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Increased methotrexate‐induced DNA strand breaks and cytotoxicity following mutational loss of thymidine kinase
Author(s) -
Sano Hirohiko,
Kubota Masaru,
Kasai Yasufumi,
Hashimoto Hisako,
Shimizu Tsunehiro,
Adachi Souichi,
Mikawa Haruki
Publication year - 1991
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910480117
Subject(s) - hypoxanthine guanine phosphoribosyltransferase , phosphoribosyltransferase , thymidine kinase , hypoxanthine , microbiology and biotechnology , cytotoxicity , thymidine , dna , biology , guanine , dna damage , dna repair , chemistry , biochemistry , genetics , nucleotide , in vitro , mutant , enzyme , gene , virus , herpes simplex virus
The cytotoxicity and DNA lesions induced by methotrexate (MTX) were compared in wild‐type, hypoxanthine‐guanine phosphoribosyltransferase‐deficient (HGPRT) and thymi‐dine‐kinase‐deficient (TK) HL‐60 cells. TK ‐ and HGPRT cells were approximately 10 and 3 times more sensitive to MTX than wild‐type cells, respectively. Following incubation with 2 m̈m MTX for 16 hr, TK ‐ cells showed a significantly higher number of DNA strand breaks. Concomitantly, DNA fragmentation at the nucleosomal linker region was detected more prominently in TK ‐ cells. Although MTX tended to decrease TTP pools similarly in all 3 cell types, the initial TTP level in TK ‐ cells was only about one‐fifth of that found in the wild type. These results indicate that the thymidine salvage pathway has a pivotal role in mediating MTX‐induced toxicity and DNA lesions.