Muhicellular Resistance: A New Paradigln to Explain Aspects of Acquired Drug Resistance of Solid Tumors

The study of the cellular and molecular basis of acquired drug resistance in cancer has been dominated by a single experimental approach for the past two decades. This approach consists of exposing established tumor cell ines--usually obtained from solid tumors--to increasing concentrations of a single cytotoxic drug. Conventional two-dimensional monolayer cell culture systems, in which the cells are exposed over prolonged periods of time, are generally used so that drug-resis-tant mutant subpopulations expressing very high levels of resistance (e.g., 10- to 1000-fold) in a stable or semi-stable fashion are selected. This invariably leads to the isolation of so-called "unicellular " resistant mutants, that is, tumor cells which express their resistance prop-erties at the single-cell evel, as a result of biochemica