Cellular effects of combined adriamycin and x-irradiation in human tumor cells

The effects on cell survival in tissue culture of Adriamycin, of various Adriamycin derivatives and of the parent compound, daunomycin, have been studied. Adriamycin and three of its C-14 derivatives show similar toxicities towards cells chronically exposed in culture. Acute (30 min) exposures are significantly less toxic than exposures to the drug throughout the period of colony formation. Daunomycin, the parent compound, is significantly more toxic than any Adriamycin compound. Both high-dose, pulsed exposures and low-dose, chronic exposures result in shoulders on the cell survival curves. Split-dose experiments show little evidence for a significant acute repair of Ad damage. Ad toxicity is additive to X-rays at high levels of cell survival and synergistic at low levels of cell survival. Both excision repair-competent and excision-deficient cells show sensitization to X-irradiation when significantly cytotoxic levels of Ad are used. No evidence for an induction of Ad resistance by previous irradiation was found. Ad does not appear to inhibit the repair of sub-lethal X-ray damage. Since Ad produces molecular lesions similar to those induced by X-rays it is hypothesized that both radiation "enhancement" and the recall of latent X-ray injuries result from the induction of Ad of DNA damage similar to that occurring following X-ray exposure. The implications of these findings with respect to clinical drug and X-ray scheduling is discussed.