tailieunhanh - Báo cáo khoa học: A comparative analysis of the time-dependent antiproliferative effects of daunorubicin and WP631

Jurkat T lymphocytes were treated with daunorubicin and WP631, a daunorubicin-based DNAbinding agent, in experiments aimed to analyze cellular uptake of these drugs and their effect on cell viability. WP631 was taken up more slowly than daunorubicin, but laser confocal microscopy and spectrofluorometricquantificationshowed that thedrug accumulated in the cells. Despite the slow uptake rate, the antiproliferative capacity of WP631 (measured as IC50after a 72-h continuous treatment) was greater than that of daunorubicin. The propensities of daunorubicinandWP631 to promote apoptosis were compared | Eur. J. Biochem. 270 764-770 2003 FEBS 2003 doi A comparative analysis of the time-dependent antiproliferative effects of daunorubicin and WP631 Silvia Villamarin1 Sylvia Mansilla1 I Neus Ferrer-Miralles1 Waldemar Priebe2 and Jose Portugal1 lDepartamento de Biologia Molecular y Celular Instituto de Biologia Molecular de Barcelona CSIC Barcelona Spain department of Bioimmunotherapy The University of Texas M. D. Anderson Cancer Center Houston TX USA Jurkat T lymphocytes were treated with daunorubicin and WP631 a daunorubicin-based DNA bidding agent in experiments aimed to analyze cellular uptake of these drugs and their effect on cell viability. WP631 was taken up more slowly than daunorubicin but laser confocal microscopy and spectrofluorometric quantification showed that the drug accumulated in the cells. Despite the slow uptake rate the antiproliferative capacity of WP631 measured as IC50 after a 72-h continuous treatment was greater than that of daunorubicin. The propensities of daunorubicin and WP631 to promote apoptosis were compared. Our results indicate that the major effect of WP631 was a G2 M arrest followed after about 72 h of treatment by polyploidy and mitotic reproductive death. In contrast daunorubicin induced a rapid response with classic features of apoptosis. Keywords anthracyclines p53 cell-cycle mitotic catastrophe Jurkat T lymphocytes. Anthracyclines are among the most potent and clinically useful drugs in cancer treatment 1 . Anthracycline antibiotics are DNA íntercnkitors 2 3 nnd the entitumor activity of daunorubicin a prominent member of this group of antibiotics may be associated with its binding to DNA although several mechanisms have been proposed to fully explain the cytotoxic actions of these antitumor molecules 1 4 5 . Detailed information on the structural and thermodynamic basis of daunorubicin binding to DNA 2 3 6 has provided the foundation upon which to design WP631 a new bisanthracycline Fig. 1 .