Camptothecin-induced sister-chromatid exchange dependent on the presence of bromodeoxyuridine and the phase of the cell cycle.
Camptothecin (CPT), a DNA topoisomerase I inhibitor, dose-dependently induced sister-chromatid exchanges (SCEs) in human lymphoblastoid cells NL3 when added with bromodeoxyuridine (BrdUrd) for 2 cell cycles. CPT given prior to the addition of BrdUrd scarcely induced SCEs. When cells with BrdUrd present for 2 cell cycles were treated with CPT in the first cell cycle, the SCE induction was evident, though its frequency was considerably lower than in cells treated in the second cell cycle, indicating that BrdUrd is essential for SCE induction by CPT. The replacement of BrdUrd with thymidine in the second cell cycle gave the same results in SCE induction and its removal without replacement resulted in a reduced but still clear induction by CPT treatment in the second cell cycle. These results indicate that BrdUrd, not only incorporated into DNA but also in the culture medium, plays an essential role in SCE induction by CPT. CPT treatment in the G1 phase of the second cell cycle also induced SCEs, as did treatment in the S phase. In phytohemagglutinin-stimulated peripheral lymphocytes, CPT given in the G1 phase of the second cell cycle, but not of the first one, also induced SCEs though to a lesser degree. These findings suggest that CPT is capable of inducing DNA lesions during the G1 phase when chromosomes contain BrdUrd-substituted DNA. The lesions are presumably formed in connection with transcription, which requires topoisomerase I activity, and are believed to be long-lived enough to induce SCEs in the following S phase.
Zhao
J H
JH
Research Institute for Tuberculosis and Cancer, Tohoku University, Sendai, Japan.
Tohda
H
H
Oikawa
A
A
D001973:Bromodeoxyuridine / Q000633:toxicity*; D002166:Camptothecin / Q000633:toxicity*; D002453:Cell Cycle; D002478:Cells, Cultured; D004347:Drug Interactions; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D012854:Sister Chromatid Exchange
D009153:Mutagens; D001973:Bromodeoxyuridine; D002166:Camptothecin