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Synergistic Antitumor Effect of Fluoropyrimidines and Polyinosinic-Polycytidylic Acid against L1210 Leukemia

Laboratory of Biological Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

The effect of polyriboinosinic·polyribocytidylic acid [poly(I)·poly(C)] on the antitumor activity of 5-fluorouracil (FUra) and 5-fluorouridine (FUrd) was evaluated in mice bearing L1210 leukemia. Coadministration intravenously of poly(l)·poly(C) and either FUra or FUrd on days 1, 5, and 9 to mice bearing L1210 leukemia implanted subcutaneously resulted in a 40% greater increase in life span at the optimal antitumor dose versus FUra and FUrd alone. This effect appeared to result from greater host tolerance of a dose of FUra or FUrd which would otherwise be cytotoxic. The protective effect of poly(I)·poly(C) was also evident in nontumor-bearing mice, as well as following administration of drug intraperitoneally to mice bearing the tumor implanted intraperitoneally. FUrd incorporation into RNA in the spleen, bone marrow, and small intestine revealed little or no changes after coadministration of poly(I)·poly(C). (2',5')Oligo(A) synthetase activity, an indication of interferon activity, was markedly depressed in the spleen and bone marrow following treatment with FUrd; however, poly(I)·poly(C) administered together with FUrd returned (2',5')oligo(A) synthetase activity to normal levels. These data indicate that poly(I)·poly(C) ameliorates the host toxicity of fluoropyrimidines, possibly via an interferon-mediated effect, and thereby results in enhanced therapeutic efficacy of the antimetabolite as an antitumor agent.

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, NIH, Building 37, Room 5D-02, Bethesda, MD 20205.

Received 12/21/84. Revised 4/16/85. Accepted 5/31/85.