turopaiscnes patentamt European Patent Office © Publication number: 0 221 382 Office europeen des brevets A1 (2) EUROPEAN PATENT APPLICATION © Application number: 86113897.2 © Int. CI.4: A61K 33/24 , ~ //(A61K33/24,31:44) © Date of filing: 07.10.86 © Priority: 10.10.85 US 786321 © Applicant: THE BOARD OF GOVERNORS OF WAYNE STATE UNIVERSITY © Date of publication of application: 5050 Cass Avenue 13.05.87 Bulletin 87/20 Detroit Michigan 48202(US) © Designated Contracting States: @ Inventor: Honn, Kenneth V. AT BE CH DE ES FR GB IT LI LU NL SE 1889 Stanhope Grosse Polnte Woods, Michigan 48236(US) Inventor: Tayior, John D. 1408 Joliet Place Detroit, Michigan 48207(US) Inventor: Onoda, James M. 212 Baker Street No. 203, Royal Oak, Michigan 48067(US) © Representative: Patentanwalte GrUnecker, Kinkeidey, Stockmalr & Partner Maximllianstrasse 58 D-8000 MUnchen 22(DE) «y Method and compositions for the treatment of tumors comprising a calcium channel blocker compound of the dlhydropyridlne class and a platinum coordination compound. (jy The invention relates to compositions for the vherein R, and R2 are methyl groups, R, and R» are treatment of malignant tumors in a mammal which ilkyi or alkyloxyalkylene groups containing I to 8 comprise: :arbdn atoms and R5 and R« are hydrogen or one or (a) a calcium channel blocker compound of wo electron withdrawing substituents; and the dihydropyridine class selected from the group (b) a platinum coordination compound which ^consisting of las antitumor properties in humans wherein the veight ratio of the calcium channel blocker com- x>und to the platinum coordination compound is >etween I and 1000 and 10 to I. Furthermore, the invention relates to a method or the treatment of malignant tumors in vitro by idministering the afore-mentioned compositions. u arm Copy Centre 0 221 382 FIG. I Cisplatin Effects on B I 6a Proliferation 251 normal CPR-0.25 CPR-5.0 CO «J Ll 004 CO "3 O c_ 75i o E 501 c o O 251 AM 1 0 <?*> 0r O' Cisplatin CpM) 1a 1 0 221 382 2 Mb I rtuu AND COMPOSITIONS FOR THE TREATMENT OF TUMORS COMPRISING A CALCIUM CHANNEL BLOCKER COMPOUND OF THE DIHYDROPYRIDINE CLASS AND A PLATINUM COORDINATION COM- POUND tastases prevents cisplatin chemotherapy from Cross-Reference to Related Application achieving partial or complete remission rates of more than 15% to 70% for testicular cancer (Stoter The present invention is a continuation-in-part et al, Cancer 54:1521, 1984), and ovarian cancer - of application Serial No. 480,704, filed March 31, 5 (Belinson et al., Cancer 54:1983, 1984), and 30-40% I983 which has inventors in common with this ap- for cancer of the head and neck (Wittes et al., plication and is assigned to a common assignee. Cancer Treat. Rep. 63:1533, 1979). The most serious problem encountered in the chemotherapeutic treatment of cancer is the pres- BACKGROUND OF THE INVENTION io ence and/or the development of drug resistance by cells of the primary tumor. If the patient dies of (I) Field of Jhe. Invention metastatic cancer, the cells of the metastatic foci are usually also characterized by their extreme The present invention relates to a method and resistance to single or combinations of the avail- compositions for the treatment of malignant tumors 75 able chemotherapeutic drugs. In general, drug re- or metastasis of malignant tumors by administering sistant tumor ceils simply accumulate less (a sub- a platinum coordination compound and a calcium lethal dose) of the chemotherapeutic drug(s) than channel blocker compound of the dihydropyridine do cells which succumb to the therapeutic agent. class. In particular the present invention relates to a Drug resistant tumors can be classified as tem- method which comprises administering cis-diam- 20 porary or permanent (DeVlta, V.T., Cancer 51:1209, minedichloroplatinum (II) and nifedipine, respective- 1983). Temporary drug resistant tumors are thought ly, as the compounds. to be resistant as a result of physiological factors such as sublethal exposure to drug by tumor cells distant from circulation (i.e., perfusion barrier; Suth- (Z) Prior Art 25 erland, R. M., et al., J. Nat. Cancer Inst. 46:113, 1971; and West, G.W., et al., Cancer Res. 40:3665, 1980). Cis-diamminedichloroplatinum (CDDP, Additionally, it has been suggested that the overall cisplatin) is the first inorganic antitumor agent used growth kinetics of the tumor (Shackney, S.E., et al., for clinical cancer therapy. Developed and first Ann. Int. Med. 89:107, 1978) are an important factor described by Rosenberg et al (Nature 205:698, - 30 in temporary tumor cell resistance (i.e., slowly or (I965); Nature 222:385, (I969)), cisplatin has proven asynchronously growing tumor cells would be less to be an effective antineoplastic agent not only likely to be exposed to (accumulate) bolus injected against germinal neoplasms as it was first utilized - anticancer agents). Permanent drug resistant tumor (Einhorn et al., Int. Med. 87:293, I977) but also cells are thought to arise spontaneously, and their against bladder and ovarian cancer and cancer of 35 probability of existence may be related to tumor the head and neck. It is possible that cisplatin mass and/or age. The concept of the spontaneous alone or cisplatin in combination with other an- genetic origin of drug resistant neoplasms (Goldie tineoplastic drugs (e.g., adriamycin, vincristine, and Coldman, Cancer Res. 44:3643, 1984) and tu- etc.) may become the accepted standard agent for mor heterogeneity in terms of metastatic potential - the chemotherapeutic treatment of a majority of 40 (Fidler, I. J., Cancer Res. 38:2651, 1978) and drug malignancies including those which are usually sensitivity (Tanigawa, N, et al., Cancer Res. considered non-responsive to chemotherapy, such 44:2309, 1984), has gained widespread acceptance as estrogen resistant prostate carcinoma (Merrin, as the mechanism of permanent tumor cell resis- C.E., Cancer Treat. Rep. 63:1579, 1979). This and tance. The two principal mechanisms of permanent other platinum coordination compounds are shown 45 drug resistance have been found to be mediated in U.S. Patent Nos. 4,140,707, 4,177,263 and by changes in the concentration or activity of an 4,419,351 for instance. enzyme in the resistant cells that "inactivates" the Unfortunately, the development of cisplatin re- drug (Bakka, A., et al., Toxicol. Applied Pharmacol. sistance in malignant tumors which initially re- 61:215, 1981) or by changes in the plasma membrane sponded to cisplatin is an all too often encountered so of the resistant cells which decreases cellular accu- problem (Lee et al., Cancer Treat. Rev. 10:39, 1983). As with other chemotherapeutic drugs, cisplatin resistance of the primary tumor and recurrent me- > 3 0 221 382 4 mulation of drug by inhibiting drug influx and/or by sults in a decrease in the LD50 concentration of the increasing the rate of drug efflux (Giavazzi, R, et antitumor agent. The ability of daunorubicin resis- al., Cancer Res. 43:2216, 1983; Yanovich, S., et al., tant and sensitive Ehriich ascites carcinoma cells to Cancer Res. 44:1743, 1984). accumulate and retain daunorubicin is inversely Initial attempts to circumvent drug resistance 5 related to the concentration of Ca2+ in the incuba- centered on alterations in the scheduling, dosages, tion medium (Murray et al, Cancer Chemotherap. and/or method of application of a single Pharmacol. 13:69, 1984). Verapamil's ability to in- chemotherapeutic agent (Benz, C, et al., Cancer crease daunorubicin cytotoxicity in resistant Ehriich Res. 42:2081, 1982; Ozols, R. F., et al., Cancer Res. tumor cells may be at least partially attributable to 42:4265, 1982). Much more promising, however, 10 its (verapamil) ability to inhibit calcium influx, which appears to be combined drug therapy using would have effects similar to those obtained by cytotoxic agents with different mechanisms of ac- decreasing extracellular CaJ+. tion. This type of therapy has improved the cure The cytotoxic mechanism of action of cisplatin rate for some cancers but the ultimate failure of is known to be its ability of the platinum moiety to even this strategy is well documented (Ling, V., et is form. DNA-DNA and DNA-protein crosslinks in the al., Cancer Treat. Rep. 67:869, 1983; Citrin, D. L, et target cell nucleus, thus preventing new mRNA al., Cancer 50:201, 1982). transcription and DNA replication (Roberts, J. J., In: Recently, a new methodology has been sug- Molecular Actions and Targets for Cancer gested which may be of great benefit in the Chemotherapeutic Agents, Academic Press, New chemotherapeutic treatment of cancer. This meth- 20 York, p. 17, I98I). The exact mechanism of resis- odology is centered on the use of agents which tance to cisplatin, however, is not known (Curt et al, function to enhance the initial kill-rate of a cytotoxic Cancer Treat. Rep. 68:87, I984). Sigdestad et al - drug and/or which enhance the ability of the drug (Cancer Treat. Rep. 65:845, I98I) reported that all to overcome drug resistant tumors. phases of the cell cycle (Gl, S, G2 and M) of a Inaba, M., et al., Cancer Res. 39:2200, 1979 25 murine fibrosarcoma were sensitive (in vivo) to reported that the significantly decreased uptake cisplatin although cells in the Gl phase were the and retention of adriamycin and daunorubicin by most sensitive by a factor of 10. This data suggests P388 leukemia cells resistant to these agents was that slowly growing cells or asynchronously grow- mediated by an active outward transport of the two ing tumor cells might be the population of cells that cytotoxic agents by resistant cells. These findings 30 eventually demonstrate cisplatin resistance. Wheth- suggested that membrane active compounds might er the growth rate or phase of cell cycle affects be utilized to overcome the outward transport of enzyme activity or the membrane of resistant cells cytotoxic agents from resistant tumor cells.