JPH05500067A - Low toxicity antitumor agent based on cytostatics and xanthogenates - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Cytostatic agents and xanthogenates Low toxicity antitumor agent based on This invention is a low-toxicity antitumor agent based on cell proliferation inhibitors and xanthogenates. Phosphorus-containing alkylating cells, especially heavy metal compounds and phosphamide esters With regard to antiproliferative agents, this antitumor agent has a synergistic effect.

German Published Patent Application No. 3146772 states that it has an antiviral effect and is therefore A xantho which is particularly suitable for the treatment of lupes disease and as a prophylactic agent against influenza. Genate compounds have been described. Xanthate-derived for antiviral chemotherapy The fitness of the body is described in Arzneim, -Forsch, 24 (vol. 21, 1). 53-157, 1974.

DE 36 25 948 describes at least one lipophilic group and at least Auxiliary compounds (especially aliphatic alcohol sulfates, fatty aliphatic alcohol ether sulfates or natural fatty acids). Pharmaceutical formulations containing the combined xanthate compounds are described.

German Published Patent Application No. 3913791 states that further developments include at least one xanthogenate, at least one Ca"'C+4 fatty acid or Antiviral antitumor agent containing an alkali metal salt and tumor necrosis factor (TNFI) is listed.

As for Takuchi, TNF triggers tumor necrosis in experimental animals, and in vitro. Can kill tumor cells. However, the concentration of TNF required to achieve a therapeutic effect It is basically known that serious side effects occur.

Heavy metal compounds, and alkylating cytostatics, especially) osfamide esters Cytostatic agents based on the It is a sign. Unfortunately, these drugs are highly toxic, making it difficult to administer TNF. There are often similar problems.

The purpose of this invention is to provide synergistic anti-tumor action and direct detoxification of heavy metal compounds. When TNF is administered simultaneously or separately, it increases cell proliferation while exhibiting sufficient efficacy. The dose of the anti-proliferative agent can be substantially reduced and the dose of TNF can also optionally be reduced. As a result, TNF, even when administered simultaneously or separately, does not suppress cell proliferation. Significantly reduce or eliminate undesirable side effects resulting from drug administration. The goal is to develop combinations of active substances that can be eliminated at will.

This objective is achieved by administering: i.e. classical heavy metal cytostatics, especially cisplatin, lobabratin and 1,2-bis (aminomethyl)cyclobutane platinum complex, preferably DE-A-38 43571, particularly preferably 1,2-bicarbonate containing chlorine. S(aminomethyl)-cyclobutane platinum complex, L-lactic acid, D, L-2-hydro Roxy-3-methylbutyric acid, 2-hydroxy-2-methylbutyric acid, glycolic acid, L (-)-3-Phenyl lactic acid, L-ascorbic acid, maleic acid, malonic acid, Oxalic acid, sulfuric acid, valmitic acid, 1.2.3-propane!・Dicarboxylic acid, N~R Acetylalanine, D, L-2-hydroxyhexadiic acid and cyclobutane- 1,1-dicarboxylic acid (see Example 1 of DE 38 43 571) ) or alkylated compounds, especially endoxan, holoxan and trophospha or tumor necrosis factor and the aforementioned cytostatic agents, and optionally fat acid (suitably in the form of a water-soluble alkali metal or ammonium salt) This is achieved by simultaneous administration and additional administration of xanthogenate. Up Preferably, the administration is carried out simultaneously in the form of a single combined anti-tumor agent. , the formulation can be administered sequentially in separate doses. The individual components of the formulation The components can be combined with each other at the appropriate dosage desired. When administered sequentially , the time interval between administrations of the individual components preferably does not exceed about 3 full hours. For example, in some conditions, cytostatic agents may be combined with xanthogenates and optionally be administered in combination with fatty acids, while TNF may be administered within 3 hours thereafter. Found it useful.

As mentioned above, it is preferable to administer all components at the same time and thus in combination. stomach.

The essential ingredients of the formulation are on the one hand a cytostatic agent and on the other hand a xanthogenate.

This is because the toxicity of the cytostatic agents is reduced by this combination, allowing for a fully active dose. This is because the dose is reduced to a level that can be administered without undue undesirable side effects. . The same applies if TNF is added if desired. It is preferable to also administer fatty acids when administering If genate itself has an antitumor effect, fatty acids are expressed as It is known to have antiviral effects according to Japanese Patent Publication No. 3146772. The xanthogenate used is the preferred xanthogenate used; The methyl compounds, especially the ethyl compounds of It is particularly suitable for detoxifying heavy metal compounds such as cisplatin. However, that The tricyclodecan-9-yl residue of Very suitable for combining compounds in the xane form. In this invention, especially In the above case, R8 is preferably an alkali metal or ammonium.

Otherwise, R1 and R2 generally mean:

R1 is adamantyl, norbornyl, tricyclodecyl, benzyl, straight chain This is a branch of CI-C. Alkyl, C3-Cz. cycloalkyl, furyl, piri Indicates a diyl or quinuclidinyl residue, and the above straight-chain or branched CI-C a. The alkyl residue is hydroxy, CI-C-alkoxy group or halogen group. and the above Cs-Cs.

Cycloalkyl residues are hydroxy, C, -C4alkoxy or C, -C4a It may be substituted with an alkyl group or a halogen atom. and, R2 is a -valent or polyvalent metal atom, a linear or branched C, -C, alkyl residues, the latter alkyl residues are hydroxyl, C,-C4 alkoxy, alkyl amine, Cl-C4 alkylamino or (C,-C4-alkyl)2-amino or (C,-C4-alkyl)3-ammonium group or halogen source may be substituted with <, 2,3-dihydroxypropyl residue or ω-hydroxypropyl residue. Droxy=FC, -C4-alkoxy)-methyl residue.

The formulation of this invention comprises 1 part by weight of a cell proliferation inhibitor and 1 to 100 parts by weight of a xanthogesin. Nah! -1 and optionally from 1 to 100 parts by weight of an alkali metal salt or ammonia Ca-C, which may be present in the form of a monocarboxylic acid, and optionally, o, 1 to 0.5 parts by weight of tumor necrosis factor in a conventional carrier and/or diluent. It is manufactured by processing with agents and excipients.

The dosage unit of the above formulation consists of 1.0 mg-10 g of cytostatic agent and 5.0 mg of cytostatic agent. ~5 g xanthogenate, and optionally 50-4.000 mg Ca-C1 Contains 4 monocarboxylic acids and/or 0.001-0.5 mg tumor necrosis factor In some cases, the formulation may be administered parenterally (e.g., intravenously, intramuscularly, subcutaneously). administration) or oral administration. The dosage unit always contains the same amount of Contains various ingredients.

C, -C, containing fatty acid or its alkali metal salt and tumor necrosis factor It is known that a combination of substances consisting of xanthogenates of species has an antitumor effect. It is. However, both the xanthogenate itself and the combination of said substances Growth inhibitors, especially cisplatin, lovabratin and 1,2-bis(aminomethyl ) Cyclobutane platinum complexes, as well as phosphamide and phosphorus-containing ethyleneimination Alkyl compounds such as endoxan, holoxan and trophosphamide It clearly has a strong synergistic effect when combined with xanthogenates, especially xanthogenates. Lower alkyl and cycloalkyl compounds have strong resistance to cytostatic agents. It is surprising that it has a toxic effect. Xanthogenate itself and Togenate, optionally combined with TNF and fatty acids, stimulates the growth of these cells. Combining growth inhibitors is not suggested at all, since each This is because we must expect that the toxicity of the substances will accumulate. surprisingly In fact, this was not the case. However, the toxicity of cytostatic drugs is due to the toxicity of TNF. It strongly decreases including gender.

Therefore, despite reduced doses of TNF and cytostatics, cell Combining a growth inhibitor with a xanthogenate and optionally a fatty acid and optionally TNF For example, human tumor xenografts in athymic mice ansplant), and its toxic side effects have been achieved. At the same time, sufficient detoxification of cisplatin, which is limited in dose due to its use, is carried out.

The invention is illustrated by the following examples.

Actual "L example" 1 Each test group consisted of 6 NMRI-nu/nu mice (6-8 weeks old). 2 x 10' small cell human bronchial carcinoma cells (SCLC) were inoculated subcutaneously into a female (female). Ta. 21 days after inoculation, the tumor is palpable and 8 to 10 mm in diameter. When this happened, treatment started. All antitumor treatment trials described below It consists of a single intravenous injection into the lateral tail vein of the mouse. tumor size The product was measured in three dimensions using a sliding caliper. Injection volume is 20g body weight The solution contains 25% bovine serum albumen along with the active ingredient. 0 recombinant human tumor necrosis factor containing min is commercially available from Knoll AG. was. Tricyclodecan-9-yl xanthate (TCDX) and lauric acid The concentration of potassium salt (K-C121) was 5 mg/ml.

Figure 1 shows the therapeutic effects of various drug combinations on 5CLC tumors in hairless mice. showing that the growth of tumors treated with TCDX/-C12 and those treated with Blacebo Tumor [Bracebo treatment = 0.9% NaC1 + 25% BSA (bovine serum albumin The growth of both test groups remained unchanged with growth of He had to be withdrawn from the study 8 days after starting treatment. I mean, This is because those tumors grew excessively. Figure 1 also shows that cisplatin itself and the combination of -C12 and TCDX/ have some antitumor activity. It is shown that this phenomenon occurs. Excellent initial action of TN-C12 to TCDX- Significant regression in tumor size was obtained during the first few days of treatment when used with F. line is achieved. Finally, TCDX/-(:12+ TNF and cisplatin fLD,. (10 mg/kg cisplatin) equivalent to a slightly lower amount The combined treatment effects are shown in the graph with black squares. Tumor volume up to day 8 The tumor decreased dramatically to its original size of 172, while the tumor size treated with Blacebo As a result of calculations, the size increases by approximately 500% during this period. some tumors are They do not start to grow and grow slowly again later. However, after starting treatment, 11 On day 1, 100% of the initial size at the start of treatment was again reached.

Actual mouth [ In other experimental settings, tumor-bearing animals (experimental method described in Example 1) were tested in the same model. Dell (SCLC) Nitsite, TCDX, /ni-C12/TNF and endoxan Treated in combination. Figure 2 shows the effect of this combination. I. 120 mg/kg), which corresponds to 50% of the amount of 0.5 g of TNF was administered intravenously per 20 g of mouse body weight (as described in Example 1). (using a solution containing 25% BSA similar to that of (compare with the bracebo control in the figure), showing a significant therapeutic effect, but the tumor volume The product does not shrink below its initial size, on the contrary, endoxan , when combined with TCDX/-C12 and TNF (black triangle) and tumor size. It has a dramatic effect on the sharpness. The tumor volume reached its first increase on day 9 after starting treatment. After 9 days, the remaining tumor cells have shrunk to about the same size and are still viable. Only then do they begin to proliferate slowly (Fig. 2).

Mitate Eyu Another type of human melanoma HTB72 (American Ti5sue Cu1 tureCollection) to TCDX/-C:12/TNF and Sysp. A combination consisting of latin [only 5 mg/kg, equivalent to 50% of LD and O] I was treated with For this treatment, melanoma is generally considered to be chemotherapy resistant. It must be noted that

This is also shown in the results in Table 1. Control animal tumor size NMRl , 5X10'(7) cells on both sides of female nu/nu mice, 4 weeks before starting treatment. The three-dimensional direction was measured 17 days after a single intravenous injection. The test conditions were the same as above), and the intestinal tumor weight was determined from the data. Blasebo vs. The average seed weight of the specimens (6 animals per experimental group) was 241 mg ± 103. The weight of the tumor treated with cisplatin alone was 259 ± 1446; Tumors treated with platin + T(:DX/ to -C12+ TNF) were 108± It was as small as 28n+g. Therefore, cisplatin's significant antitumor The effect is made possible by the combination of TCDX/-C12+ TNF, Cisplatin itself did not reduce tumor growth.

1: Human black HTB72 G: Misuru TCDX/Ni-CI2, TCDX and Kisa To ethyl cisplatin and 115 November Each of 10 mice (CDJ+ female, 6-8 weeks old) was inoculated with various amounts of cisplatin. Intracavitary injection followed immediately by various doses of TCDX or ethyl xanthate. (10 mg/ml in 25% BSA, 0.9% NaCl) in the lateral tail vein. was injected into. The weight evolution of the experimental group was controlled and the remaining weight was recorded.

Figure 3a shows the weight loss of a group of treated mice as a function of cisplatin concentration. The dose-effect curve is shown as .

Figure 3 shows the detoxifying effect of TCDX against cisplatin. This is evidenced by a decrease in body weight in animals treated with .

Figure 3C finally shows the detoxification effect of ethyl xanthate. From this test result , it can be concluded that the structure of xanthogenate itself is involved in the detoxification effect. Ru.

Figure 4 again shows the detoxification effect of TCDX, but the statistical significance of the test results is - indicated.

Reduced lethal effects of cisplatin after injection with varying concentrations of xanthogenate Only when administering 9.38 mg/kg of cisplatin, as shown in the figure below, 10 0% of experimental animals survived. In contrast, the group administered 12.5 mg/kg One animal in the loop died after 6 days; doses above 15 mg caused all This is a lethal dose to the human body, and death occurs as early as 4 days after treatment (Figure 5).

Figure 6 shows that additional administration of 200 mg/kg of TCDX significantly shortens the lifespan of the animals. 20 mg/kg of cisplatin was administered to that group of animals. being administered. In this group, the survival time of some animals was increased by up to 33%. lengthened.

As can be seen from Figure 7, survival time was extended by additional administration of ethyl xanthate. becomes more favorable after treatment (does not exhibit antitumor activity itself)6 ! five five balls In a separate study setup, each of the four mice was treated with the xanthogen ethyl cisplatin. (P2S5-leukemic mice) were given lomg/kg of Bratinex (platinex). nexl solution (cisplatin) was administered intraperitoneally. Immediately afterwards, various amounts of Ethyl nitogenate (200 mg/kg, 500 mg/kg) was administered orally. child 1. per 20g of body weight. (1 ml of ethyl xanthate solution (3 x Sodium phosphate buffer pH 8.5) was administered using Probank. Experiment group The development of the weight of the loop was checked and its survival period was recorded (Table 2 and Figure 8).

Li±1 Other measured parameters of detoxification include cisplatin, which causes kidney damage; Measurement of blood urea fBUNl after treatment. As a result, treatment with cisplatin The BUN of animals that have been fed will increase. Xanthogenate significantly lowers this BUN value. Ru.

Blood 12 + j) i Standing 10mg/kg of cisplatin (containing 0.5mg of cisplatin per ml) Bratinex solution) was added to the abdomen of a mouse (NMRI-Nu/Nu female, 6-8 weeks old). Injected intracavitally. Immediately thereafter, 200 mg/kg (7) TCDX (25% Bovine serum albumin, 0.9% NaCl (10mg/ml TCDX) or The concentration of 0 body weight and blood urea (BUNI) was determined 4 days after intravenous injection of Blacebo solution. was measured.

The latter measurement was performed using a commercially available kit (method of Crocker, Sigma, Munich). )It was used.

Shishi: 2388- Cisplatin D-18225 and ELXD- in hemological mice 21479) 1 - + - 0/12 12/12 11.0 - 0/122 - +163 0/6 6/6 11. (100/6”usT: Intermediate survival time ILS: Lifespan increase rate LTS: Long Term Survivor Table 3: Poison of cisplatin Treatment method 0 Weight (%l BUN (B/dll Cisplatin + Bracebo 70 130 Cisplatin + T CD X 86 78° 4 animals/group FIG.1 Fake rF uniform's scale FIG.4 number of days Eliminate the Ministry by force 8-force) Leah-1 creation E force and write 8Ij=? Ketshi collection 6N) Gu-1Et (Ding htsu 0 9.38 mg/kg fi =, = Suff'ra Ken 12.50 mg/kg a Sysphritea 015.00 mg/kg I? I Cisfuritea ■ 20.00 mg/kg (Q Cisaraken 0 9. 38　rr+q/kg　a+　;Suf”;’poppy +200　mq/kgs Kibu Ent Key/IIL Tricyclote mq/kq cp+? /Suf'9chin + 200 m (J/k (J, l Ki7v TogevtpLx-KeIV・12-50 mcJ/kq Lt+”/Suf 0 latin + 200 mg/kg o, 1 ge °yl nickel mouth 15. 00 mg/kg ep=”/Suf 6 Rage/+200 mq/ni’J f Quintoden 1LT-Ke1 ■ 20.00 mg/kg th Cisaraken +200 mq/kq cs Quinacitoten 1IL-su) VFIG, 7 FIG.8 CisPt　”　EtX　I71no-71) Summary document This invention is based on xanthogenate drugs, optionally Cll-014 mono carboxylic acid and/or its alkali metal salt or ammonium salt; Contains tumor necrosis factor and further contains heavy metals or phosphamide esters. The present invention relates to an antitumor agent characterized in that it contains a cell growth inhibitor that contains a substance containing a cell proliferation inhibitor.

, 6″″′″″′” bell S yeah international search report Continuation of page 1 ■Int, C1, S Identification symbol Internal office reference number A 61 K 31/675 8 314-4C371028314-4C Priority claim [Phase] May 13, 1991 [Phase] Germany (DE) [Phase] P411 5559.9 Entrepreneur Amtmann, Eberhard Federal Republic of Germany 6 7”--6900 Heidelberg, Hausagarve

Claims (18)

[Claims] 1. Based on xanthogenate agents, optionally C8-C14 monocarboxylic acids and/or its alkali metal or ammonium salts and optionally tumor necrosis. further contains heavy metal or phosphamide ester-based substances. Antitumor with synergistically enhanced action characterized by containing a cell proliferation inhibitor agent. 2. The xanthogenate contained is preferably an alkali metal salt or an ammonia salt. C1-C20 alkyl xanthate or C6 xanthate in the form of um salt The antitumor agent according to claim 1, which is -C30 cycloalkyl. 3. The heavy metal-based cell growth inhibitors containing cisplatin, Robavu It is confirmed that it is latin or 1,2-bis(aminomethyl)cyclobutane platinum complex. The antitumor agent according to claim 1 or 2, characterized in that: 4. The phosphamide ester-based cytostatic agent contained in Claims characterized in that they are xane, holoxane or trophosphamide. The antitumor agent according to Box 1 or 2. 5. xanthogenates and monocarboxylic acids such as cisplatin, lovabratin or or in combination with 1,2-bis(aminomethyl)cyclobutane platinum complex. The antitumor agent according to any one of claims 1 to 3, characterized in that: 6. Xanthogenates and monocarboxylic acids are combined with endoxan, holoxan or Claim 1 characterized in that it contains in combination with trophosphamide. , 2 or 4. 7. Xanthogenates are used as heavy metal-based cytostatics, especially in cispra Chin, Lovabratin or 1,2-bis(aminomethyl)cyclobutane platinum complex Any one of claims 1 to 3, characterized in that it contains in combination with The antitumor agent described in. 8. The xanthogenate contained is methyl xanthate or xanthate The antitumor according to any one of claims 1 to 7, characterized in that it is ethyl. agent. 9. Each of the one or more individual substances is divided into effective dosages and presented in separate forms. According to any one of claims 1 to 8, the present invention is presented as a kit containing Antitumor agents as described. 10. Heavy metal or phosphamide ester-based cytostatics and and optionally a Ca-C14 monocarboxylic acid and/or its Alkali metal or ammonium salts and optionally tumor necrosis factor are combined to inhibit cell growth. Contained as a combination preparation for simultaneous, separate or sequential use in therapeutic therapy products that do. 11. Cisplatin, lovabratin or 1,2-bis(aminomethyl)-cyc Robtane platinum complex is contained as a heavy metal-based cell growth inhibitor. 11. The product according to claim 10. 12. Endoxan, holoxan or trophosphamide are A claim characterized in that it is contained as a cell-based cell growth inhibitor. Products listed in Range 10. 13. Methyl xanthate or ethyl xanthate is the same as xanthogenate. According to any one of claims 10 to 12, characterized in that the Products listed. 14.1 parts by weight of a cytostatic agent and 1 to 100 parts by weight of a xanthogenate, and and optionally in the form of an alkali metal or ammonium salt. parts of Ca-C14 monocarboxylic acid and optionally 0.001 to 0.5 parts by weight of Tumor necrosis factor is processed with conventional carriers and/or diluents and excipients. ; 1.0 mg to 10 g of cytostatic agent and 5.0 mg to 10 g of the cytostatic agent in the resulting dosage unit; 5 g of xanthogenate and optionally 50-4,000 mg of Ca-C14 Contains monocarboxylic acid and/or 0.001-0.5 mg of tumor necrosis factor. Product according to any one of claims 10 to 13, characterized in that: manufacturing method. 15. Heavy metal or phosphamide ester-paced cytostatics and drugs Santogenate and optionally added Ca-C14 monocarboxylic acid and/or or its alkali metal or ammonium salts and optionally to control cancer. Uses of xanthogenates for tumor necrosis factor addition. 16. Methyl xanthate or ethyl xanthate is xanthogenate The use according to claim 15, characterized in that it is used as a. 17. Xane used to produce pharmaceutical preparations for controlling cancer cell proliferation Uses of Togenato. 18. Methyl xanthate or ethyl xanthate is the same as xanthogenate. The use according to claim 17, characterized in that it is used as a.