Modulation of anthracycline activity in canine mammary tumour cells in vitro by medroxyprogesterone acetate

Failure of chemotherapy with anthracyclines as a result of drug resistance and toxicity is a major problem in the clinical management of neoplasia. Th e aim of the present study was to evaluate the activity of medroxyprogester one acetate (MPA) as a chemosensitiser on anthracycline cytotoxicity. The s tudy investigated whether such an effect could be related to an increase in lipid peroxidation, nitric oxide production, membrane fluidity and intrace llular anthracycline concentration. The results showed that anthracyclines decreased nitric oxide production but increased membrane viscosity (polaris ation constant) and lipid hydroperoxide formation in canine mammary tumour cells. Moreover, it was found that both drug-induced cytotoxicity and membr ane viscosity increased in the presence of MPA. Conversely, lipid hydropero xides decreased in MPA-supplemented cells. Medroxyprogesterone acetate did not show any effect on nitric oxide production. The two anthracyclines used (doxorubicin and idarubicin) showed differential intranuclear accumulation in canine mammary tumour cells, and MPA significantly modified intracellul ar concentration of anthracyclines. (C) 2000 Harcourt Publishers Ltd.