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- W2007726988 abstract "1. The measurement of the net rate of influx of amethopterin was based on the rate of formation of the intracellular folic acid reductase-amethopterin complex. This rate was found to be identical for the sensitive and resistant sublines of Sarcoma-180 cells cultured in vitro. It was slow (4.6·10−8 cm/sec at 36°) and proportional to the concentration of amethopterin over a 1000-fold range. The net rates of influx of amethopterin and aminopterin were the same. 2. It was mathematically proven that the degree of resistance to amethopterin would be directly proportional to the content of folic acid reductase in these cells if amethopterin were irreversibly bound by the enzyme. The lack of direct proportionality is caused by the intracellular dissociation of the enzyme-amethopterin complex. The final degree of resistance to amethopterin is determined by (a) the cellular folic acid reductase (EC 1.5.1.3) content, (b) the rate of growth, which determines the rate of synthesis of new enzyme, (c) the slow influx of amethopterin and its great affinity to folic acid reductase. These cause the concentration of the intracellular free amethopterin to be only a fraction of the extracellular amethopterin. Consequently, even a small degree of dissociation of the enzyme-amethopterin complex contributes to the degree of resistance to amethopterin. This dissociation becomes especially significant in the 3000-fold resistant subline in which folic acid reductase constitutes about 4% of the total cellular protein. In this subline less than 1% of the total enzyme needs to be functional for normal growth." @default.
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- W2007726988 date "1965-05-01" @default.
- W2007726988 modified "2023-09-28" @default.
- W2007726988 title "On the role of drug penetration in amethopterin resistance of Sarcoma-180 cells in vitro" @default.
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- W2007726988 doi "https://doi.org/10.1016/0926-6585(65)90213-x" @default.
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