The review is conceptual and includes background information for those who are unfamiliar with the field, as well as an evaluation of the clinical impact of this research area. Ever since we defined and cloned the human MDR1 (P-glycoprotein) gene 20 years ago, and showed that it was an energy-dependent efflux pump for multiple anti-cancer drugs, the relevance of this mechanism of drug resistance to clinical situations has been debated. The review is an up-to-date, critical analysis of the evidence for and against a role of ABC transporters in conferring resistance to cancer cells in patients.

This review describes a family of 48 energy-dependent pumps, known as ABC (ATP-binding cassette) transporters, which are encoded in the human genome. Many of these are involved in important physiological processes, and several appear to confer chemotherapy resistance to cancer cells when tested in the laboratory. Resistance to anti-cancer drugs is based on the ability of these pumps to remove toxic drugs from cancer cells. One important question has been whether expression of these pumps is responsible for failure of chemotherapy in some cancers in patients and whether inhibition of these pumps leads to a

better response to chemotherapy. Most of the trials conducted so far to answer these questions have been flawed in various ways, but the preponderance of evidence suggests that some of these pumps, in some cancers, do confer multidrug resistance and that inhibition of these pumps may improve the response to chemotherapy.

When chemotherapy was first used clinically, it became obvious not only that it could cure some cancers which had spread widely in the body, but that others were either intrinsically resistant to most chemotherapy, or responded to chemotherapy and then developed multidrug resistance. We set out to study this problem by developing human cancer cell lines in tissue culture which displayed this phenotype of multidrug resistance. In a 1985 collaboration with Igor Roninson (University of Illinois College of Medicine at Chicago) and Ira Pastan (NCI), we used a novel technique to clone amplified genes in the multidrug-resistant cell lines, and were able to demonstrate that the gene we had cloned (MDR1) was able to confer multidrug resistance on cultured cells. MDR1 belonged to a family of energy-dependent protein pumps called ABC transporters, which had first been described as nutrient uptake transporters in bacteria. Subsequently, many other laboratories have shown that MDR1, although still a dominant cause of multidrug resistance, is only one of 48 ABC transporters encoded in the human genome.