Purine de novo synthesis as the basis of synergism of methotrexate and 6-mercaptopurine in human malignant lymphoblasts of different lineages

Bökkerink, J.P.M.; Bakker, Marinka A.H.; Hulscher, Tilly W.; Abreu, Ronney A. De; Schretlen, E. D. A. M.

doi:10.1016/0006-2952(88)90358-9

Cited by 41 publications

(21 citation statements)

References 40 publications

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“…The subsequent accumulation of dihydrofolate can inhibit de novo purine synthesis. 15,28 In addition, MTX can inhibit purine de novo synthesis by virtue of the polyglutamate metabolites which directly inhibit aminoimidazole carboxamide ribonucleoside monophosphate. 28 Finally, low-dose MTX as well as HDM can inhibit xanthine oxidase and enhance the bioavailability of 6MP.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 In recent years both in vitro and in vivo studies have supported that the interaction between 6MP and MTX is of clinical significance. 2,15,20,32,33 However, this is the first study which, in detail, explores the influence of 6MP dose and pharmacokinetics on the myelotoxicity of HDM.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] MTX may increase the bioavailability of 6MP, 14 and in addition, through inhibition of de novo purine synthesis, enhance the availability of 6TGN and its incorporation into DNA. 15 We speculated that this drug interaction could in part be responsible for the bone marrow toxicity which follows HDM given during 6MP/MTX maintenance therapy. In the present study, we demonstrate that the dose of concurrently given oral 6MP and the individual variations in 6MP metabolism significantly influence the degree of myelotoxicity following HDM.…”

Section: Introductionmentioning

confidence: 99%

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6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Schmiegelow

Bretton-Meyer

2001

Leukemia

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were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir Ͻ0.5 × 10 9 /l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir Ͻ100 × 10 9 /l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (␤ = −0.017, P = 0.001), the average ANC level during maintenance therapy (␤ = 0.82, P = 0.004), and E-6TGN (␤ = −0.0029, P = 0.02). The best-fit model to predict the thrombocyte nadir following HDM during maintenance therapy included only mPLATE (␤ = 0.0057, P = 0.046). In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of significant myelotoxicity following HDM during maintenance therapy of childhood ALL. Leukemia (2001) 15, 74-79.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Schmiegelow

Bretton-Meyer

2001

Leukemia

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“…3 In addition, several studies of cytotoxicity have indicated that MTX and 6MP act synergistically. [4][5][6][7][8] In hemopoietic cells, 6MP is anabolized to 6-thioguanine nucleotides (6TGNs), which are the most important mediators of the cytotoxic effect of 6MP through incorporation into DNA. 9 Erythrocytic accumulation of 6TGN correlate with the degree of myelotoxicity and remission duration in childhood ALL.…”

Section: Introductionmentioning

confidence: 99%

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Nygaard

Schmiegelow

2003

Leukemia

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High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m 2 /24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m 2 /week) and 6MP (75 mg/m 2 /day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir p60 Â 10 9 /l and/or a neutrophil nadir p0.7 Â 10 9 /l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 Â 10 9 /l (range: 6-214) to 133 Â 10 9 /l (range: 21-305; Po0.001) and the median neutrophil nadir from 0.5 Â 10 9 /l (range: 0.0-1.4) to 0.9 Â 10 9 /l (range: 0.2-3.2; Po0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (Po0.001).The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.

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“…In rat hepatocytes, AICA metabolites directly inhibit glucokinase and block the formation of fructose 2,6-bisphosphate, an important activator of 6-phosphofructo-1-kinase and the net effect is an inhibition of glycolysis (Vincent et al, 1992). The concentrations of AICA compounds used in these experiments ranged between 10 and 100 μM, which can be achieved in lymphoblasts exposed to only 20 nM MTX (Bokkerink et al, 1986;Bokkerink et al, 1988), or in inflammatory cells of animals treated with low-dose MTX (Cronstein et al, 1994;Cronstein et al, 1993;Gadangi et al, 1996). Glycolysis is an important energy-producing pathway for the immune system since leukocytes do not have an active pyruvate dehydrogenase complex; thus, energy derived from the Krebs cycle cannot be obtained using glucose as the metabolic fuel (Biswas et al, 1998;Haji-Michael, et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Methotrexate and erythro-9-(2-hydroxynon-3-yl) adenine therapy for rat adjuvant arthritis and the effect of methotrexate on in vivo purine metabolism

Baggott

Morgan

2007

European Journal of Pharmaceutical Sciences

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The objectives were: 1) to test the association of methotrexate (MTX) efficacy in rat adjuvant arthritis (rat AA) with interference of purine biosynthesis and adenosine metabolism and 2) to test the efficacy of erythro-9-(2-hydroxynon-3-yl) adenine (EHNA), an inhibitor of adenosine deaminase, and the efficacy of aminoimidazolecarboxamide (AICA) riboside plus MTX in rat AA. Radiographic and histologic examinations of the hind limbs were measures of efficacy. Urinary excretions of AICA and adenosine were markers of AICA ribotide transformylase inhibition (ie, blockage of purine biosynthesis) and interference with adenosine metabolism, respectively. AICA and adenosine excretions increased during the day of MTX dosing (treatment day) compared to the previous baseline day in animals responding well to MTX (ie. low radiographic and histologic scores). Based on radiographic and histologic scores, adjuvant injected rats were separated into two disease categories (ie, no/mild and moderate/severe). Only AICA excretion was significantly elevated on the treatment day in rat AA with no/mild disease (ie. those responding well to MTX therapy). AICA (not adenosine) excretion was significantly correlated with the above scores. EHNA was not efficacious, even at toxic levels, while AICA riboside potentiated the efficacy of MTX. The data suggests that efficacious MTX therapy in rat AA 1) blocks purine biosynthesis; 2) increases in in vivo AICA levels. Also adenosine accumulation and blockage of adenosine deaminase (i.e., by EHNA) appear to be less critical to MTX efficacy. Increased levels of AICA metabolites may suppress the immune response in rat AA

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Purine de novo synthesis as the basis of synergism of methotrexate and 6-mercaptopurine in human malignant lymphoblasts of different lineages

Cited by 41 publications

References 40 publications

6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Methotrexate and erythro-9-(2-hydroxynon-3-yl) adenine therapy for rat adjuvant arthritis and the effect of methotrexate on in vivo purine metabolism

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