P53 MUTATIONS, O-6-ALKYLGUANINE DNA ALKYLTRANSFERASE ACTIVITY, AND SENSITIVITY TO PROCARBAZINE IN HUMAN BRAIN-TUMORS

Background. In human brain tumors, sensitivity to procarbazine as meas ured by sensitivity in a xenograft tumor model correlated inversely wi th amounts of the DNA repair enzyme O-6-alkylguanine DNA alkyltransfer ase (AT). Methods. To test the hypothesis that mutations of the p53 tu mor suppressor gene in human tumors also can correlate with the respon se to chemotherapy, p53 mutations were identified in primary human mal ignant brain tumors and cell lines in which AT activity and procarbazi ne sensitivity in a xenograft model was ascertained. Results. Mutation s were identified in 7 of 21 (33%) specimens tested. Specimens contain ing p53 mutations tended to exhibit an increased growth delay in proca rbazine-treated xenografts and lower amounts of AT. Conclusions. p53 m utations in brain tumors may contribute to procarbazine sensitivity by failing to induce arrest at the G(1)/S cell-cycle checkpoint, thereby preventing the repair of procarbazine-induced genetic alterations.