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Sydney 2005:
The Influence of the Tumour Microenvironment on Drug Response & Drug Resistence
By Melissa Alsina , MD
04.12.05
Dr. Alsina opened Plenary Session 6 with a discussion about the influence of the tumor microenvironment on drug response and drug resistance in multiple myeloma. She identified that drug resistance, both de novo and acquired, limits the success of MM therapies. Drug resistance is accommodated by multiple mechanisms, including increases in DNA repair, altered drug targets, decreased drug accumulation, decreased drug uptake, metabolic changes in cells, and increased efflux of drugs from cells. The microenvironment of tumors, including the bone marrow (BM) and cell adhesion molecules (CAM) likely influence drug interactions with cells and confer drug resistance (cell adhesion mediated drug resistance, CAM-DR). Dr. Alsina and associates, as well as other investigators, use in vitro cell models of drug resistance to determine the causes of drug resistance and to develop therapies or strategies to avoid drug resistance. These models demonstrate that the interaction of myeloma cells with BM or certain molecules (fibronectin, FN) leads to resistance to drugs. When cells from MM patients were tested in these models and exposed to melphalan, the cells were protected from the effects of melphalan. Researchers are investigating whether interaction between myeloma cells and FN may alter the expression of genes that may in turn influence cell survival or de novo drug resistance. Another area of research focuses on comparing de novo and acquired drug resistance. Data suggests that de novo and acquired drug resistance operate by different mechanisms and by expression of different genes and that acquired drug resistance is a more complex process. The clinical relevance of these findings is that the microenvironment of the tumor may influence its ability to survive. Inhibiting interactions between the microenvironment and tumor cells may enhance therapeutic effect of drugs. Dr. Alsina closed by suggesting that tumor microenvironment and drug resistance mechanisms should be explored when developing new drugs.


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