IN-VITRO AND IN-VIVO ANTIPROLIFERATIVE ACTIVITY OF IPCAP, A NEW PYRAZOLE NUCLEOSIDE ANALOG

IPCAR is a pyrazole nucleoside analog which belongs to a class of comp ounds structurally related to the inosine monophosphate (IMP) dehydrog enase (IMPDH) inhibitors ribavirin, selenazofurin and tiazofurin. Unli ke other anticancer drugs, IPCAR showed a potent and broad-spectrum an tiproliferative activity in vitro coupled with low cytotoxicity for re sting PBL and CFU-GM. IPCAR proved fully inhibitory against human naso pharyngeal carcinoma KB cells expressing the MDR phenotype, whereas IP CAR-resistant renal adenocarcinoma ACHN/R1 cells were fully susceptibl e to inhibition by a number of anticancer drugs, with the exception of 6TG, 6MP and 5FU towards which they showed a partial cross-resistance . In combinations studies,IPCAR proved synergistic with 6MP, 6TG, 5FU and ribavirin, and additive with ara-A, MTX, doxorubicin, taxol and ti azofurin. Antagonistic effects were never observed. Although the preci se molecular target of IPCAR remains to be identified the data present ed herein suggest that, unlike ribavirin and tiazofurin, this drug inh ibits a step of the de novo purine biosynthesis different from the con version of IMP into GMP. In vivo IPCAR showed low acute toxicity (DL10 > 1000 mg/kg) and was active against the L1210 murine lymphocytic leu kemia model Drug doses of 125 and 250 mg/kg on a day-1, -3 and -5 dosi ng schedule increased the life span (ILS) relative to untreated contro l mice of 36.4 and 68.2%, respectively whereas administration of 500 m g/kg on days I and 3 resulted in a ILS of 86.4% and also increased the 30-day survival rate (25% of the mice).