Pleiotropic drug resistance (PDR), the development of resistance to one agent which confers a cross-resistance to several other structurally dissimilar agents, has been hypothesized as a cause of treatment failure in a number of tumor types. Experimental tumor models using various animal cell lines have indicated that PDR may occur via the amplification of certain genes, which results in the overproduction of specific cell membrane proteins, resulting in altered drug transport. Whether this same phenomenon occurs in human tumors or is clinically relevant remains to be determined. Recent preliminary evidence has shown that multiple drug resistance does develop in multiple myeloma, a tumor with a high initial chemotherapeutic response rate but virtually no cures. We propose to investigate the development and mechanisms of drug resistance in multiple myeloma using clinically derived human tumor cell populations and well established human myeloma cell lines. Specifically, the mechanism of resistance to doxorubicin and its possible cross resistance with melphalan will be analyzed. Select patients with multiple myeloma will be followed from presentation and initial chemotherapeutic responsiveness to relapse and development of drug resistance. Serial tumor specimens will be obtained via bone marrow aspirations and analyzed for specific plasma cell membrane glycoproteins as well as the ability to accumulate doxorubicin or melphalan. In addition, human myeloma cell lines will be made individually resistant to doxorubicin and melphalan to determine if these variant cell lines are in fact cross-resistant and if there is an associated change in cell membrane glycoproteins as well as drug uptake. Collaborative studies have also been designed to study the acquisition of multi-drug resistance at the chromosomal and DNA level. We believe that the understanding of multi-drug resistance in human multiple myeloma may provide possible avenues to circumvent this unfortunate occurrence.
