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Effect of Tetrahydrouridine on the Action of 1-ß-D-Arabinofuranosylcytosine in Synchronized Cultures of Normal Rat Kidney Cells¹

Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M4X 1K9

Tetrahydrouridine (THU) is a reduced pyrimidine nucleoside and has been found to be a potent cytidine deaminase inhibitor. We have examined the effect of THU on the action of 1-ß-D-arabinofuranosylcytosine (ara-C) on DNA synthesis and its cytotoxic effect on normal rat kidney (NRK) cells. The results indicated that THU, when present alone, has no effect on the DNA synthesis or viability of the NRK cells. The addition of THU can, however, further increase the cytotoxic effect of sublethal doses of ara-C and can enhance its ability to inhibit DNA synthesis. Studies on the duration of exposure of the NRK cells to ara-C and on the effect of ara-C on synchronized cultures of NRK cells also support the earlier reports that ara-C, through its active compound 1-ß-D-arabinofuranosylcytosine 5'-triphosphate, is capable of blocking cells from progression from G₁ into S phase of the cell cycle. Furthermore, we have shown that this inhibition is reversible after the drug has been removed. The addition of THU in the presence of noninhibiting levels of ara-C can also result in the blocking of cells from progression into S phase of the cell cycle. Similar to the effect of ara-C, this inhibition is also reversible. These studies suggest that the addition of THU enhances the cytotoxicity of sublethal doses of ara-C and its ability to inhibit DNA synthesis.

¹ This work was supported by a grant from the Medical Research Council of Canada.

² Recipient of a studentship from the National Research Council of Canada.

³ To whom requests for reprints should be addressed.

Received 12/29/78. Accepted 7/17/79.