Tirapazamine (SR 4233) interrupts cell cycle progression and induces apoptosis.
Tirapazamine (Tira), a bioreductive agent, is highly toxic to cells under low oxygen conditions. Since active investigations of this agent are focusing on its potential as an adjunct of radiotherapy to improve overall effects on radioresistant hypoxic tumor cells, understanding its toxic mechanisms under aerobic conditions is important to the clinical application of this agent. Tira-treated V79 Chinese hamster cells were tested for cytotoxicity by colony assay and growth inhibition by the MTT assay. The survival of V79 cells after being exposed to 100 microM of Tira for 2 h was about 78% of untreated controls. The mitotic cell counts of V79 cells approached zero after 4 h treatment of Tira at 100 microM or 3 h at 300 microM. The fragmentation pattern of DNA isolated from cells 2 h after 300 microM Tira treatment showed characteristics of apoptotic cells. The induction of apoptosis by Tira was also detected by flow cytometric analysis and microscopic observation. These effects of Tira may be part of underlying toxic mechanisms to cells (including normal cells) under aerobic conditions.
Lin
P S
PS
Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Ho
K C
KC
Yang
S J
SJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004587:Electrophoresis, Agar Gel; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D005434:Flow Cytometry; D008940:Mitotic Index / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D011003:Ploidies; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*; D000077704:Tirapazamine; D014227:Triazines / Q000633:toxicity*
D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D002110:Caffeine; D009543:Nifedipine