Emergence of the drug-resistant phenotype in tumor subpopulations: a hybrid model.
A mathematical model is proposed that describes the emergence of drug resistance in a tumor cell population. The model is termed a hybrid in the sense that the population-wide dynamics are described by a stochastic birth-death-migration model with transition probabilities dependent on the deterministic distribution of drug within the average cell. In the model, the probability that a cell dies is proportional to the concentration of drug within the target site in the cell. The micropharmacology describing the distribution of drug within the average cell is described by a standard well-mixed compartment model. Possible mechanisms that can confer drug resistance on a cell are described: decreased drug uptake, increased drug efflux, intracellular metabolism or inactivation, or both, of a drug, and a change in the level or sensitivity of a target. The biologic mechanisms underlying resistance and potential strategies for overcoming it are discussed within the context of our model. Results from a numerical simulation are presented as verification of the initial theory.
Michelson
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Institute for Research Data Management, Syntex Corporation, Palo Alto, CA 94303.
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D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D004351:Drug Resistance; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects; D008954:Models, Biological; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D010641:Phenotype; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents