MDR: Misunderstood Drug Resistance?

Since the coining of the phrase "multidrug resistance" in 1985 to describe experimental observation of cross resistance to various structurally-unrelated cytotoxic agents in animal tumor models, the phrase has taken on a second meaning among many scientists, and some clinicians, perhaps better described as "misunderstood drug resistance," said Stanley Kaye, professor of medical oncology at the department of medical oncology, University of Glasgow, UK, at the 19th Congress of the European Society for Medical Oncology in Lisbon, Portugal, last month.

This situation arose, said Prof Kaye, from the clinical observation in cancer patients treated with chemotherapy of resistance to a wide range of cytotoxic drugs (either primary or acquired) which was thought to be due to a common mechanism, namely high levels of P-glycoprotein expression. However, he noted, the weight of evidence from clinical studies, at least in solid tumors, would indicate that this is not the case.

Resistance to cytotoxic agents is attributed to the expression of P-glycoprotein, which is found in many human tumors and normal tissues. The protein is coded by the gene mdr-1. P-glycoprotein acts as an energy-dependent membrane bound efflux pump in resistant tumor cells, which pumps out natural cytotoxic products resulting in the cell being resistant to the effects of these drugs. This mechanism, said Prof Kaye, does not appear to play a role in the resistance of tumor cells to platinum-based cytotoxic compounds and drugs, such as some doxorubicin analoges which do not use P-glycoprotein as a substrate, "contrary to the belief of some clinicians."