MMPR in combination with 6-mercaptopurine is effective in inducing remission in adults with acute myelogenous leukemia

MMPR2 is an adenosine analog with substantial antitumor activity in experimental systems (1 , 12). It is not cross resistant with 6-mercaptopurine; Le., it maintains its activity in Ll210 mouse leukemia and human cancer cells in culture, which are resistant to 6-mercaptopurine (2, 4). The biochem ical basis for this lack of cross-resistance has been established (1, 4, 14). Resistance to the thiopurines often results from deletion of the enzyme hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8), which is essential for the conversion of the base to the active intermeatate, the ribonucleotide. However, the phosphorylation of MMPR, an adenosine analog, is mediated through adenosine kinase (EC 2.7.1 .10) (2, 5), which persists in cell lines resistant to 6-mercaptopurine. In addition, MMPR in combination with 6-mercaptopurine is synergistic both in the Ehrlich ascites carcinoma (18) and in the Ll2 10 mouse leukemia (17). These important experi mental observations have been extended to the clinic. It has been found that MMPR is not effective in treatment of acute leukemia refractory to 6-mercaptopurine (1 1). However, MMPR in combination with 6-mercaptopurine is effective in inducing remission in adults with acute myelogenous leukemia (3). Because of the above biological and biochemical observations in experimental systems, pharmacological studies of MMPR in the mouse have been undertaken. In an earlier study in man, the major urinary metabolite excreted was reported to be MMPR-P (9). The excretion and metabolism of MMPR has been further studied in man, and the current report is con cerned with the comparative biochemical pharmacology of MMPR in the mouse and in man.