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. The aim of the present study was to evaluate the activity of medroxyprogesterone acetate (MPA) as a chemosensitiser on anthracycline cytotoxicity. The study investigated whether such an effect could be related to an increase in lipid peroxidation, nitric oxide production, membrane fluidity and intracellular anthracycline concentration. The results showed that anthracyclines decreased nitric oxide production but increased membrane viscosity (polarisation constant) and lipid hydroperoxide formation in canine mammary tumour cells. Moreover, it was found that both drug-induced cytotoxicity and membrane viscosity increased in the presence of MPA. Conversely, lipid hydroperoxides 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 intracellular concentration of anthracyclines.
Pagnini
U
U
Department of Pathology and Animal Health, School of Veterinary Medicine, University of Naples Federico II, Naples, Italy. upagnini@unina.it
Florio
S
S
Lombardi
P
P
d'Angelo
D
D
Avallone
L
L
Galdiero
M
M
Iovane
G
G
Tortora
G
G
Pagnini
G
G
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor / Q000662:veterinary*; D005260:Female; D005454:Fluorescence Polarization / Q000662:veterinary; D015255:Idarubicin / Q000494:pharmacology; D015227:Lipid Peroxidation; D015674:Mammary Neoplasms, Animal; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D018943:Anthracyclines; D009569:Nitric Oxide; D004317:Doxorubicin; D017258:Medroxyprogesterone Acetate; D015255:Idarubicin