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Potentiation of the Antitumor Activity of 5-Fluorouracil in Colon Carcinoma Cells by the Combination of Interferon and Deoxyribonucleosides Results from Complementary Effects on Thymidine Phosphorylase¹

Department of Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10467

-Interferon (IFN) potentiates the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy in advanced colorectal cancer. We have reported previously an IFN-mediated elevation in cellular FdUMP levels accompanied by the stimulation of thymidine phosphorylase (TP) activity in extracts from HT-29 human colon carcinoma cells treated with IFN. We have now found that this effect of IFN can be measured in vivo as an increase in thymine incorporation in intact cells. The increase was only 3-fold, however, compared to the 12-fold increase seen in TP activity in cell extracts. This suggested that the cosubstrate for TP, deoxyribose-1-phosphate, was rate limiting in the cells. Since the synthetic pathway of TP can also proceed via a transferase reaction, natural and modified deoxyribonucleosides were tested as deoxyribosyl donors. TP activity was measurable in cell extracts using deoxyinosine as cosubstrate with either thymine or FUra, although activity was only 10% of that measured with deoxyribose-1-phosphate. The pyrimidine analogue 5-propynyloxy-2'-deoxyuridine (PO-dUrd) had 15% of the maximal TP activity in cell extracts and also increased thymine incorporation in intact cells 10-fold. Both 2'-deoxyinosine and PO-dUrd potentiated the cytotoxicity of FUra by 8–11-fold. IFN potentiated the cytotoxicity of FUra by 1.8-fold, and the combination of IFN and PO-dUrd produced a 25-fold increase in the cytotoxicity of FUra. Neither the corresponding analogue riboside, 5-propynyloxyuridine, nor the analogue base, 5-propynyloxyuracil, had any effect on FUra cytotoxicity. There was a significant correlation between the ability of a nucleoside and/or IFN combination to increase thymine incorporation and to reduce the 50% inhibitory concentration for FUra. IFN and PO-dUrd also potentiated the inhibition by FUra of thymidylate synthase activity. These findings suggest that the use of a deoxyribonucleoside to provide the rate limiting cosubstrate would complement the stimulation of TP by IFN, and together they should further enhance the antitumor activity of FUra.

¹ Supported by NIH Grants CA54422 and CA36517, by Cancer Center Support Grant CA13330 from the National Cancer Institute, and by a grant from the Wendy Will Case Cancer Fund.

² To whom requests for reprints should be sent, at Department of Oncology, Albert Einstein Cancer Center, 111 East 210th Street, Bronx, NY 10467.

Received 6/24/93. Accepted 1/17/94.

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