Phenotypic Expression of Drug Resistance in Cell Cultures2

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Abstract
Clonal lines of pig kidney cells were used to analyze factors affecting the expression of puromycin resistance at the population level. Nominal mutation rates for the transition from sensitivity to resistance were estimated by two modifications of the Luria-Delbrück fluctuation test. Discrepancies in these data suggest that the incidence of spontaneous variation was obscured by nongenetic resistance which increased in proportion to population density. Large colonies or aggregates of sensitive cells grew progressively in puromycin at concentrations which destroyed the same populations completely when present in dispersed form. These findings indicate that response to puromycin is conditioned by cellular interactions as well as by genetic susceptibility. Under such conditions, the incidence of mutant cells cannot be determined by one-step selection with inhibitor media, as assumed by previous investigators. It follows that estimates of mutation rates based on drug resistance in somatic cells are of questionable validity, unless a clear distinction can be drawn between heritable alterations in resistance and refractory responses by sensitive cells in the system used.

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