Intracellular pH and the uptake of carcinostatic drugs by selected experimental tumors Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/d791sj627

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  • The relationship of intracellular drug levels and resultant drug activity to intracellular pH (pHi) was studied in the experimental tumors. Glucose (5 g/kg) and/or sodium oxamate (0.1 mmol) were administered to Walker 256 ascites cells and Ehrlich ascites cells, in an attempt to alter pHi as measured by the distribution of the weak electrolyte, 5, 5- dimethyl -2, 4 oxazolidinedione (DMO), between extracellular and intracellular fluids. Drugs employed included 5- fluoroura rd. (FU), cytosine arabinoside (CA), 1- (2 chloroethyl)-3 cyclohexyl-l-nitrosourea (CCNU), and procarbazine (PZ). As measured by DMO distribution, pHi in the Walker 256 ascites cells was significantly increased following prior glucose administration. This increase occurred both with and without concurrent sodium oxamate pretreatment. Intracellular FU concentrations in the Walker 256 ascites cells were increased approximately two-fold when glucose was part of the pretreatment regimen, again either alone or in combination with oxamate. These increases were accompanied by an enhancement of FU activity. The increases in Fu activity observed did not seem to be associated with a corresponding increase in FU toxicity; however, they were observed to be positively related to the dose of glucose employed as adjunct therapy. These results supported the concept that prior exposure of neoplastic tissues to glucose could enhance both the uptake and the resultant activity of FU. In Ehrlich ascites tumor cells, pHi decreased following glucose pretreatment. This decrease was not evident when sodium oxamate was added to the pretreatment regimen. Following a glucose-oxamate pretreatment, the pHi of the Ehrlich cells remained at control levels. The intracellular concentration of FU was always enhanced following the administration of glucose to Ehrlich ascites cells as part of the pretreatment regimen. Since the pHi of the cells was not significantly altered from controls when sodium oxamate was added to the pretreatment regimen along with glucose, the intracellular concentration of FU was more dependent upon the presence of glucose as part of the pretreatment than upon the pHi of the Ehrlich cells. Enhancement of Fu activity in this model was only achieved by the prior administration of both glucose and sodium oxamate. This result indicated that although glucose increased FU levels within neoplastic tissues, the higher intracellular FU concentration might not lead to increased FU activity. Procarbazine (PZ) concentrations within Ehrlich ascites cells were increased only by the prior administration of glucose and sodium oxamate. The fluctuation in pHi due to the prior administration of glucose alone had no effect on intracellular PZ levels. The increased uptake following glucose-oxamate pretreatment was accompanied by an increase in PZ activity upon Ehrlich ascites tumor cells. The intracellular levels and resultant activity of both CCNU and CA remained unchanged following any of the pretreatments despite the changes in pHi. The independence of CCNU uptake from alterations in pHi was probably a reflection of its non-ionized, neutral state within the physiological pH range, while the absence of any change in the intracellular levels of the acidic compound, CA, suggested that factors other than pHi were the major determinants of CA concentration within Ehrlich ascites cells. These results indicated that in evaluating the utility of adjunct glucose and/or sodium oxamate therapy for the enhancement of drug effect, any changes in neoplastic pHi which are caused by the administration of either or both of these agents are neither the only, nor in some cases the main, factor which may influence drug uptake. Moreover, the metabolic effects of either glucose or oxamate might affect the activity of specific drugs upon neoplastic tissues to a greater extent than their influence upon pHi. Thus, adjunct antineoplastic therapy with glucose and/or oxamate should not be considered in terms of general therapeutic application, but rather should be considered for each antineoplastic drug separately.
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