Quinacrine enhances carmustine therapy of experimental rat glioma

OBJECTIVE: The high rate of mutagenesis in malignant cells has been conside red to be a primary factor in the appearance of chemotherapy-resistant cell clones in glioblastomas. Quinacrine binds strongly to deoxyribonucleic aci d, preventing mutagenesis. We investigated whether quinacrine could improve carmustine therapy in C6 cell cultures and in C6 malignant gliomas implant ed subcutaneously into Wistar rats. METHODS: A potential chemopreventive effect of quinacrine on acquired resis tance to carmustine therapy was studied in vitro and in vivo. Deoxyribonucl eic acid damage was measured in cultured C6 cells by using the micronucleus test. Wistar rats with subcutaneously implanted C6 gliomas were treated wi th carmustine, quinacrine, or carmustine plus quinacrine, using pharmacolog ical schemes similar to those used for human patients. RESULTS: The addition of quinacrine to cultured C6 cells did not modify car mustine-induced cytotoxicity; however, the deoxyribonucleic acid damage in surviving cells was minor, as indicated by the frequency of micronucleated cells. The surviving cells continued to be susceptible to a second exposure to carmustine, in contrast to non-quinacrine-treated control cells, which developed resistance to carmustine in a subsequent exposure (P < 0.05). The rate of tumor remission was higher for glioma-bearing rats treated with qu inacrine plus carmustine, compared with rats treated with carmustine alone (P < 0.01). CONCLUSION: The addition of quinacrine to carmustine therapy increases the antineoplastic effect of the carmustine therapy. Our results suggest that c hemical inhibition of mutagenesis in malignant glial cells during chemother apy prevents the appearance of resistant clones.