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Interactions of cis-Diamminedichloroplatinum(II) with 1-ß-D-Arabinofuranosylcytosine in LoVo Colon Carcinoma Cells¹

Departments of Medicine [R.J.F., N.R.], Pharmacology [R.J.F., J.M.W.], and Pharmacy [J.M.W.], University of Massachusetts Medical School, Worcester, Massachusetts 01655

Prior reports demonstrated more than additive cytotoxic effects of cis-diamminedichloroplatimum(II) (CDDP) and 1-ß-D-arabinofuranosylcytosime (ara-C) in LoVo colon carcinoma cells. We have extended these findings by analyzing mechanisms that may underlie the effect of ara-C on CDDP-induced cytotoxicity. In contrast to a previous study, ara-C neither enhances DNA interstrand cross-link formation by CDDP nor affects the excision of platinum from DNA. Features peculiar to ara-C, such as its misincorporation into DNA, probably contribute since more than additive cytotoxic effects do not occur by combinations of CDDP with inhibitors of DNA synthesis that are not incorporated into DNA. Also, while ara-C does not significantly enhance the degree of inhibition of DNA synthesis caused by CDDP, the recovery of DNA synthesis after drug removal is significantly slowed when cells are exposed to both drugs. These findings contrast with those obtained with CDDP and aphidicolin (the latter agent resembles ara-C in competing with dCTP for binding to DNA polymerase but, unlike ara-C, is not incorporated into DNA). Lastly, ara-C is incorporated into LoVo cell DNA undergoing replicative synthesis as well as into DNA undergoing repair synthesis after CDDP-induced DNA damage.

¹ This work was supported by USPHS Grant R32 CA 38613-02 awarded by the National Cancer Institute, Department of Health and Human Services (R. J. F.).

² To whom requests for reprints should be addressed.

Received 7/14/86. Revised 1/20/87. Accepted 4/ 6/87.

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