Pharmacokinetic/cytokinetic principles in the chemotherapy of solid tumours

Clinical and Experimental Pharmacology & Physiology
B C Baguley, G J Finlay

Abstract

1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti-tumour drugs. 2. This applies particularly to two general classes of anti-cancer drugs which already play an important role in chemotherapy: mitotic poisons and topoisomerase poisons. Such compounds bind strongly to proteins and/or DNA, and their diffusion from the bloodstream into solid tumours is slow, as is their clearance from tumour tissue. 3. The specific questions posed here is whether anti-cancer compounds of these types are more cytotoxic when administered at a low concentration for a long time (mimicking conditions in solid tumours) than at a correspondingly high concentration for a short time (mimicking conditions in host tissue). Two possible principles may be involved, the first based on cytokinetic considerations and then second on self-inhibition of drug cytotoxicity. 4. Using cultured human cancer cells we have shown that taxol, which acts on mitotic cells and camptothecin, which acts on S-phase cells, are examples of the first principle. Exposures to high drug concentrations for short times are much less cytotoxic than exposure ...Continue Reading

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Citations

Apr 27, 2013·Pharmaceutical Development and Technology·Sarah E LeeRobert M Hoffman

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