ANTITUMOR-ACTIVITY OF INTOPLICINE (RP-60475, NSC-645008), A NEW BENZOPYRIDO-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 topoisome rases I and II. In vitro it was found cytotoxic against various cell t ypes with greater cytotoxicity towards solid tumor cells. We report he re the anticancer activity of RP 60475 against a variety of transplant able tumors of mice, and also its cross-resistance profile in leukemia s. The end points used were % T/C (median tumor weight of the Treated over the Control x 100) and logCK (log(10) cell kill total). RP 60475 administered i.v. was found schedule-independent with a peak plasma le vel problem. It had a good therapeutic index and host recovery usually occurred 7.5 days post last treatment. RP 60475 was found to be highl y active against early stage colon 38 (T/C=0%, 2.9 logCK) and could in duce 5/5 complete regressions of advanced stage tumor. It was found ac tive against colon adenocarcinoma 51 (T/C=3.6%, 1.9 logCK) and colon c arcinoma 26 (T/C=11.7%, 1.2 logCK). Most of the mammary adenocarcinoma s were found very responsive, MA16/C (T/C=O%, 2.8 logCK), MA14/A (T/C= O%, 1.4 logCK), MA13/C (T/C=0%, 3.1 log CK) and MA44 (T/C=34%). Excell ent activity was also observed against early stage pancreatic ductal a denocarcinoma 03 (T/C=0%) and RP 60475 could achieve 5/5 complete regr essions of upstaged tumor. Activity was also obtained on Glasgow osteo genic 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%). Evaluati on of RP 60475 against leukemia sublines with acquired resistance, rev ealed 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 R P 60475 broad activity against transplantable tumors of mice, its effe ctiveness against some resistant sublines,its original mechanism of ac tion and its acceptable toxicological profile, this compound was selec ted for clinical trials.