Conclusions

Abstract

Some general rules appear to apply to multidrug resistance; some of these only confirm that very much is left to be explained and done. So far, no single parameter accounts totally for the spectrum of MDR. The mechanisms involved are, at least in part, elements of a global, nonspecific protection system which ensures survival. Undesirable compounds (which encompass antineoplastic agents, unfortunately) are transported by a variety of mechanisms, some of which are switched on or amplified by the agents themselves. Even profound understanding of such mechanisms is not offering perfect solutions: individual patients show very different patterns of MDR, with none, few or several resistance mechanisms active at any one time. There is continuous adaptation to timing, dosage and targets of drug administered, both within the tumor and in secondary growth. Metastases of solid tumors are notoriously difficult to erradicate by chemotherapy. It is to be expected that the number of cell generations reached by a metastatic growth to be clinically detectable exceeds 100, which allows for a large number of mutations. Adaptation, in response to injury from chemotherapy, leads to a predominantly MDR cell population, which requires radical new approached in treatment. So far, all new modalities do not achieve even the modest goal of longer growth suppression without toxicity (Israel, 1990).