflavonoid or chromone type analogous compound is administered at the beginning of the chemotherapy treatment and each chemotherapy cycle.