Multiple Drug Resistance

Dominic Fan, Ph.D.

Professor of Cancer Biology

One of the major concerns in cancer therapeutics is the development of a multidrug resistance (MDR) phenotype in metastatic diseases. Although MDR is associated with multiple mechanisms -- such as overexpression of a 22-kDa calcium-binding cytoplasmic protein, an increase in glutathione transferase levels, altered cellular calcium and calmodulin levels, formation of double-minute chromosomes, lack of drug interference with topoisomerase activities and elevated levels of protein kinase C (PKC) activities -- MDR is more commonly associated with an amplification of the mdr-1 gene and overexpression of its product, a 170- to 180-kDa plasma membrane P-glycoprotein (P-gp). P-gp functions as an efflux pump for various compounds and prevents intracellular accumulation of certain anticancer drugs.

P-gp and mdr-1 are regulated differentially in sparse and confluent cultures of many tumor cell lines. The expression level of mdr-1 mRNA transcript (by northern blot and in situ hybridization) and P-gp (by fluorescence-activated cell sorting, immunohistochemistry and western blot analysis) inversely correlated with cell density. The modulation of mdr-1 expression in sparse and confluent cells was not related to cell division, nutrient depletion, protein synthesis, gap junction status, extracellular ATP or the presence of various extracellular matrixes, but it may be related to cell-cell contact-mediated changes in phosphatase activity. The confluence-mediated downmodulation of mdr-1 increased the chemosensitivity of the cells to several anticancer drugs commonly associated with an in vitro MDR phenotype by increasing the intracellular accumulation of the drugs. Previous studies in this group suggested that MDR may be influenced by the microenvironment and/or factors of specific host organs. In many cases, P-gp expression may be regulated by cytokines, such as TGF-alpha, TGF-beta and IFN-gamma.

My current research includes reversing cancer resistance to anticancer drugs by means of pharmacologic modifiers and studying the effects of the microenvironment, cytokines and growth factors on MDR and tumor angiogenesis.