Part VI. Mechanisms of resistance to metabolite analogues with anticancer activity

Nonclassical Antimetabolites XIII

“…Groups on a reversible inhibitor that can bridge to and specifically bind other enzymic functional groups would be of use in both chemotherapy and protein structure because of the mutational loss of the inosinic pyrophosphorylase that converts I and hypoxanthine to their ribonucleotides, I1 and IV (5,8). Although 6-mercaptopurine ribotide (11) is still effective as an inhibitor of the enzymes utilizing inosinic acid (IV) in a cell-free extract of resistant cell lines ( i ) , I1 has little effect on the intact resistant cells (T, 9,10). This lack of activity probably is because 6-mercaptopurine ribonucleotide (11), like natural nucleotides (1 l ) , suffers enzymic cleavage back to the corresponding base (I) during entrance into the cell by active transport.…”