title: Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites.
abstract: In order to gain insight into the mechanisms 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 greater than RNA greater than 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 adenocarcinoma 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- much greater than alpha/beta-interferon and with 5-fluorodeoxyuridine greater than 5-fluorouracil much greater than 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-fluorouracil or 5-fluorodeoxyuridine 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-fluorouracil. Analysis of this interaction by [3H]thymidine incorporation, which can reflect thymidylate synthase inhibition, revealed exaggerated responses of interferon-treated cells to either 5-fluorouracil or 5-fluorodeoxyuridine. 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.
authors: Department of Medicine, University of New Mexico School of Medicine, Albuquerque 87131.
authors: L
authors: L
authors: Elias
authors: H A
authors: HA
authors: Crissman
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D005467:Floxuridine / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D005467:Floxuridine; D007372:Interferons; D005472:Fluorouracil