Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution

Shea N Gardner

doi:10.1080/10273660008833047

Abstract

Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application that balances this tradeoff.The models predict that a CS drug may be applied most effectively by splitting the cumulative dose into many (>40) fractions applied by long-term chemotherapy, while CNS drugs may be better applied in fewer than 10 fractions applied over a shorter term. The model suggests that administering each fraction by continuous infusion may be more effective than giving the drug as a bolus, whether the drug is CS or CNS. In addition, tumors with a low growth fraction or slow rate of cell division are predicted to be controlled more easily with CNS drugs, while those with a high proliferative fraction or fast cell division rate may respond better to CS drugs.

Highlights

For the majority of cancer chemotherapeutics, the optimal schedule of administration has not been established (Donehower 1990)
When CS drug delivery is too fast (Figure 3A), not all the cells divide during the period of infusion, and come cells escape drug exposure and survive despite that they are genetically susceptible to the drug (Figure 3B)
The same cumulative amount of a CS drug as used in Figure 3B may be applied at too slow a rate if continuous infusion (CI) is too prolonged (Figure 3C)

Summary

Introduction

For the majority of cancer chemotherapeutics, the optimal schedule of administration has not been established (Donehower 1990). Skipper et al (1967, 1979) and Bruce et al (1966) showed that the chemotherapy dose response curve resulting from a single dose (applied as a spike) of cell cycle specific drugs (CS drugs) levels off with increasing doses (reviewed in vanputten 1974, Steel 1977). This tapering dose response curve contrasts with the log linear increase in cell kill with increasing dose for cycle non-specific drugs (CNS drugs).

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Conclusion