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Incorporation of 1-ß-D-Arabinofuranosylcytosine into DNA from Herpes Simplex Virus Resistant to 9-ß-D-Arabinofuranosyladenine¹

Divisions of Medicine, Sidney Farber Cancer Institute [D. K., D. H.], of Infectious Diseases, Department of Medicine, Beth Israel Hospital [C. C.], and of Oncology, Department of Medicine, Beth Israel Hospital [L. S.], Harvard Medical School, Boston, Massachusetts 02115

We have demonstrated previously that 1-ß-D-arabinofuranosylcytosine (ara-C) incorporates specifically in cellular DNA and that the formation of (ara-C)DNA correlates significantly with inhibition of DNA synthesis and loss of clonogenic survival. Similar results have been obtained with 9-ß-D-arabinofuranosyladenine (ara-A). These findings have been extended by studying the incorporation of ara-C in DNA of a wild-type herpes simplex virus (HSV) and a mutant virus resistant to ara-C and ara-A. The results demonstrate that HSV resistance to ara-A is associated with formation of less (ara-C)DNA and less inhibition of DNA synthesis when compared to wild-type virus. This effect on formation of (ara-C)DNA is reversed upon exposure to higher (>10^-6 M) ara-C concentrations, and this pattern of resistance corresponds to drug effect on virus plaque formation. The results also demonstrate a highly significant relationship between incorporation of ara-C in HSV DNA and inhibition of DNA synthesis for both viruses. Further, higher concentrations of ara-C that result in greater inhibition of DNA synthesis are associated with an increasing number of ara-C residues at the 3'-terminus of the DNA strand, thus suggesting that ara-C functions as a poor primer terminus for viral chain elongation. These results also suggest that HSV cross-resistance to ara-A and ara-C may be related to an altered viral DNA polymerase and that incorporation of ara-C in HSV DNA is at least one mechanism responsible for slowing viral synthesis and inducing lethal events.

¹ This work was supported by Grant CH-199 from the American Cancer Society, Contract AI-52530 from the National Institute of Allergy and Infectious Diseases, and USPHS Grant PO1-AG0059.

² Recipient of an American Cancer Society faculty research award. To whom requests for reprints should be addressed.

Received 4/ 4/83. Accepted 9/27/83.

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