Alteration of CDKN2/p16 in human astrocytic tumors is related with increased susceptibility to antimetabolite anticancer agents

A slowly proliferating cell fraction in tumors shows reduced sensitivity to cell cycle-dependent anticancer agents. To understand the molecular basis of drug resistance observed in brain tumors, we examined the relationship b etween alteration of p16, a cyclin dependent kinase inhibitor whose functio ns are frequently lost in many human gliomas, and chemosensitivity of tumor cells to various kinds of anticancer agents. Alterations of the p16 gene t hat include mutation(s) and homozygous deletion as well as p16 protein expr ession level, were examined in 56 specimens of astrocytic tumors. Their in vitro chemosensitivities to 30 kinds of anticancer agents were analyzed wit h flow cytometry which detects drug-induced cell death. We found that the a lterations were correlated with increased sensitivity to antimetabolite ant icancer agents but not with other kinds of agents, including alkylating age nts, antibiotics, topoisomerase inhibitors and antimicrotubule agents. The present results suggest that p16 plays a role in determining chemosensitivi ty of brain tumors, depending on pharmacological mechanisms of anticancer a gents. Proper understanding of the molecular machinery which regulates the chemosensitivity may contribute to the choice of anticancer agents for indi vidual patients.