ANTI-TUMOR SYNERGETIC COMPOSITION

Abstract: There are provided the combined use of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methansulfonyl daunorubicin or 4-demethoxy-N,N-bis(2-chloroethyl)-4'-methansulfonyl daunorubicin and an anti-neoplastic anti-mitotic compound and/or a platinum derivative in the treatment of tumors, as well as in the prevention or treatment of metastasis or in the treatment of tumors by inhibition of angiogenesis.

Description: Anti-tumor Synergetic Composition The present invention relates m general to the field of cancer treatment and, more particularly, provides an anti- tumor composition comprising an alkylatmg anthracyclme and an anti-mitotic compound and/or a platinum derivative, having a synergistic or additive anti-neoplastic effect. The present invention provides, m a first aspect, a pharmaceutical composition for use m anti-neoplastic therapy m mammals, including humans, comprising - an anthracyclme of formula la or lb : - an anti-neoplastic anti-mitotic compound and/or a platinum derivative, and a pharmaceutically acceptable carrier or excipient. The chemical names of the anthracyclmes of formula la and lb are 4-demethoxy-3' -deammo-3' -azιrιdmyl-4 ' - methansulfonyl daunorubicin (la) and 4-demethoxy-N, N-bis (2- chloroethyl) -4' -methansulfonyl daunorubicin (lb). These anthracyclmes were described m Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively m US-A- 5,532,218 and US-A-5, 496, 800. Both compounds intercalate into DNA via the chromophore and alkylate guanme at N position m DNA minor groove via their reactive moiety on position 3' of the ammo sugar. Compounds la and lb are able to circumvent the resistance to all major classes of cytotoxics, indicating that the compounds represent a new class of cytotoxic anti-tumor drugs. Anti-mitotic and platinum derivatives anti-neoplastic agents are described m various scientific publications. The mam representatives of the anti-mitotic class are: Paclitaxel, Docetaxel, Vmblastme, Vmcristme, Vmdesme and Vmorelbme; see for example the review: Cancer, Principles and Practice of Oncology, Lippmcott-Raven Ed. (1997), 467-483. Platinum derivatives used m clinical practice are: CisPlatm, Carboplatm, Oxaliplatm, Nedaplatm and Lobaplatm; see review Cancer, Principles and Practice of Oncology, Lippmcott-Raven Ed. (1997), 418- 432. 4-Demethoxy-3' -deammo-3' -azιπdmyl-4' -methansulfonyl daunorubicin is the preferred compound to be used m the present invention, more preferably m combination with oxaliplatm docetaxel or paclitaxel. The present invention also provides a product comprising an anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, as combined preparation for simultaneous, separate or sequential use m antitu or therapy. A further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neoplastic disease state comprising administering to said mammal an anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, m amounts effective to produce a synergetic anti-neoplastic effect. The present invention also provides a method for lowering the side effects caused by anti-neoplastic therapy with an anti-neoplastic agent m mammals, including humans, m need thereof, the method comprising administering to said mammal a combination preparation comprising an anti-neoplastic anti-mitotic compound and/or a platinum derivative as defined above and an anthracyclme of formula la or lb, as defined above, m amounts effective to produce a synergistic anti-neoplastic effect. By the term *a synergistic anti-neoplastic effect" as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an anthracyclme of formula la or lb as defined above and an anti-mitotic compound and/or a platinum derivative to mammals, including human. By the term Vλ administered w or * administering" as used herein is meant parenteral and /or oral administration. By X parenteral" is meant intravenous, subcutaneous and mtramuscolar administration. In the method of the subject invention, the anthracyclme may be administered simultaneously with the compound with anti-mitotic activity, and/or a platinum derivative, or the compounds may be administered sequentially, m either order. It will be appreciated that the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the anthracyclme of formula la or lb being utilized, the particular formulation of the anti-mitotic compound, such as one of taxane analog class and of the platinum derivative being utilized, the particular tumor model being treated, and the particular host being treated . In the method of the subject invention, for the administration of the anthracyclme of formula la or lb, the course of therapy generally employed is from about 0.1 to about 200 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m of body surface area. In the method of the subject invention, for the administration of the anti-mitotic compounds the course of therapy generally employed is from about 1 to about 1000 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 10 to about 500 mg/m " of body surface area. In the method of the subject invention, for the administration of the platinum derivative the course of therapy generally employed is from about 1 to about 1000 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 100 to about 500 mg/m of body surface area. The anti-neoplastic therapy of the present invention is m particular suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors m mammals, including humans . In a further aspect, the present invention is directed to the preparation of a pharmaceutical composition containing an effective amount of an anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative m the prevention or treatment of metastasis or for the treatment of tumors by angiogenesis inhibition, as well as to the use of an anthracyclme of formula I_a or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative for the treatment of tumors by angiogenesis inhibition or for the treatment or prevention of metastasis. As stated above, the effect of an anthracyclme of formula la or lb and an anti-neoplastic anti-mitotic compounds, such as taxane derivatives, and/or a platinum derivative is significantly increased without a parallel increased toxicity. In other words, the combined therapy of the present invention enhances the antitumoral effects of the alkylating anthracycline and/or of the anti-mitotic compound and/or of the platinum derivative and thus yields the most effective and less toxic treatment for tumors. The superadditive actions of the combination preparation of the present invention are shown for instance by the following in vi vo tests, which are intended to illustrate but not to limit the present invention. Table 1 shows the antileukemic activity on disseminated L1210 murine leukemia obtained combining la. with oxaliplatinum. At the dose of 8 mg/kg of oxaliplatmum alone (day +3) and at the dose of 1 mg/kg of I_a alone (day +1,2) were associated, without toxicity, with increase in life span (ILS?>) values of 83 for both. Combining oxaliplatinum and la at the same doses with the same schedule an increase antitu or activity with ILS° value of 125 was observed, indicating a synergistic effect of the combination. For these experiments la was solubilized in [Cremophor® /EtOH= 6.5:3.5]/ [normal saline] =20/80 v/v, while oxaliplatinum was solubilized in saline solution. Table 1: Antileukemic activity against disseminated L1210 1 murine leukemia of la in combination with Oxaliplatinum 1) L1210 leukemia cells (10 5 /mouse) are injected iv on day 0 2) Treatment is given starting on day 1 after tumor transplantation (day 0). 3) Increase in life span: [(median survival time of treated mice/median survival time of controls )x 100 ]-100 4) Number of toxic deaths/number of mice. Table 2 shows the antitumor effect on subcutaneous implanted A549 human lung carcinoma obtained combining la with CisPlatin. At the doses of 3 mg/kg of CisPlatin alone (q4dx2) and at the dose of 1.5 mg/kg of la alone (q4dx3) were associated, without toxicity, with T.I.o values of 16 and 48, respectively. Combining CisPlatin and I_a, a significant increase in tumor growth delay was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone. Table 2: Antitumor activity on A549 human lung carcinoma 1 of la in combination with CisPlatin 1) Tumor fragments are implanted s.c. 2) Treatment is given starting when the tumor is palpable. 3) Tumor inhibiton. 4) Number of toxic deaths/number of mice. 5 ) umor growth delay; T, median time to reach a tumor size of 1 g treated nude mice; C, median time to reach a tumor size of 1 g in control nude mice. 6) reatment with CisPlatin started two days after treatment with la Table 3 shows the antitumor effect on subcutaneus implanted A549 human lung carcinoma obtained combining la with paclitaxel. At the doses of 22 and 33 mg/kg of paclitaxel alone (days +9, 13, 17) and at the dose of 2 mg/kg of la. alone (days +7, 11, 15) were associated, without toxicity, with T.I.% values of 69,90 and 93, respectively. Combining paclitaxel and la., a significant increase in tumour growth delay was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone. Table 3: Antitumor activity on A549 human lung carcinoma 1 of la in combination with paclitaxel 1) Tumor fragments are implanted s.c. 2) Treatment is given starting when the tumor is palpable. 3) Tumor inhibiton. 4) Number of toxic deaths/number of mice. 5) Tumor growth delay; T, median time to reach a tumor size of 1 g treated nude mice; C, median time to reach a tumor size of 1 g in control nude mice. Table 4 shows the antitumor effect on subcutaneous implanted H207 human ovarian carcinoma obtained combining la with paclitaxel. At the doses of 22 and 33 mg/kg of paclitaxel alone (q4dx3)and at the dose of 1.5 mg/kg of la. alone (q4dx3) were associated, without toxicity, with T . I . % values of 100,80 and 86, respectively. Combining paclitaxel and I_a, a significant increase in tumor growth delay and the appearance of the tumor free survivors (1/7 and 4/7) was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone. Table 4: Antitumor activity on H207 human ovarian carcinoma 1 of la in combination with paclitaxel 1) Tumor fragments are implanted s.c. 2) Treatment is given starting when the tumor is palpable. 3) Tumor inhibiton. 4) Number of toxic deaths/number of mice. 5) Tumor growth delay; T, median time to reach a tumor size of 1 g treated nude mice; C, median time to reach a tumor size of 1 g in control nude mice. 6) Treatment with paclitaxel started two days after treatment with la Table 5 shows the antitumor effect on subcutaneous injected MX1 mammary carcinoma obtained combining la with docetaxel. At the doses of 5 and 10 mg/kg of docetaxel alone (q4dx3)and at the dose of 0.5 and 1 mq/kg of I_a alone (q4dx3) were associated, without toxicity, with T . I . % values of 60,99 and 46,94 respectively. Combining docetaxel and la, a significant increase in tumor growth delay and of the tumor free survivors (3/8, 5/8 and 7/8) was observed indicating a therapeutic advantage of the combination m comparison with the administration of the drug alone. Table 5: Antitumor activity on MXl mammary carcinoma 1 of la m combination with paclitaxel 1) Tumor fragments were injected s.c. 2) Treatment is given starting when the tumor is palpable. 3) Tumor mhibiton. 4) Number of toxic deaths/number of mice. 5) TGD : Tumor growth delay treated - Tumor growth delay control

Claims: Claims 1. Products containing an anthracyclme of formula la or lb : and an anti-neoplastic anti-mitotic compound and/or a platinum derivative as a combined preparation for simultaneous, separate or sequential use m the treatment of tumors. 2. Products according to claim 1 wherein the anthracyclme is 4-demethoxy-3' -deammo-3' -azιπdmyl-4' -methansulfonyl daunorubicin . 3. Products according to claim 1 or 2 wherein the anti- mitotic compound is paclitaxel or docetaxel. 4. Products according to claim 1 or 2 wherein the platinum derivative is oxaliplatm. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as active ingredient, an anthracyclme of formula la or lb as defined claim 1 and an anti-neoplastic anti-mitotic compound and/or a platinum derivative . 6. A composition according to claim 5 wherein the anthracyclme is 4-demethoxy-3' -deammo-3' -azιrιdmyl-4' - methansulfonyl daunorubicin. 7. Use of an anthracycline of formula la or lb as defined in claim 1 and an anti-neoplastic anti-mitotic compound and/or a platinum derivative in the preparation of a medicament for use in the treatment of tumors. 8. Use according to claim 7 wherein the anthracycline is 4- demethoxy-3' -deamino-3' -aziridinyl-4' -methansulfonyl daunorubicin . 9. Use of a product as defined in claim 1 in the preparation of a medicament for use in the prevention or treatment of metastasis or in the treatment of tumors by inhibition of angiogenesis.

Inventors: CARUSO MICHELE, GERONI CRISTINA, RIPAMONTI MARINA, SUARATO ANTONINO, CARUSO, MICHELE, GERONI, CRISTINA, RIPAMONTI, MARINA, SUARATO, ANTONINO
Applicants: CARUSO MICHELE, GERONI CRISTINA, PHARMACIA & UPJOHN SPA, RIPAMONTI MARINA, SUARATO ANTONINO, CARUSO, MICHELE, GERONI, CRISTINA, PHARMACIA & UPJOHN S.P.A., RIPAMONTI, MARINA, SUARATO, ANTONINO
Application year: 2000
Main classification: A61K31
IPC codes: A61K45, A61P35