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Effects of 1-ß-D-Arabinofuranosylcytosine Incorporation on Elongation of Specific DNA Sequences by DNA Polymerase ß¹

Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [Y. O., D. S., T. O., D. K.]; and Laboratory of Cell Biology, Aichi Cancer Center Research Institute, Nagoya, Japan [A. M.]

1-ß-D-Arabinofuranosylcytosine (ara-C) is an effective antileukemic agent which acts as an inhibitor of DNA synthesis. The precise mechanism responsible for this inhibitory effect, however, remains unclear. The present work has examined the effects of the triphosphate derivative, ara-CTP, on purified DNA polymerase ß. These studies were performed on M13 phage DNA templates of defined sequence. The results demonstrate that ara-C is incorporated into DNA by DNA polymerase ß. The results also demonstrate that the incorporated ara-C residue acts as a relative chain terminator. Moreover, the relative chain terminating effects of ara-C are sequence specific. In this regard, DNA strand elongation was progressively slowed at sequences of two, three, and four contiguous sites for cytosine incorporation. We also demonstrate that the inhibitory effects of ara-C are reversed by competition with deoxycytidine-triphosphate for incorporation into the DNA strand. Taken together, these findings are consistent with structural differences of the incorporated arabinosyl moiety which alter reactivity of the 3'-terminus and thereby inhibit chain elongation. These findings also provide new insights regarding the inhibitory effects of ara-C on elongation of specific DNA sequences.

¹ This investigation was supported by United States Public Health Services Grants CA29431 and KO8-CA0994 (D. S.) awarded by the National Cancer Institute, Department of Health and Human Services, and by a Burroughs-Wellcome Scholar Award in Clinical Pharmacology (D. K.).

² To whom requests for reprints should be addressed, at the Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115.

Received 9/ 2/87. Revised 12/ 4/87. Accepted 12/14/87.

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