Increased methotrexate-induced DNA strand breaks and cytotoxicity following mutational loss of thymidine kinase

✍ Scribed by Hirohiko Sano; Masaru Kubota; Yasufumi Kasai; Hisako Hashimoto; Tsunehiro Shimizu; Souichi Adachi; Haruki Mikawa

• Book ID: 102277740
• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: French
• Weight: 484 KB
• Volume: 48
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910480117

✦ Synopsis

Abstract

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.