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PubMed2004

A comparison of red blood cell thiopurine metabolites in children with acute lymphoblastic leukemia who received oral mercaptopurine twice daily or once daily: a Pediatric Oncology Group study (now The Children's Oncology Group).

INTRODUCTION: Mercaptopurine is an important antimetabolite for treatment of childhood acute lymphoblastic leukemia (ALL). It has been prescribed to be given daily without therapeutic monitoring of drug levels. After first-pass metabolism by hepatic xanthine oxidase (XO), mercaptopurine is converted into two major intracellular metabolites, thioguanine nucleotide (TGN) and methylated mercaptopurine metabolites (including methylated thioinosine nucleotides), which are cytotoxic in vitro. Its short plasma half-life and S-phase-dependent pharmacokinetics suggest that biologically active concentration and exposure duration may be critical to cell kill. METHODS: Pediatric Oncology Group (POG) 9605, a randomized, open label phase III study of standard-risk ALL, was designed to compare daily with twice-daily mercaptopurine during continuation therapy. Red blood cell (RBC) TGN and methylated mercaptopurine metabolite levels were measured as surrogates of leukemic cell levels in a randomly selected subset of patients. TGN and methylated mercaptopurine metabolites were analyzed quantitatively by high-performance liquid chromatography (HPLC) and reported in ng/8 x 10.8 RBC. Statistical inferences utilized multiple linear regression. RESULTS: One hundred eighteen patients received mercaptopurine 75 mg/m(2) daily and 108 received 37.5 mg/m(2)/dose twice daily. Descriptive statistics for the daily group showed the median TGN was 42 ng (mean and standard deviation [SD] = 48 +/- 35, quartiles 29-64). For the twice daily group, it was 40 ng (mean and SD = 40 +/- 27, quartiles 26-53). For methylated mercaptopurine metabolites, the daily group median was 2,020 ng (mean and SD = 2,278 +/- 1,559, quartiles 1,247-3,162); the twice daily group median was 1,275 ng (mean and SD = 1,580 +/- 1,240, quartiles 599-2,369). When adjusted for the covariables: actual dosage, days on study, age at diagnosis, white blood cell count, gender, Black race compared with not, and Hispanic compared with not, daily dosing resulted in significantly higher average methylated mercaptopurine metabolites by 668 (standard error [SE] = 179, P = 0.001) and a trend toward higher average TGNs by 6.2 (SE = 4.2, P = 0.14). CONCLUSIONS: Daily dosing of mercaptopurine resulted in higher mean red cell methylated mercaptopurine metabolites when compared to split (twice a day dosing). The data were inconclusive with respect to TGNs. The relationships of methylated mercaptopurine metabolites and TGNs to clinical outcomes will be elucidated as part of the maturing 9605 data.

Administration, Oral↗
PubMed1990

Long-term 6-mercaptopurine treatment in adolescents with Crohn's disease.

Although 6-mercaptopurine is often used to treat adolescents with intractable Crohn's disease, its long-term efficacy has not yet been studied in this population. This study shows data derived from 36 adolescents (mean age +/- SD, 16.5 +/- 3.3 years; 27 males, 9 females) treated at least 6 months with 6-mercaptopurine (1.5 mg.kg-1.day-1, maximum of 75 mg/day). Sites of Crohn's disease at the start of 6-mercaptopurine therapy included 17 ileocolic, 9 pancolic, 7 small bowel, and 3 partial colon. All had received corticosteroids, sulfasalazine, antibiotics, and nutritional support for 5.0 +/- 3.0 years before administering 6-mercaptopurine, but intractable symptoms persisted. Disease activity lessened during the first year of 6-mercaptopurine, reflected by a higher Lloyd-Still disease activity score (pre, 64 +/- 9 vs. 6-mercaptopurine, 72 +/- 11; P less than 0.0001). General activity, physical examination, nutrition, and laboratory subscores all improved (P less than 0.004). Lessened disease activity occurred despite concomitant decrease in duration of prednisone use (pre, 9.5 +/- 4.2 vs. 6-mercaptopurine, 6.6 +/- 4.9 months/year; P less than 0.001) and cumulative annual prednisone exposure (pre, 3672 +/- 2106 vs. 6-mercaptopurine, 1964 +/- 1460 mg; P less than 0.0007). The frequency of perianal fistulae and abscesses also decreased (P less than 0.01) during treatment. Annual rates of hospitalization decreased in 44% of subjects during 6-mercaptopurine treatment, while increasing in only 22%. Follow-up beyond 1 year of 6-mercaptopurine treatment showed continued remission in 23 of 30 subjects. No serious complications were seen. 6-mercaptopurine is an effective long-term therapy for adolescents with intractable Crohn's disease. While inducing remission, it also has a significant steroid-sparing effect which may be of particular benefit to this population.

Abscess↗
PubMed2003

Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia.

BACKGROUND: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. METHODS: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m(2) over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m(2), or high dose, 1 g/m(2) intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. RESULTS: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 +/- 14.7 micromol/L versus 23.5 +/- 18.0 micromol/L, P <.001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 +/- 0.66 pmol/5 x 10(6) cells versus 7.4 +/- 15.2 pmol/5 x 10(6) cells, P <.001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 +/- 13.5 micromol/L versus 3.8 +/- 2.5 micromol/L, P =.029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% +/- 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% +/- 35%) compared with those in patients receiving mercaptopurine alone (P <.0001). CONCLUSION: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine.

Antimetabolites, Antineoplastic↗
PubMed1990

Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.

BACKGROUND: Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS: To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS: There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS: Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Experiences with 6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis.

BACKGROUND: The effectiveness of 6-mercaptopurine combined with azathioprine in treating severe ulcerative colitis has been shown in several adult studies. Reported pediatric experiences are rare. The purpose of this study was to investigate the safety and the potential efficacy of 6-mercaptopurine and azathioprine in the treatment of active ulcerative colitis in a pediatric population. METHODS: The medical records of patients with active ulcerative colitis who were under observation at The Children's Hospital of Philadelphia and its satellite clinics from January 1984 through December 1997 were retrospectively reviewed. Patients were included who had received a diagnosis of ulcerative colitis, who met no criteria for Crohn's colitis, and who had received treatment with 6-mercaptopurine and azathioprine. They were then analyzed for the development of side effects, the indication to use 6-mercaptopurine and azathioprine, and the ability to discontinue corticosteroid use in those patients taking 5-acetylsalicylic acid products who were corticosteroid-dependent or whose disease was refractory to treatment. Excluded from the corticosteroid analyses were patients who underwent surgery for their disease and patients treated with 5-acetylsalicylic acid only. Statistical analysis was performed by the Kaplan-Meier survival curve and paired Student's t-test. RESULTS: In a review of 200 medical records of patients with active ulcerative colitis, 20 patients met the criteria. The patients' average age at the initiation of treatment with 6-mercaptopurine and azathioprine was 13.8 years. Sixteen patients (80%) were corticosteroid dependent and 3 (15%) had ulcerative colitis refractory to corticosteroid treatment. One patient had severe colitis treated with 5-acetylsalicylic acid only. Discontinuation of corticosteroid was accomplished in 12 (75%) of 16 patients. The median time to discontinuation of corticosteroid after initiation of 6-mercaptopurine and azathioprine therapy was 8.4 months. Eight patients (67%), observed from 3 months to 65 months, have continued without corticosteroid therapy. Side effects included pancreatitis and shingles that resulted in discontinuation of 5-acetylsalicylic acid, leukopenia corrected by withholding 6-mercaptopurine, and self-resolved hepatitis. CONCLUSIONS: The data support the safety of 6-mercaptopurine and azathioprine use in the treatment of pediatric patients with ulcerative colitis; side effects were minimal and reversible. Eighteen (90%) of 20 patients tolerated the therapy well. The results also show that 12 (75%) of 16 pediatric patients with ulcerative colitis will benefit from the use of 6-mercaptopurine and azathioprine after initial discontinuation of corticosteroid therapy. Although 6-mercaptopurine and azathioprine may not prevent further relapses, medical management of these flares may be less intense and may not require long-term corticosteroid use. Prospective clinical trials in pediatric patients are necessary to delineate further the role of 6-mercaptopurine and azathioprine in pediatric ulcerative colitis.

Adolescent↗
PubMed2004

Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity.

BACKGROUND: Hepatotoxicity with elevation of aminotransferase levels is common during combined methotrexate and thiopurine therapy. However, the mechanism of hepatotoxicity induced by these drugs remains obscure. We have investigated the relationship of a rise in aminotransferase levels to erythrocyte levels of methotrexate and its polyglutamates, 6-thioguanine nucleotides, the major cytotoxic metabolites of 6-mercaptopurine, and methylated metabolites of 6-mercaptopurine generated by thiopurine methyltransferase in competition with the formation of 6-thioguanine nucleotides. METHOD: Weighted means of alanine aminotransferase levels and metabolites of methotrexate and 6-mercaptopurine were calculated from a total of 929 blood samples from 43 patients with acute lymphoblastic leukemia during maintenance therapy with methotrexate and 6-mercaptopurine. RESULTS: Weighted means of aminotransferase levels were significantly related to the average doses of 6-mercaptopurine (r(s) = 0.60, P <.001), erythrocyte levels of methylated metabolites of 6-mercaptopurine (r(s) = 0.63, P <.001), and thiopurine methyltransferase activity (r(s) = 0.32, P =.03). Weighted means of aminotransferase levels were negatively correlated with erythrocyte levels of 6-thioguanine nucleotides and were not related to the average doses of methotrexate or erythrocyte levels of methotrexate and its polyglutamates. CONCLUSION: It was found that 6-mercaptopurine and its methylated metabolites are correlated with the degree of hepatotoxicity during methotrexate and 6-mercaptopurine maintenance therapy. Further studies are needed to explore whether aminotransferase levels could be used as a surrogate marker for methylated metabolites of 6-mercaptopurine and thus to evaluate 6-mercaptopurine treatment compliance.

Alanine Transaminase↗
PubMed1992

Inhibition of 6-phosphofructo-2-kinase activity by mercaptopurines.

The activity of 6-phosphofructo-2-kinase (PFK-2), the enzyme that catalyses the synthesis of fructose 2,6-bisphosphate (Fru-2,6-P2), was inhibited by mercaptopurines in vitro. Inhibition was observed with the purified enzyme from rat liver and bovine heart, and in extracts from rat lymphocytes and hepatoma cells, chick embryo fibroblasts, and human HeLa and lymphoblastoid cells. Half-maximal effect was obtained with 0.1-0.2 mM mercaptopurine and maximal inhibition ranged between 50 and 90% depending on the enzyme preparation. The inhibition resulted from a decrease in Vmax with no change in Km for ATP. The inhibition was relieved by treatment of the enzyme with thiol reducing agents, suggesting that it involves the formation of a mixed disulfide between mercaptopurine and thiol group(s) essential for enzyme activity. Incubation of intact lymphocytes or lymphoblastoid cells with 2- or 6-mercaptopurine resulted in a decrease in Fru-2,6-P2 content and lactate release. A decrease in Fru-2,6-P2 content but no change in lactate release was observed in HeLa cells and fibroblasts treated with 6-mercaptopurine but not with 2-mercaptopurine. Treatment of HeLa cells with 6-mercaptopurine resulted in a decreased PFK-2 activity which could be restored by treatment of the cell extract with dithiothreitol. In isolated rat hepatocytes and perfused rat hearts mercaptopurines had little or no effect on the Fru-2,6-P2 content and lactate release. These results suggest that the effect of 6-mercaptopurine of arresting growth in lymphoid cells might involve the inhibition of glycolysis in addition to the known inhibition of de novo purine nucleotide synthesis.

Animals↗
PubMed1999

Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus.

BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.

Antimetabolites, Antineoplastic↗
PubMed2005

Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia.

CONTEXT: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity. OBJECTIVE: To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. DESIGN, SETTING, AND PATIENTS: TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Münster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses. MAIN OUTCOME MEASURES: Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10(-4) were defined as negative. RESULTS: Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86). CONCLUSIONS: TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.

Adolescent↗