METHOD AND COMPOSITION FOR REDUCING TUMOR DEVELOPMENT WITH A COMBINATION OF PLATINUM AND TELLURIUM OR SELENIUM COMPOUNDS

Abstract: There are provided compositions for, and a method of, treating malignancies which comprise effective amounts of a novel combined therapy comprising a platinum compound and a tellurium or selenium compound, e.g., ammonium trichloro(dioxoethylene-O,O-tellurate), and administering the respective compounds simultaneously or separately.

Description: METHOD AND COMPOSITION FOR REDUCING TUMOR DEVELOPMENT WITH A COMBINATION OF PLATINUM AND TELLURIUM OR SELENIUM COMPOUNDS BACKGROUND OF THE INVENTION The present invention provides a novel combination therapy for application to the treatment of neoplastic diseases. The therapy is based on the sequential or concurrent administration of a platinum compound and a tellurium and/or a selenium compound in combination to provide an improved chemotherapeutic regimen for the treatment of neoplastic diseases or the treatment of malignant neoplasms. It has been discovered that the combination of a platinum compound and a tellurium and/or a selenium compound significantly reduces the development of tumor volume over what would be predicted from administration to tumor-infected mammals of either a platinum compound alone, or the tellurium and/or selenium compound, alone. It has also been suggested in the prior art to use tellurium compounds in combination with other chemotherapeutic agents for the treatment of such malignant neoplasms. In fact, it is known that a combination of ammonium trichloro(dioxoetnylene-0,0-tellurate (AS101) and the known chemotherapeutic agent cyclophosphamide (CYP) shows synergism in extending the rate of survival of mice infected with Madison lung carcinoma tumor cells. Cancer Res. 51(5)1499-1503(1991). It has now been discovered, and is the subject of the present invention, that a novel combination of the platinum compound cisplatin and a tellurium and/or a selenium compound shows an unexpectedly strong synergistic effect on the reduction in tumor volume in mice infected with cells of the solid tumor P388 and in L1210 leukemia. Such findings are unexpected because the use of either the platinum compound alone or the tellurium and/or selenium compound alone at the same respective dosages produce anti-tumor effects which are shorter lasting an incrementally much closer to the saline control. The present invention is concerned with a nove treatment regimen which combines a platinum compound and tellurium and/or selenium compound. It also contemplates novel composition with anti-neoplastic activity comprisin a combination of a platinum compound and a tellurium and/o selenium compound. Among the preferred features of th invention are regimens and novel therapeutic combination wherein the ratios of the platinum compound and telluriu and/or selenium compound provide synergistic activity especially in the reduction of solid tumor growth. It is therefore an object of the invention t provide novel therapeutic regimens and compositions whic are based on the sequential or concurrent administration o novel combination of a platinum compound and a telluriu and/or selenium compound to mammals afflicted wit neoplasms. It is also an object of this invention to provid a novel method for the treatment of neoplastic disease which uses a particular dose of a novel combination of platinum compound and a tellurium and/or selenium compound These and other objects of the invention wil become apparent from a review of the specification. Brief Description of the Drawings Fig. 1 shows in graphical form the effect of administratio of the citrate buffer control, cisplatin, the telluriu compound, ammonium trichloro(dioxoethylene-0,0-tellurate (ASlOl) and the combination of the cisplatin, the telluriu compound, ammonium trichloro(dioxoethylene-0,0-tellurate (ASlOl) on the development of solid P388 tumor in vivo ove a 32 day period in mice. Fig. 2 shows in graphical form the effect of administratio of the citrate buffer control, cisplatin, the telluriu compound, ammonium trichloro(dioxoethylene-0,0-tellurate (ASlOl) and the combination of the cisplatin, the tellurium compound, ammonium trichloro(dioxoethylene-0,0-tellurate) (ASlOl) on the development of L1210 leukemia in vivo over a 32 day period in mice. Summary of the Invention In accordance with the present invention there is provided a method of treating malignancies which are sensitive to the combination of a platinum compound, and a tellurium and/or selenium compound, said method comprising administering, sequentially or concurrently, an amount of the combination which is effective to treat malignancies which are sensitive to the combination. Preferred features of the invention comprise administering the combination in weight ratios which are synergistically-effective to treat malignancies, especially solid tumors. Cisplatin is preferred but other platinum compounds, such as carboplatin and other platinum compounds, can be used. Ammonium trichloro(dioxoethylene- 0,0-tellurate) (ASlOl) is preferred but other tellurium and/or selenium compounds, such as dichlorodioxoethylene- 0,0-tellurate, and the corresponding selenium isosteres, may be employed. DETAILED DESCRIPTION OF THE INVENTION The tellurium compounds for use in the invention include those of the formula: or or TeX 4 (C) e0 2 (D) or T or PhTeCl, (E) or (C 6 H 5 ) + P(TeCl 3 (0 2 C 2 H 4 ))- (F) wherein Q is Te or Se; t is 1 or 0; u is 1 or 0; v is 1 or 0; R, R 1# R 2 , R 3 , R., R 5 , R 6 , R 7 , R β and R 9 are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, acyl, amido, cyano, amidoalkyl of 1 to 6 carbons, N- monoalkylamidoalkyl of 2 to 10 carbons, N,N- dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -COR 10 wherein R 10 is alkyl of from 1 to 6 carbons; and X is halogen. Although the ammonium salt is illustrated, it is understood that other pharmaceutically acceptable salts are within the scope of the invention. The compounds with the five membered rings are preferred. As used herein, for compounds of formulae (A) and (B), the term alkyl of 1 to 6 carbon atoms includes straight and branched chain alkyl groups such as methyl; ethyl; n- propyl; n-butyl, and the like; the term hydroxyalkyl of 1 to 6 carbon atoms includes hydroxymethy1; hydroxyethyl; hydroxy-n-butyl; the term haloalkyl of 1 to 6 carbon atoms includes chloromethyl; 2-iodoethyl; 4-bromo-n-butyle; iodoethyl; 4-bromo-n-pentyl and the like; the term alkanoyloxy of 1 to 6 carbon atoms includes acetyl, propionyl, butanoyl and the like; the term carboxyalkyl includes carboxymethyl, carboxyethyl, ethylenecarboxy and the like; the term alkylcarbonylalkyl includes methanoylmethyl, ethanoylethyl and the like; the term amidoalkyl includes -CH 2 CONH 2 ; -CH 2 CH 2 CONH 2 ; -CH 2 CH 2 CH 2 CONH 2 and the like; the term cyanoalkyl includes -CH 2 CN; -CH 2 CH 2 CN; -CH 2 CH 2 CH 2 CN and the like; the term alkoxy of 1 to 6 carbon atoms includes methoxy, ethoxy, n-propoxy, n- pentoxy and the like; the terms halo and halogen are used to signify chloro, bromo, iodo and fluoro; the term ac includes R 16 C0 wherein R 16 is H, or alkyl of 1 to 6 carbo such as methanoyl, ethanoyl and the like; the term ar includes phenyl, alkylphenyl and naphthyl; the term monoalkylamidoalkyl includes -CH 2 CH_C0NHCH_, -CH 2 CONHCH 2 CH the term N,N-dialkylamidoalkyl includes -CH 2 C0N(CH 3 ) CH 2 CH 2 CON(CH 2 CH 3 ) . Compounds which are based on tellurium a the presently preferred compounds of the invention. Ammonium (trichloro(dioxoethylene-0,0-tellurat is a compound of the structure This compound is a member of a family of organic 9,10,11 derivatives of tellurium and selenium found to have th ability to stimulate the in vivo and in vitro production o cytokines and their receptors. As is set forth in U.S Patent No. 4,761,490, these compounds may be utilized i the treatment of certain tumors, autoimmune diseases immune diseases and infectious diseases. The derivatives of tellurium or selenium tha are useful in the present invention include those compound of the above mentioned general formulas (A) - (F) whic stimulate cells to produce lymphokines. The compounds are made by combining substantiall equimolar amounts of the reactants in a suitable reactor a room temperature or at elevated temperatures up to th reflux temperature. It is preferred to utilize a solven that is capable of dissolving the reactants such a acetonitrile, benzene, toluene, xylene, dimethylsulfoxide mixtures thereof and the like. Compounds of structure (A are only obtained in acetonitrile. The preferred metho requires heating the reaction mixture to the reflu temperature of the solvent while stirring the reactio mixture with a suitable magnetic or mechanical stirrer. The reaction may be carried out for a sufficient period of time to ensure complete reaction of the reactants. This time will vary with the reaction conditions, the particular compound being made and the nature of the solvents. The reaction may be run at atmospheric pressure but if desired may be carried out at reduced or elevated pressure. The reaction is practically carried out in the presence of an oxygen containing atmosphere such as air but inert atmospheres such as nitrogen, argon, helium or mixtures thereof may be utilized if desired. Reaction times of 1 minute to 168 hours may be used although reaction times of 6-16 hours are preferred Other compounds which are based on tellurium and may be used in the practice of the invention include PhTeCl 3 , Te0 2 and TeX. (C.H.). P+ (TeCl_(0 2 C 2 H.) )- (Z. Naturforsh, 36, 307-312 (1981). Compounds of the following structure are also included: These compounds are described in United States Letters Patent No. 4,761,490 which is incorporated by reference. In addition, TeCl.; TeBr. and compounds which give in aqueous solution TeO ∑ prferably in the form of a complex such as for example Te0 2 complex with citric acid or ethylene glycol. The platinum compounds are described in the literature include those compounds described in U.S. 4,500,465; U.S.4,410,544; JP-255943; U.K. 2,024,823; U.K. 2,128,615A; U.S. 4,730,069 and U.S. 4,140,707, all of which are incorporated by reference. For the treatment of malignancies which are susceptible to treatment, the tellurium compound may be administered by the oral, intramuscular, intravenous, transdermal or intraperitoneal route to mammals including humans. The oral dose will be 0.15 to 0.5 mg/kg of body weight daily and preferably from 0.03 to 0.1 mg/kg of bo weight daily in one dose or in divided doses. T parenteral dose will be 0.03 to 0.2 mg/kg of body weig daily and preferably from 0.006 to 0.02 mg/kg daily giv as a bolus injection or as a continuous parenter infusion. The dose of the platinum compound to be used an effective amount to exert an anti-tumor effect on t particular tumor which is being treated. The dose wi depend on the particular platinum compound and these dos are disclosed in the literature. In the case of cisplat the dose will depend upon the condition which is treat and may be from 20mg/m 2 daily for 5 days or 100mg/m 2 on every 4 weeks. Carboplatin may be administered at a dose 360mg/m 2 once every 4 weeks. The PDR, 1994 Edition at pag 662-669 discloses how to use cisplatin and carboplatin a these pages are incorporated by reference. Combined compositions of the platinum compou and the tellurium compound may comprise from about 90 about 10 parts by weight of the platinum compound and fr 10 to 90 parts by weight of the tellurium or seleni compound. The invention may be used to treat benign tum and malignancies which are sensitive to the describ treatment regimen. The malignancies may be primary metastatic such as solid tumors, leukemias or lymphomas These malignancies include colorectal carcinoma, espohage carcinoma, stomach carcinoma, pancreatic carcinoma, liv carcinoma, small bowel carcinoma, lung tumors, CM mesothelioma, melanomas, biliary carcinoma, breas carcinoma and adenocarcinoma of unknown origin. DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 DBA/2J mice, 18-22g. both male and female wer used to confirm the activity of ammonium trichloro (0,0' dioxoethylene tellurate) and cisplatin. Each mouse received intraperitoneally, 0.5ml of a 1 X 10 6 viable tumor cells of the P388 tumor cell line suspension in saline on day 1. Ammonium trichloro (0,0'- dioxoethylene tellurate) and cisplatin were dissolved in 0.05M citrate buffer, pH 6.4. The solution of ammonium trichloro (0,0'-dioxoethylene tellurate) contained 50mg/ml and the solution of cisplatin contained 750mg/ml. The solutions were freshly prepared or kept at 4°C. for a maximum period of 48 hours prior to use. Drugs were administered peritoneally with an initial treatment 24 hours after tumor inoculation. In the treatment of the mice with the P388 tumor, the treatment schedules were as follows: (a) cisplatin: one injection of 150mg/mouse days 1, 4 and 7; (b) ammonium trichloro (0,0'-dioxoethylene tellurate) : one injection of lOmg/mouse every second day until end of treatment. Four groups of mice with 10 mice in each group were treated as follows: (1) citrate buffer as control; (2) cisplatin alone; (3) ammonium trichloro (0,0'-dioxoethylene tellurate) alone and (4) a combined therapy of cisplatin alone and ammonium trichloro (0,0*- dioxoethylene tellurate). The synergistic antitumor effect of ammonium trichloro (0,0'-dioxoethylene tellurate) and cisplatin in the P-388 leukemia tumor bearing mice significantly enhanced survival of treated mice. As shown in Fig.l, combined treatment of ammonium trichloro (0,0'- dioxoethylene tellurate) and paclitaxel resulted in 75% survival of all treated animals by day 32(p<0.01). Cisplatin alone enhanced the rate of survival for a limited period of time with no survivors on day 32 after tumor implantation. Ammonium trichloro (0,0'-dioxoethylene tellurate) alone was very similar to the control, showing no significant cumulative effect on the percentage of survival. The cumulative percentage of survival of mice treated with ammonium trichloro (0,0'-dioxoethylene tellurate) and cisplatin was significantly higher compared to control mice (p<0.05). When cisplatin was administere alone, it had a slight but non-significant effect on th cumulative percentage survival of mice. A second series of experiments was carried ou with the L-1210 tumor cell line with same type of mice tha were used in the experiments described above. The mice wer inoculated with 1 X 10 6 viable L-1210 tumor cells accordin to the dosage schedule and the treatment regimen set fort above. The test data showed that the L-1210 tumor cel line is less sensitive to cisplatin alone which showed limited and non-significant effect on the rate of surviva by day 32. Ammonium trichloro (0,0'-dioxoethylen tellurate) alone had a very slight effect with no survivor after 22 days. Both ammonium trichloro (0,0'-dioxoethylen tellurate) and cisplatin alone did not have any significan effect on the cumulative percentage of survival. In contrast, the combination of ammoniu trichloro (0,0'-dioxoethylene tellurate) and cisplatin showed a clear synergistic effect resulting in 80% surviva by day 32 (p<0.01) and a significant effect (p<0.01) on th cumulative percentage or survival compared to the contro or ammonium trichloro (0,0*-dioxoethylene tellurate) or cisplatin alone.

Claims: We Claim: 1. A composition comprising a combination of a platinum compound and a tellurium or selenium compound in respective amounts effective to treat malignancies so as to produce more than a merely additive increase in therapeutic effect when compared to the platinum compound and the tellurium or selenium compound used alone, said tellurium or selenium compound being selected from the group consisting of those of the formulae: or TeX. (C) or Te0 2 (D) or PhTeCl 3 (E) or (C 6 H 5 ) + P(TeCl 3 (0 2 C 2 H 4 )) * (F) wherein Q is Te or Se; t is 1 or 0; u is 1 or 0; v is 1 or 0; R, R,, 2 ' 3' 4 ' 5' R 6 , R 7 , R β and R g are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, acyl amido, cyano, amidoalkyl of 1 to 6 carbons, monoalkylamidoalkyl of 2 to 10 carbons, N, dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 t 10 carbon atoms and -COR 10 wherein R 10 is alkyl of from 1 t 6 carbons; and X is halogen. 2. A composition as defined in Claim 1 wherei the platinum compound is selected from the group consistin of cisplatin and carboplatin. 3. A composition as defined in Claim 2 wherein the platinum compound is cisplatin. 4. A composition as defined in Claim 2 wherei the platinum compound is carboplatin. 5. A composition as defined in Claim 2 wherei the tellurium or selenium compound is ammoniu trichloro(dioxoethylene-0,0-tellurate) . 6. A composition as defined in Claim 1 wherei the platinum compound comprises from about 10 to about 9 parts by weight and the tellurium or selenium compoun comprises from about 90 to about 10 parts by weight of th combination. 7. A method of treating a benign tumor o malignancies which are sensitive to the combined therapy o a taxane compound and a tellurium or selenium compound said method comprising administering simultaneously o separately, an amount of each drug which i synergistically-effective to treat benign tumors o malignancies which are sensitive to the combined therapy said tellurium or selenium compound being selected from th group consisting of those of the formulae: or TeX. (C) or Te0 2 (D) or PhTeCl 3 (E) or (C 6 H 5 ) + P(TeCl 3 (0 2 C 2 H.))- (F) wherein Q is Te or Se; t is 1 or 0; u is 1 or 0; v is 1 or 0; R, R,, j R j* R 4 j R 6 , R 7 , Rβ β and R α 9 are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, acyl, amido, cyano, amidoalkyl of 1 to 6 carbons, N- monoalkylamidoalkyl of 2 to 10 carbons, N,N- dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and ~COR 10 wherein R 10 is alkyl of from 1 to 6 carbons; and X is halogen. 8. A method as defined in Claim 7 wherein the platinum compound is selected from cisplatin and carboplatin. 9. A method as defined in claim 8 wherein the tellurium or selenium compound is ammoniu trichloro(dioxoethylene-O,O-tellurate) , a compound o formula (A) wherein Q is tellurium; R, R_, R β and R 9 ar hydrogen; and t, u, and v are 0. 10. A method as defined in Claim 7 wherein th platinum compound and the tellurium or selenium compoun are administered sequentially. 11. A method as defined in Claim 7 wherein th platinum compound and the tellurium or selenium compoun are administered simultaneously. 12. A pharmaceutical composition which contain a platinum compound and a tellurium or selenium compound further combined with one or more pharmaceuticall acceptable, inert or physiologically active diluents o adjuvants.

Inventors: ALBECT MICHAEL, SREDNI BENJAMIN, ALBECT, MICHAEL, SREDNI, BENJAMIN
Applicants: BAKER NORTON PHARMA, BAKER NORTON PHARMACEUTICALS, INC.
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61K33, A61P35, A61P43, C07D329, C07F15