Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and inhibits cisplatin-DNA cross-link repair

LY Yang, L Li, MJ Keating and W Plunkett

Division of Laboratory Medicine, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Cytotoxicity was increased significantly when arabinosyl-2- fluoroadenine (F-ara-A) was administered in simultaneous combination with cisplatin (CDDP) to human colon tumor cell lines relatively sensitive (LoVo) or resistant (CP2.0) to CDDP. Because the mechanism of action of F-ara-A indicates that it may be an effective inhibitor of DNA repair, we hypothesized that F-ara-A induces cytotoxic augmentation by suppressing cellular repair in CDDP-damaged DNA lesions. To test this, we compared the repair of CDDP-induced DNA interstrand cross- links in the total genome and in ERCC1 gene-specific sequences of LoVo and CP2.0 cells for treatments with CDDP and CDDP plus F-ara-A. We determined the DNA repair by measuring the rate of removal of the cross- links, using two methods, i.e., an ethidium bromide fluorescence binding assay, which detects the DNA lesion in the total genome, and a method combining denaturation/renaturation neutral agarose gel electrophoresis and Southern hybridization to detect gene-specific lesions. When F-ara-A (15 microM) was coadministered with CDDP (15 micrograms/ml for LoVo cells and 30 micrograms/ml for CP2.0 cells) for 4 hr, the initial cross-link index for the total genome was increased 67% (4.5 versus 2.7 with CDDP alone) in LoVo cells and 93% (2.9 versus 1.5 with CDDP alone) in resistant CP2.0 cells. At 10 hr after the treatment, only 5% of the cross-links had been removed in combination- treated LoVo cells, compared with 40% in CDDP-treated LoVo cells; in CP2.0 cells, F-ara-A inhibited the removal of cross-links from 95% to 45%. Similar results were obtained for ERCC1 gene-specific DNA sequences. These data suggest that F-ara-A enhances the accumulation of CDDP-induced cross-links in LoVo and CP2.0 cells by suppressing the repair of such lesions, thereby enhancing the cytotoxicity of CDDP in combination treatment.

Volume 47, Issue 5, pp. 1072-1079, 05/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

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