Pre-treatment of a human T-lymphoblastoid cell line with L-asparaginase reduces etoposide-induced DNA strand breakage and cytotoxicity.
The effect of L-asparaginase (L-asp) pre-treatment on etoposide-induced DNA strand breakage and cytotoxicity was investigated. In a T-lymphoblastoid cell line, Molt 4, etoposide-induced DNA strand breaks, DNA-protein cross-links and cytotoxicity were reduced by pre-treatment with L-asp for 15 hr, but it did not cause these changes in a promyelocytic-leukemia cell line, HL-60, which is less sensitive than Molt 4 to L-asp. However, pre-treatment of Molt 4 cells with L-asp did not significantly alter the accumulation of [3H]-etoposide. Cell-cycle analyses showed an increase in G1-phase cells, a significant decrease in both S-phase cells and G2/M-phase cells pre-treated with L-asp in Molt 4 cells, but L-asp exposure did not result in any significant changes in HL-60 cells. On the other hand, L-asp pre-treatment did not affect topoisomerase-I (Topo-I) inhibitor, camptothecin (CPT)-induced DNA strand breaks or toxicity in Molt 4 cells. Our data imply that a decrease in S- and G2/M-phase cells following L-asp treatment may explain the reduction of etoposide-induced DNA lesions and cytotoxicity in Molt 4 cells, since topoisomerase-II (Topo-II) content or activity is a function of cellular proliferation status.
Shimizu
T
T
Department of Pediatrics, Kyoto University, Japan.
Kubota
M
M
Adachi
S
S
Sano
H
H
Kasai
Y
Y
Hashimoto
H
H
Akiyama
Y
Y
Mikawa
H
H
D001215:Asparaginase / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D005047:Etoposide; D004247:DNA; D001215:Asparaginase; D002166:Camptothecin