Synergistic killing of virus-transformed human cells with interferon and N-methyl-N'-nitro-N-nitrosoguanidine

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Abstract
Interferons potentiate the cytotoxic effects of certain anti-neoplastic drugs on human tumor cells both in vitroand in vivo, although the mechanism of interferon's synergistic action is unknown. Interferon may act by modulating the expression of DNA repair activity in cells. To test this hypothesis, we maintained parallel cultures of normal O6-methylguanine repair-proficient human fibroblasts and tumor cells, or RSV-and SV40-transformed repair-deficient Mer− human fibroblasts in medium containing 0, 100, 500 or 680 U/ml human interferon α or β; after 1–10 weeks, cultures were challenged with N-methyl-N-nitro-N-nitrosoguanidine (MNNG, CAS: 70–25–7) and assayed for colony-forming ability. Based on the dose at 99% lethality, MNNG cytotoxicity was potentiated from 1.3- to 9-fold in interferon-treated cultures, compared with control cultures (no interferon). A significant potentiation was observed both with Mer+normal fibroblasts (KD strain) and tumor cells (HOS) and with Mer− SV40-transformed fibroblasts (IMR90–830 and GM638) as well as with RSV-transformed cells (RHOS). However, the degree of potentiation was greater in Mer− virus-transformed cells than in Mer+ cells. The greatest effects were observed with Mer− IMR90–830 cells (5- to 9-fold reduction of dose at 99% lethality). Therefore, because the Mer+ phenotype is not required in order for HuIFNs to sensitize cells to killing by MNNG, interferon does not act by modulating O6-methylguanine repair. However, the effect of interferon on O6-methylguanine-DNA methyltransferase levels and on DNA excision repair should be examined in future experiments.