INTERFERON EFFECTS UPON THE ADENOCARCINOMA-38 AND HL-60 CELL-LINES - ANTIPROLIFERATIVE RESPONSES AND SYNERGISTIC INTERACTIONS WITH HALOGENATED PYRIMIDINE ANTIMETABOLITES

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  • 1 September 1988
    • journal article
    • research article
    • Vol. 48  (17) , 4868-4873
Abstract
In order to gain insight into the mechanism affecting combination treatment of tumor cells with interferon and halogenated pyrimidine antimetabolites, in vitro studies of murine colon adenocarcinoma 38 and HL-60 cell lines were undertaken. Interferons exhibited modest antiproliferative effects against these lines with DNA synthesis inhibited > RNA > protein synthesis, as studied by 3H-precursor incorporation. The adenocarcinoma cell line was considerably more sensitive to recombinant .gamma.- than to purified .alpha./.beta.-interferon, while HL-60 was slightly more sensitive, in short term studies, to antiproliferative effects of recombinant .alpha.- than to .gamma.-interferon. Interferon treatment was further associated with suppression of a hyperdiploid component of the adenocarcionoma cell line, as detected by flow cytometry. Combination treatment of the adenocarcinoma cell line with interferon and halogenated pyrimidines, under 4-day continuous exposure conditions, revealed significant synergy for growth inhibition with .gamma.- .mchgt. .alpha./.beta.-interferon and with 5-fluorodeoxyuridine > 5-fluorouracil .mchgt. 5-fluorouridine. Thus, synergy was much greater with the more antiproliferative interferon and with the antimetabolite derivative most likely to lead to thymidylate synthetase inhibition rather than RNA incorporation. Sequential 2-day + 2-day treatment revealed greater synergy when interferon preceded 5-flourouracil or 5-fluorodeoyuridine rather than the reverse protocol. The synergy of .gamma.-interferon and 5-fluorodeoxyuridine could be blocked by thymidine, which bypasses inhibition of thymidylate synthetase. HL-60 also exhibited thymidine antagonized synergistic growth-inhibitory effects of interferon and 5-flourouracil. Analysis of this interaction by [3H]thymidine incorporation, which can reflect thymidylate synthase inhibition, revealed exaggerated responses of interferon-treated cells to either 5-flourouracil or 5-flourodeoxyuridine. These results indicate that interferon-halogenated pyrimidine antimetabolite synergistic interactions may be common to several cell types. Evidence is further presented for a mechanism of synergy entailing enhanced thymidylate synthetase inhibition by the antimetabolite of interferon-treated cells.

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