A study of the mechanism of resistance to Adriamycin® in vivo: Glutathione metabolism, P-glycoprotein expression, and drug transport

摘要: Abstract A spontaneously originated murine mammary adenocarcinoma (16C), selected for its sensitivity to agents active against breast cancer in women, and one of the very few experimental solid tumor models responsive Adriamycin® (ADR) was used study mechanism induced ADR resistance vivo . resistant variant obtained from explant a regrown following dose (12 mg/kg) that caused complete repression but not cure. Progressive refractoriness observed up six repeated cycles treatment, regression regrowth. However, beyond sixth no further degree could be obtained. The cell line so established, designated 16C/ADR R , has glutathione (GSH) content 1.67 times greater than parent 16C line. Depletion GSH by buthionine sulfoximine (BSO) enhanced cytoxicity both lines. sensitization effect appeared dependent on depletion, requiring threshold level depletion approximately 30% control. however, directly related increased absolute per se since reduction levels similar did restore original ADR. activities two important elements detoxification system, peroxidase S -transferase, were found elevated cells factors 2.4 4.7–5.6 respectively. In studies with diverse spectrum antineoplastic drugs revealed pattern cross-resistance consistent idea -transferase may responsible decreased (2.8- 5.3-fold) exhibited melphalan (MEL), none vincristine (VCR), vinblastine (VBL) or etoposide (VP-16). These results clearly demonstrate non-adherence tumors well characterized multidrug ( mdr ) phenotype. Further affirmation this conclusion immunochemical pharmacological studies. When monoclonal antibody prepared associated, 170 kD P-glycoprotein (170 P-gp), used, presence P-gp sensitive lines detected, although lower molecular weight form ruled out entirely. High performance liquid chromatographic measurement accumulation elimination also failed reveal any significant differences between variants. results, therefore, argue possibility drug transport membrane changes as resistance, strongly implicate increases basis situ tumor.