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Formation and Repair of Cisplatin-induced Adducts to DNA in Cultured Normal and Repair-deficient Human Fibroblasts¹

Department of Chemistry, Gorlaeus Laboratories, Leiden University, 2300 RA Leiden [F. J. D., J. R.], and TNO Medical Biological Laboratory, 2280 AA Rijswijk [A. M. J. F-S., F. B.], The Netherlands

The formation and repair of cisplatin [cis-PtCl₂(NH₃)₂] adducts in the DNA of cultured normal and repair-deficient human fibroblasts are presented in relation to cell survival after cisplatin treatment. Directly after treatment with cisplatin, in normal (MB), Fanconi's anemia (FA), and xeroderma pigmentosum (XP) fibroblasts four platinated products are found. The major adduct is cisplatin bound to two neighboring guanines, Pt-GG (62–75%). A less abundant product is cisplatin bound to an AG sequence (Pt-AG). Binding to two guanines separated by one or more bases or to two guanines in opposite DNA strands (together measured as G-Pt-G) and cisplatin bound monofunctionally to guanine (Pt-G) are also found in small amounts. The distribution of the four products is similar to that found previously, in in vitro systems as well as in living cells. Directly after cisplatin treatment, the removal of cisplatin-DNA adducts is fast in normal and FA fibroblasts, whereas in XP fibroblasts adduct removal proceeds slowly throughout the repair period studied. Both FA and XP fibroblasts are extremely sensitive to cisplatin with regard to cell killing. For FA fibroblasts this sensitivity may be attributed to the fact that in these cells initially more DNA-adducts are formed than in normal fibroblasts, and/or to their known deficiency in the repair of DNA interstrand cross-links. For XP fibroblasts this sensitivity may be caused by their deficiency in the fast repair process, known as excision repair.

¹ This investigation was supported by The Netherlands Cancer Foundation (Koningin Wilhelmina Fonds), Grant MBL 83-1.

² To whom requests for reprints should be sent, at TNO Medical Biological Laboratory, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.

Received 4/11/88. Revised 7/19/88. Accepted 7/28/88.

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