Cancer cells elude chemotherapy because of intrinsic or acquired changes in expression of specific proteins. We have studied resistance to natural product chemotherapeutic agents such as doxorubicin, Vinca alkaloids, and taxol, and to the synthetic drug cisplatin. In both cases, cells become simultaneously resistant to multiple drugs because of reductions in intracellular drug concentrations. For the natural product drugs this cross-resistance is due to expression of an energy-dependent drug efflux system known as P-glycoprotein (P-gp), the product of the MDR1 gene. To further understand the function of P-gP, we are preparing new antibodies that react with various portions of the protein. Initially mice were immunized with DNA encoding P-gP and an antibody phage cDNA library prepared from the spleen. This library is being used to screen for Fvs specifically reacting with various portions of P-gP.
