Graduate Thesis Or Dissertation

A comparison of the effect of pH change upon the uptake of 5-fluorouracil into rat liver and Walker 256 carcinosarcoma slices

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  • An enhancement of the therapeutic effect and/or a reduction in the toxicity have been shown by a variety of antineoplastic compounds when glucose is added to the treatment schedule. A possible explanation for this involves a selective change in intracellular pH of the tumor tissue initiating a greater uptake of the antineoplastic agent. The present study was carried out to show the effect of alterations in intracellular pH upon the uptake of one of the compounds studied above, 5-Fluorouracil (5-FU), into both Walker 256 carcinosarcoma and normal liver slices. Two methods, the addition of glucose and the addition of glucose plus sodium oxamate to the incubation medium, were utilized in an attempt to lower intracellular pH selectively in the tumor slices. Intracellular pH was determined by the distribution of ¹⁴C- labeled 5, 5-dimethyl-2, 4-oxazolidinedione between extracellular and intracellular fluid, and uptake of 5-FU was determined by using ¹⁴C- labeled 5-FU. In the absence of glucose in the incubation medium the intracellular pH of both the liver and tumor slices was measured with good precision and agreed with values reported in the literature. The addition of 5mM glucose resulted in a decrease of intracellular pH within the liver slices, but a significant increase in pH of the tumor slices. Twenty minute preincubation of the slices with 40mM sodium oxamate before glucose addition further lowered the pH of the liver slices, but maintained intracellular pH of the Walker 256 slices at control levels. Studies of the uptake of 5- FU suggested that it partitions into normal liver slices as a weak acid. The 5-FU uptake into Walker 256 tumor slices was significantly increased by the addition of 5mM glucose and this increase persisted upon the addition of 40mM oxamate. This indicates that 5-Fluorouracil uptake into Walker 256 carcinosarcoma slices was more dependent upon the presence of glucose than alterations in intracellular pH.
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