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Antagonistic Effect of Polyinosinic-Polycytidylic Acid on the Cell Lethality Produced by 5-Fluorouracil in Human Colon Carcinoma Cells in Vitro

Applied Pharmacology Section, Laboratory of Medicinal Chemistry and Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

The effect of polyinosinic·polycytidylic acid [poly(I)·poly(C)] on the cell lethality produced by 5-fluorouracil [FUra] and 5-fluo-rouridine [FUrd] was examined in human colon carcinoma cell line HT-29. Pretreatment of cells with poly(I)·poly(C) as well as during exposure to FUra or FUrd resulted in antagonism of the cell lethality generated by the fluoropyrimidines. Antagonism of FUra cytotoxicity was also produced by the 2'-O-methylated analogue, polyinosinic·poly-2'-O-methylcytidylic acid, but not by the individual single-stranded polynucleotides or by the component mononucleotides, cytidine 5'-phosphate and inosine 5'-phosphate. In contrast, cytidine 5'-phosphate blocked the toxicity of FUrd. The antagonism by poly(I)·poly(C) of FUra and FUrd cytotoxicity was related to the inhibition of their metabolism to fluorouridine triphosphate and their incorporation into RNA and not to inhibition of the synthesis of RNA. Antibodies to leukocyte and fibroblast interferons did not reverse the antagonistic activity of poly(I)·poly(C). These results indicate that poly(I)·poly(C) may be interfering with the transport and/or initial metabolism of FUra and FUrd to fluorouridine monophosphate which is independent of the ability of the double-stranded RNA to induce interferon.

¹ Present address: National Cancer Center Research Institute, Pharmacology Division, Tokyo, Japan.

² To whom requests for reprints should be addressed, at National Cancer Institute, Building 37, Room 6028, Bethesda, MD 20205.

Received 9/28/84. Revised 1/18/85. Accepted 1/25/85.