Chronic deprivation of glucose or oxygen induces a stress protein system previously referred to as the glucose-regulated proteins (grps). Subsequent addition of glucose or oxygen (i.e., releasing the cell from the deprived state) induces the heat shock protein system. The abundance of these proteins may be valuable in assessing the physiologic state of a tissue with respect to oxygen or glucose levels. We have shown previously that the expression of the heat shock proteins are associated with the phenomenon of thermotolerance. In this proposal we present data which show that the glucose-regulated protein-induced state confers a tolerance to the drug adriamycin. In this proposal we will: (1) more rigorously describe the degree of adriamycin resistance induced by glucose deprivation and grp induction and examine other methods of inducing the grps to determine if the association with adriamycin resistance follows; (2) investigate the possibility that the grp-induced state is related to the phenomenon of """"""""multi-drug resistance"""""""" (of which the appearance of the P-glycoprotein is one property). We will see if grp induction results in resistance to other compounds including vinblastine, actinomycin D, and colchicine and if the P-glycoprotein is a grp (i.e., identical to the major grp of the same molecular weight); and (3) examine the induction of the glucose-regulated and heat shock proteins in tumors in situ. Since grps are induced by anoxia and glucose deprivation, are they induced in tumors where a restricted blood flow can lead to an analogous environment? We will examine this question using EMT6 and RIF tumor systems. Lastly, does reoxygeneration in situ induce the heat shock proteins? We will utilize antibodies against these proteins to study the microanatomy of oxygen or glucose deprivation. Since oxygen and/or nutrient deprivation can occur during tumor development this proposal has important implications in tumor biology wherein a potentially restricted nutrient/oxygen supply and increased glucose usage by cancer cells could result in the differential induction of the glucose-regulated proteins between normal and tumor tissue. (W)
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