Clinicians have long observed that treatment with one anticancer drug can confer resistance to that drug and to other anticancer drugs with different chemical structures and mechanisms of action. This is the multidrug resistance (MDR) phenomenon, which frequently occurs in the absence of previous chemotherapy in primary cancer of the liver, colon, kidney and other organs and after chemotherapy in virtually any malignancy. Study of the MDR phenomenon has revealed important information regarding molecular and cellular mechanisms of membrane transport, drug resistance and chemotherapy. Interest in the structure and function of this system was further stimulated by its discovery in normal liver and other tissues.
In the early 1970s three groups of investigators described the MDR phenomenon in cultured cells (1-3). As with many advances in medicine, discovery of its mechanism was serendipitous. Ling and Thompson ( 1) developed colchicine-resistant Chinese hamster ovary (CHO) cells to determine whether resistance was caused by altered binding of colchicine to microtubules. Contrary to their initial hypothesis, resistant CHO cells accumulated less colchicine in their cytoplasms than did normal cells. At the same time, Reihm and Beidler (2) reported that hamster cells made resistant to actinomycin D showed cross-resistance to structurally unrelated drugs and Dan0 (3) described cross-resistance between Vinca alkaloids and anthracyclines in Ehrlich ascites tumor cells. Using these findings, Ling and Thompson ( 1) observed that colchicine-resistant CHO cells, which can be maintained in drug-free medium, had acquired resistance to other cytotoxic agents such as actinomycin D and vinblastine.
They presciently wrote: "Permeability changes of a stable, heritable nature appear to be relatively common alterations in cultured cells. . . cross resistance to dissimilar agents provides a strong operational indication of altered permeability as the basis of the resistance" (1).
Juliano and Ling (4) performed gel electrophoresis of Research in the author's laboratory was supported by grants from the National Institutes of Health (DK 35652 and P30DK34928-06) and a Fogarty Scholarship.