Doses and time-dependent effects of 3'-azido-3'-deoxythymidine on T47D human breast cancer cells in vitro.
The objective of the present work was to study the effects of 3'-azido-3'-deoxythymidine (azidothymidine, Zidovudine) on human breast cancer cells by using, as a model, the T47D cell line (typified as oestrogen-dependent and p53-mutated). Low azidothymidine doses (3.125 microM) increase the percentage of cells in S-phase, with the effect reversing after 24 hr of incubation; as azidothymidine doses increase, the magnitude and duration of its effect increase proportionally, although, even with the highest concentrations (50-100 microM) the effects decline after 48 hr of incubation. If media (containing azidothymidine or vehicle) are daily renewed, the azidothymidine effects (accumulation of cells in S-phase) are higher and decline later than when media and drug are not changed during the whole culture period, thereby suggesting that the reversion of azidothymidine effects could be related with a degradation of the drug or accumulation in media of substances which counteract its effects. Azidothymidine inhibits T47D cell proliferation at concentrations higher than 50 microM. The exposure to 50 or 100 microM azidothymidine induced cell apoptosis after 48 hr or more of incubation. We conclude that: a) azidothymidine, with appropriate doses and duration of treatment, synchronizes cells in S-phase, inhibits proliferation, and induces apoptosis, b) the discontinuous application of the drug rather than continuous exposure to it increases its efficiency to synchronize the T47D cell cycle. This in vitro anti-breast cancer activity suggests that a possible clinical usefulness of azidothymidine, either alone or associated with other drugs with cycle-specific antitumoural activity circumscribed to the S-phase of cell cycle, is worthy of investigation.
Mediavilla
M D
MD
Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.
Sánchez-Barceló
E J
EJ
D000704:Analysis of Variance; D000963:Antimetabolites / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005434:Flow Cytometry; D006801:Humans; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use*
D000963:Antimetabolites; D015215:Zidovudine