Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice.
Intoplicine (RP 60475, NSC 645008) is a new 7H-benzo[e]pyrido [4,3-b] indole derivative which interacts with DNA and inhibits both topoisomerases I and II. In vitro it was found cytotoxic against various cell types with greater cytotoxicity towards solid tumor cells. We report here the anticancer activity of RP 60475 against a variety of transplantable tumors of mice, and also its cross-resistance profile in leukemias. The end points used were % T/C (median tumor weight of the Treated over the Control x 100) and logCK (log10 cell kill total). RP 60475 administered i.v. was found schedule-independent with a peak plasma level problem. It had a good therapeutic index and host recovery usually occurred 7.5 days post last treatment. RP 60475 was found to be highly active against early stage colon 38 (T/C = 0%, 2.9 logCK) and could induce 5/5 complete regressions of advanced stage tumor. It was found active against colon adenocarcinoma 51 (T/C = 3.6%, 1.9 logCK) and colon carcinoma 26 (T/C = 11.7%, 1.2 logCK). Most of the mammary adenocarcinomas were found very responsive, MA16/C (T/C = 0%, 2.8 logCK), MA14/A (T/C = 0%, 1.4 logCK), MA13/C (T/C = 0%, 3.1 log CK) and MA44 (T/C = 34%). Excellent activity was also observed against early stage pancreatic ductal adenocarcinoma 03 (T/C = 0%) and RP 60475 could achieve 5/5 complete regressions of upstaged tumor. Activity was also obtained on Glasgow osteogenic sarcoma (T/C = 0%, 3.3 logCK), on B16 melanoma (T/C = 14%, 1.3 logCK) and to a lesser extent on Lewis lung carcinoma (T/C = 33.2%). Evaluation of RP 60475 against leukemia sublines with acquired resistance, revealed that L1210/cisplatin and L1210/BCNU were not cross-resistant to RP 60475 whereas P388/vincristine was partially cross-resistant to RP 60475 and P388/doxorubicin was cross-resistant to RP 60475. Based on RP 60475 broad activity against transplantable tumors of mice, its effectiveness against some resistant sublines, its original mechanism of action and its acceptable toxicological profile, this compound was selected for clinical trials.
Bissery
M C
MC
Rhône-Poulenc Rorer S.A., Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Nguyen
C H
CH
Bisagni
E
E
Vrignaud
P
P
Lavelle
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; C081834:intoplicine