DRUG-RESISTANCE AND APOPTOSIS IN ENU-INDUCED RAT-BRAIN TUMORS TREATEDWITH ANTICANCER DRUGS

To cast light on the mechanisms of drug-resistance, experimental brain tumors were immunohistochemically evaluated for expression of glutath ione S-transferase (GST)-alpha, mu, pi, p-glycoprotein and apoptosis-r elated factors, such as bcl-2 and p53, as well as by the terminal deox ynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNE L) method. Rat brain tumors induced by means of prenatal exposure to e thylnitrosourea (ENU) were treated with pyrimidinyl)methyl-3-(2-chloro ethyl)-3-nitrosourea hydrochloride (ACNU) and/or vincristine. Tumors m ore than 2 mm in size were considered to be drug resistant. The expres sion of GST-mu was strongly positive in ACNU-treated brain tumors, whi le p-glycoprotein was overexpressed in vincristine-treated brain tumor s. Neither p53 nor bcl-2 expression directly correlated with apoptosis identified by TUNEL method, but tumors lacking apoptotic cells always demonstrated the expression of either GST-mu or p-glycoprotein. These results indicate that tumors resistant to chemotherapy might not be s usceptible to induction of apoptosis, and therefore that mechanisms of drug resistance are related to programmed cell death in brain tumors.