Enzymatic Cleavage of Methotrexate provides a Method for Prevention of Drug Toxicity

Chabner, Bruce A.; Johns, D. G.; Bertino, Joseph R.

doi:10.1038/239395b0

Cited by 63 publications

(21 citation statements)

References 6 publications

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“…In 1967, a bacterial enzyme that cleaves glutamate from folates was identified and named carboxypeptidase G [9,10]. Carboxypeptidase G1, isolated from Pseudomonas stutzeri, was successfully used to lower MTX blood levels in animal models and man, but its bacterial source was lost [11,12]. In 1983, the gene for carboxypeptidase G2 (now termed glucarpidase), derived from Pseudomonas sp.…”

Section: Introductionmentioning

confidence: 99%

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

et al. 2007

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After completing this course, the reader will be able to:1. Identify risk factors for kidney failure associated with high-dose MTX therapy.2. Discuss the therapeutic options in patients with delayed MTX elimination.3. Discuss the potential risks and benefits of glucarpidase intervention.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME Conclusions. Glucarpidase is well tolerated and produces a rapid inactivation of substantial amounts of MTX. However, overall results are still unsatisfactory in adult and elderly patients, suggesting that earlier recognition of delayed MTX elimination and more rapid intervention are needed. The Oncologist ABSTRACT

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Section: Introductionmentioning

confidence: 99%

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

et al. 2007

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“…It has been proposed that intestinal toxicity to methotrexate results from a prolonged third phase. 17 The potential effects of altering drug pharmacoki- In this study, the animals were not malnourished. The qualitative alteration of dietary intake by administration of an elemental diet resulted in enhanced gastrointestinal toxicity and delayed clearance of methotrexate from both serum and tissues.…”

Section: Discussionmentioning

confidence: 99%

Reversibility of Elemental Liquid Diet-Enhanced Methotrexate Toxicity by Refeeding with Chow

Harvey

McAnena

Mehta

et al. 1987

Journal of Parenteral and Enteral Nutrition

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The toxic effects of methotrexate administration [20 mg/kg, bolus intraperitoneally (ip)] to rats fed a regular chow diet (n = 10) was compared with results in animals fed an elemental, chemically defined, liquid diet (n = 10) for 7 days. All animals receiving an elemental diet became anorectic and lethargic within 60 hr of methotrexate injection. All animals in this group subsequently developed enteritis and died within 150 hr. There was no clinical evidence of enteritis in rats fed a regular chow diet and mortality as zero in this group (p < 0.001). In a second study one group of rats (n = 9) was fed a regular chow diet for 7 days; four groups were fed an elemental, chemically defined, liquid diet (n = 9 per group) for 7 days. At 24 hr and 8 hr prior to, or 24 hr after methotrexate administration, one group was refed a regular chow diet; the fourth group was maintained on an elemental liquid diet throughout the study period. All rats fed a regular chow diet survived following methotrexate injection (20 mg/kg, ip). All rats fed an elemental diet throughout the study period died. Those rats refed a regular diet 24 or 8 hr prior to methotrexate injection demonstrated a significant improvement in survival (100% in the 24-hr group, 55% in the 8-hr group). However, those animals refed a regular diet 24 hr after methotrexate injection demonstrated a 100% mortality.

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“…Bone marrow, duodenal mucosa, and ascitic cells from the three animals in each group were pooled for determination of [ Other experimental evidence supports the concept that the persistence of low levels of methotrexate is responsible for host toxicity. Previous work from this laboratory has shown that the toxicity of otherwise lethal doses of methotrexate may be prevent by administration of a methotrexate-metabolizing enzyme, carboxypeptidase G1, 24 h after the antifolate (11). In this instance, rescue from methotrexate toxicity was associated with eliminating low levels of residual methotrexate, less than 10-' M, from extracellular fluid without affecting the established intracellular blockade of dihydrofolate reductase.…”

Section: Preliminary Studies Of ['H]udr Incorporation Into Dnamentioning

confidence: 98%

Threshold Methotrexate Concentration for In Vivo Inhibition of DNA Synthesis in Normal and Tumorous Target Tissues

Chabner¹,

Young²

1973

J. Clin. Invest.

213

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Enzymatic Cleavage of Methotrexate provides a Method for Prevention of Drug Toxicity

Cited by 63 publications

References 6 publications

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

Reversibility of Elemental Liquid Diet-Enhanced Methotrexate Toxicity by Refeeding with Chow

Threshold Methotrexate Concentration for In Vivo Inhibition of DNA Synthesis in Normal and Tumorous Target Tissues

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