Time- and concentration-dependent apoptosis and necrosis induced by free and HPMA copolymer-bound doxorubicin in human ovarian carcinoma cells

A2780 sensitive and A2780/AD doxorubicin (DOX) resistant human ovarian carc inoma cells were exposed to different concentrations (0.25, 0.5, 1, 5 and 1 0XIC(50)) of free and HPMA copolymer-bound DOX for 12, 24, 36, 48, 60 and 7 2 h. Apoptosis and necrosis were evaluated using the FITC-conjugated annexi n V and propidium iodide staining. The data obtained showed that the induct ion of apoptosis and necrosis by both free DOX and HPMA copolymer-bound DOX were time- and concentration-dependent. The data also showed significant d ifferences between the drugs. It was found that: (i) under the action of HP MA copolymer-bound doxorubicin the alterations in the plasma membrane perme ability preceded disturbances in cellular metabolism; (ii) HPMA copolymer-b ound doxorubicin kills the cells mainly by necrosis; (iii) HPMA copolymer-b ound doxorubicin is a more effective anticancer drug than free doxorubicin. (C) 2000 Elsevier Science B.V. All rights reserved.