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Hyperthermic modulation of SN‐38‐induced topoisomerase I DNA cross‐linking and SN‐38 cytotoxicity through altered topoisomerase I activity
Author(s) -
Katschinski Dörthe M.,
Robins H. Ian
Publication year - 1999
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/(sici)1097-0215(19990105)80:1<104::aid-ijc20>3.0.co;2-a
Subject(s) - cytotoxicity , topoisomerase , sn 38 , cell culture , microbiology and biotechnology , hyperthermia , dna , fibrosarcoma , cell , biology , biochemistry , chemistry , in vitro , irinotecan , cancer , genetics , paleontology , colorectal cancer
The effect of different temperatures (37–42.5°C) on SN‐38 (the active metabolite of CPT‐11) cytotoxicity was examined in the human lung carcinoma cell lines H460 and Calu‐6 as well as the murine fibrosarcoma cell line L929. The cytotoxicity of SN‐38, determined by MTT cell survival assay, was significantly increased in each cell line in combination with 41.8°C hyperthermia (×60–120 min); the combination of SN‐38 with 40.5°C and 42.5°C, however, was unchanged compared to 37°C. Determination of topoisomerase (Topo) I DNA cross‐linking in Calu‐6 cells and L929 cells after treatment with SN‐38 showed the same temperature profile as seen in the cell‐survival assays with increased Topo I DNA cross‐linking after treatment with the combination of SN‐38 and 41.8°C hyperthermia and unchanged Topo I DNA cross‐linking at 40.5°C and 42.5°C. To test the hypothesis that increased Topo I DNA cross‐linking and SN‐38 cytotoxicity at 41.8°C is caused by hyperthermia‐modulated changes in Topo I activity, catalytic activity of Topo I extracted from each cell line and of purified human Topo I was determined at 20–42.5°C. Topo I activity was found to be gradually increased with rising temperatures, resulting in significantly higher activity at 41.8°C compared to 37°C; further increase of temperature past 41.8°C decreased Topo I activity back to levels found at 37°C. Our data are used to explain a series of events resulting in hyperthermic enhancement of Topo I DNA cross‐linking and SN‐38 cytotoxicity in combination with 41.8°C hyperthermia via increased Topo I activity. Int. J. Cancer 80:104–109, 1999. © 1999 Wiley‐Liss, Inc.