Pharmacokinetic/cytokinetic principles in the chemotherapy of solid tumours.
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 to correspondingly lower drug concentrations for a longer time (with the same concentration x time of exposure). We also show that the drug DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) developed in this laboratory and currently undergoing clinical trial, achieves the same result through the principle of self-inhibition of cytotoxicity. 5. Matching of the cytokinetic or self-inhibitory profile of a drugs' action with the pharmacokinetics of drug in tumours may provide new drugs with increased anti-tumour effects.
Baguley
B C
BC
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Finlay
G J
GJ
D000166:Acridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000166:Acridines; D000970:Antineoplastic Agents; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D017239:Paclitaxel; D002166:Camptothecin