Synchronization of cells in the S phase of the cell cycle by 3'-azido-3'-deoxythymidine: implications for cell cytotoxicity.
The mechanism of synergy between 3'-azido-3'-deoxythymidine (AZT) and anticancer agents was investigated with emphasis on cell-cycle events. Exposure of exponentially growing WiDr human colon carcinoma cells to AZT resulted in synchronization of cells in the S phase of the cell cycle. Following treatment with AZT at 50 or 200 microM, 62% +/- 3% or 82% +/- 4% of the cells were in the S phase as compared with 36% +/- 2% in the control. Bromodeoxyuridine uptake studies revealed that the synchronized cells actively synthesized DNA. At concentrations of up to 200 microM, AZT produced a cytostatic rather than cytotoxic effect as indicated by viability and cell growth measurements. At 200 microM, AZT-induced synchronization was significant (P = < 0.001) after 12 h of drug exposure, reached a maximum at 24 h, and reversed to baseline levels by 72 h even in the continued presence of the drug. This indicates that AZT-induced cytostasis is a transient and reversible effect. The cell-cycle events seen with AZT in WiDr cells were also observed in eight of nine human tumor cell lines tested. Isobologram analysis of WiDr cells preexposed to AZT for 24 h and then exposed to either AZT-5-fluorouracil or AZT-methotrexate for a further 72 h revealed synergy between AZT and the anticancer agents, indicating that AZT-induced synchronization may have therapeutic benefits.
Chandrasekaran
B
B
Division of Cell Biology, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Kute
T E
TE
Duch
D S
DS
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D003198:Computer Simulation; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D016196:S Phase / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000627:therapeutic use / Q000633:toxicity*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D015215:Zidovudine; D005472:Fluorouracil; D008727:Methotrexate