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Dominic Fan, PhD

Research Summary (up to 350 words): Help

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--an 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 activities--it is more commonly associated with an amplification of the multiple drug resistance-1 (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 down-modulation 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 my group suggested that MDR is influenced by the microenvironment or factors of specific host organs or both. In many cases, P-gp expression may be regulated by cytokines, such as transforming growth factor-alpha, transforming growth factor-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.