How does the method of drug application and pharmacokinetics affect cell kill and resistance evolution in tumors?

Shea Gardner

First, a model was developed to investigate how drug kinetics and the schedule of drug application affects the cell kill that can be achieved with a given drug dose and level of toxicity. Model predictions suggest that prolonging the duration of drug infusion and increasing the number of fractions into which the total dose is divided, but holding the total dose constant, may increase cell kill without elevating various measures of toxicity. Prolonging infusion and dividing the dose into fractions are well known methods of improving the cell kill that can be achieved by a cell cycle phase specific drug, but the model predicts the surprising result that these methods may be even more effective in elevating cell kill by a phase nonspecific drug.

Second, this model was extended to include tumor cell population dynamics and resistance evolution. Applying drugs at low concentrations for prolonged periods may allow cells with partial resistance to low doses to evolve resistance to higher doses through stepwise processes requiring multiple mutations. The second model of tumor cell population dynamics and evolution focuses on the trade-off between prolonged infusions to increase cell kill and short, high-concentration exposures to delay the evolution of resistance.

The model predicts the schedule of chemotherapy to result in the smallest tumors, and how this schedule depends on factors such as the fraction of cells in S phase, the cell division and apoptotic rates, and the drug half life.

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