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• W2083201501 abstract "Abstract Current information about dihydrofolate reductase provides one of the most detailed models of a drug receptor yet available. The affinity of amethopterin for the substrate site of this enzyme is greater than in the case of most drug-receptor interactions. This property accounts for the retention of amethopterin for prolonged periods in the tissues of treated animals. The general properties of dihydrofolate reductase in mammalian tissues are quite similar with regard to molecular weight, cofactor requirement, substrate specificity and inhibition by 4-aminofolate antagonists. Among microorganisms, however, marked differences in the properties of this enzyme seem to reflect differences in its fine structure. Several lines of evidence indicate that there are differences in the properties of dihydrofolate reductase in different mammalian tissues which remain to be explored in relation to chemotherapy. Dihydrofolate reductase is being studied not only as a model drug receptor but also to elucidate the various factors which contribute to the selectivity for certain neoplasms of drugs known to inhibit this enzyme. In some cells capable of growing in the presence of high concentrations of amethopterin, the slow rate of drug entry, the rate of cell division and the high rate of formation of this enzyme allow sufficient dihydrofolate reductase to remain drug-free to maintain normal metabolism. The intracellular enzyme level may be regulated to some extent by the availability of substrates or cofactor since these, as well as the presence of inhibitors, confer remarkable stabilization against proteolytic digestion. Drug sensitivity is related to capacity for cellular uptake of amethopterin in both microbial and tumor systems in which factors influencing the susceptibility to inhibition of growth have been studied. A structural basis for cross sensitivity has been defined in microbial cell lines selected for increased sensitivity to amethopterin. Several diaminopyrimidines effectively inhibited an amethopterin refractory solid tumor. Marked differences in the content and distribution pattern of tetrahydrofolate cofactors in two solid tumors which differ in their response to amethopterin suggest that tissues vary with respect to the tetrahydrofolate requiring pathways most vital to their growth. The basis for the selective action of cytotoxic drugs may be elucidated by consideration of factors such as those found to be important in the selective inhibition of growth by drugs capable of inhibiting dihydrofolate reductase." @default.
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• W2083201501 date "1968-01-01" @default.
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• W2083201501 title "Studies on dihydrofolate reductase related to the drug sensitivity of microbial and neoplastic cells" @default.
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• W2083201501 doi "https://doi.org/10.1016/0065-2571(68)90019-8" @default.
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