Biochemical parameters of mercaptopurine activity in patients with acute lymphoblastic leukemia.
Mercaptopurine (MP) is a purine antimetabolite widely used for remission maintenance in the therapy of acute lymphoblastic leukemia. In order to study the biochemical parameters affecting MP activity, leukemic cells were obtained from ten patients with acute lymphoblastic leukemia at the time of diagnosis and from the same patients at the time of their initial marrow relapse. Hypoxanthine phosphoribosyltransferase (HPRT), the enzyme that converts MP to its active, nucleotide metabolite, thioinosine monophosphate; alkaline phosphatase, the primary catabolic enzyme of thioinosine monophosphate; and 5-phosphoribosyl-1-pyrophosphate (PRPP), the cellular ribose-phosphate donor essential for MP activation, were all measured within the patients' leukemic cells. There was marked interpatient variability in the three biochemical parameters studied with a greater than 10-fold range in alkaline phosphatase activity and an approximately 100-fold range in HPRT activity and PRPP levels. Four patients developed changes in biochemical parameters that influence MP activity at the time of relapse. In three of the four patients, alterations in more than one of these three biochemical parameters were noted. Three of four patients had a greater than 50% decrease in intracellular HPRT activity, four of four had a greater than 50% decrease in intracellular PRPP, and two of four had a greater than 9-fold increase in intracellular alkaline phosphatase activity at relapse. Two of four patients demonstrated changes in all three parameters at relapse in the directions that could have resulted in decreased MP sensitivity (i.e., decreased HPRT, decreased PRPP, and increased alkaline phosphatase). There was no correlation between pretreatment values of HPRT, PRPP, and alkaline phosphatase and remission duration. These results indicate that: (a) there is marked variation in HPRT, PRPP, and alkaline phosphatase in patients with acute lymphoblastic leukemia and b) following MP-containing maintenance chemotherapy, some patients develop biochemical changes that may result in decreased sensitivity to MP.
S
S
Zimm
G
G
Reaman
R F
RF
Murphy
D G
DG
Poplack
D000469:Alkaline Phosphatase / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism*; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D015122:Mercaptopurine / Q000494:pharmacology / Q000627:therapeutic use*; D010428:Pentosephosphates / Q000378:metabolism*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism*
D010428:Pentosephosphates; D010754:Phosphoribosyl Pyrophosphate; D015122:Mercaptopurine; D007041:Hypoxanthine Phosphoribosyltransferase; D000469:Alkaline Phosphatase