Effects of adriamycin and etoposide on the replication of adenovirus 5 in sensitive and resistant human tumour cells

Adenovirus is a potential probe for identifying and understanding drug sensitivity in primary, nonproliferating cultures of human normal and tumour cells but the scope and limitations of such an approach first need to be evaluated in established cell lines. For this purpose we have identified an ovarian tumour cell line (CI-80-13S) with natural resistance to adriamycin, etoposide and crosslinking agents compared with other human tumour lines. Resistance to adriamycin correlated poorly with resistance to etoposide in these cell lines (r = 0.05). Adenovirus replication in drug-treated cells (viral capacity) was found to be differentially inhibited in sensitive cells when the drug was administered to cells simultaneously with infection (adriamycin) or 20 hr after infection (etoposide). Viral capacity could not be inhibited by more than 90% in sensitive cells. In contrast, no such plateau was exhibited in the dose-responses of cell survival or inhibition of cellular DNA synthesis, both of which distinguished sensitive from resistant cells. Adenovirus was not inactivated by preincubation with high doses of adriamycin or etoposide, thus confirming that no functionally-relevant damage is directly induced by these agents in DNA. Uptake of adriamycin and etoposide was similar in sensitive and resistant cells and both agents blocked cells in the G2 phase of the cell cycle. Protein-linked DNA was induced in sensitive cells. The results indicate that (a) these drugs have two dose-dependent effects in cells, one of which does not inhibit replication of adenovirus; and (b) inhibition of adenovirus replication could in principle be used to predict sensitivity to adriamycin and etoposide.