Commentary: Metabolic Impediments to the use of Nucleotide Derivatives to Circumvent Resistance to Purine and Pyrimidine Analogs

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Abstract
Many attempts have been made to design derivatives of analog nucleotides that might circumvent resistance due to deficiency of enzymes that convert analogs of purines, pyrimidines and nucleosides to nucleotides. None of these prodrugs that have been evaluated has been active against resistant tumor cells in vivo. The probable reason for this failure is that host cells, but not the resistant cells, have the capacity to form toxic nucleotides from bases or nucleosides resulting from degradation of the prodrugs. These considerations indicate that this strategy for circumvention of resistance will be successful only if the prodrug has some property, other than ability to enter the cell and be converted to toxic nucleotide, that will result in selective toxicity to resistant cells.