Synthesis of Methotrexate Polyglutamates by Bone Marrow Cells
from Patients with Leukemia and Lymphoma

Witte, Axel; Whitehead, V. Michael; Rosenblatt, David S.; Vuchich, M J

doi:10.1159/000455520

Cited by 37 publications

(5 citation statements)

References 4 publications

(7 reference statements)

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“…

Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. It has been shown that MTX is metabolized to polyglutamyl derivatives (Baugh et al, 1973; Whitehead et al, 1975;Whitehead, 1977;Witte et al, 1980). Certain tissues can convert methotrexate to polyglutamates.

…”

mentioning

confidence: 99%

“…It has been shown that MTX is metabolized to polyglutamyl derivatives (Baugh et al, 1973; Whitehead et al, 1975;Whitehead, 1977;Witte et al, 1980). It has been shown that MTX is metabolized to polyglutamyl derivatives (Baugh et al, 1973; Whitehead et al, 1975;Whitehead, 1977;Witte et al, 1980).…”

mentioning

confidence: 99%

“…Other less frequent toxic effects of methotrexate include bone pain, osteoporosis and pulmonary fibrosis.The pathogenesis of chronic MTX toxicity is not fully understood. It has been shown that MTX is metabolized to polyglutamyl derivatives (Baugh et al, 1973; Whitehead et al, 1975;Whitehead, 1977;Witte et al, 1980). These conjugates may persist in the cells and lead to…”

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confidence: 99%

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Methotrexate Accumulation and Folate Depletion in Cells as a Possible Mechanism of Chronic Toxicity to the Drug

et al. 1981

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Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. In this study the intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in nine of 12 red cell and three of five liver samples. It is proposed that persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.

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“…

Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. It has been shown that MTX is metabolized to polyglutamyl derivatives (Baugh et al, 1973; Whitehead et al, 1975;Whitehead, 1977;Witte et al, 1980). Certain tissues can convert methotrexate to polyglutamates.

…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Methotrexate Accumulation and Folate Depletion in Cells as a Possible Mechanism of Chronic Toxicity to the Drug

et al. 1981

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Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. In this study the intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in nine of 12 red cell and three of five liver samples. It is proposed that persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.

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“…The mechanism of MTX hepatotoxicity is not fully understood. It has been shown that MTX is metabolized to polyglutamyl derivatives (Whitehead et al 1975;Hendel 1978;Witte et al 1980) and stored as such in both liver cells and erythrocytes, eventually decreasing the cellular folate stores (Kamen et al 1981).…”

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confidence: 99%

Changes in Liver Histology during Methotrexate Therapy of Psoriasis Correlated to the Concentration of Methotrexate and Folate in Erythrocytes

Hendel¹,

Poulsen

Nyfors

et al. 1985

Acta Pharmacologica et Toxicologica

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To investigate, whether an assessment of the folate and methotrexate concentrations in erythrocytes could be used to indicate incipient histological liver changes, these 2 parameters were related to liver histology in series of liver biopsies (means 4.3 biopsies) from 31 long‐term methotrexate‐treated psoriasis patients. Logistic regression analysis showed that the probability of changes in liver histology during methotrexate therapy increased significantly with increasing erythrocyte methotrexate concentrations and with decreasing erythrocyte folate concentration. The application of these variables as a decisive criterion when to institute liver biopsy surveillance needs further studies, but can probably help reduce the number of liver biopsies to be taken during long‐term methotrexate therapy considerably.

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“…Each of the peptide-forming coupling steps shown in Scheme I was done with diphenylphosphoryl azide in lV,)V-dimethylformamide containing triethylamine according to the procedure of Yamada and co-workers.16 L-Glutamic acid dibenzyl ester p-toluenesulfonate was coupled with [ (terf-butyloxy) carbonyl] -L-glutamic acid -benzyl ester (7) to give 8. The protective Boc group of 8 was removed by treatment with dry HC1 in dioxane solution.14 Following removal of the dioxane, the residual 9-HC1, a syrup that resisted crystallization, was converted to the crystalline p-toluenesulfonate.…”

mentioning

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A synthetic approach to poly(.gamma.-glutamyl) conjugates of methotrexate

Piper¹,

McCaleb²,

Montgomery³

1983

J. Med. Chem.

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Methotrexate poly(gamma-L-glutamate)s bearing two and three glutamate units above that present in methotrexate have been synthesized by extension of a previously described route used to synthesize the lower conjugate bearing one added glutamate unit. Key steps in the sequence are the peptide coupling of N-[4-[[(benzyloxy)carbonyl]-methylamino]benzoyl]-L-glutamic acid alpha-benzyl ester (5) with oligo(gamma-L-glutamate) benzyl esters, removal of blocking groups by catalytic hydrogenolysis, and introduction of the (2,4-diamino-6-pteridinyl)methyl grouping by alkylation with 6-(bromomethyl)-2,4-pteridinediamine hydrobromide. Elaboration of the required oligo(gamma-L-glutamate) chain was achieved one unit at a time, beginning with the coupling of L-glutamic acid dibenzyl ester with [(tert-butyloxy)carbonyl]-L-glutamic acid alpha-benzyl ester (7), followed by selective removal of the tert-butyloxycarbonyl grouping and another coupling step with 5 or 7 as required. Diphenylphosphoryl azide was used as the coupling reagent in each conversion producing a peptide linkage.

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Synthesis of Methotrexate Polyglutamates by Bone Marrow Cells from Patients with Leukemia and Lymphoma

Cited by 37 publications

References 4 publications

Methotrexate Accumulation and Folate Depletion in Cells as a Possible Mechanism of Chronic Toxicity to the Drug

Methotrexate Accumulation and Folate Depletion in Cells as a Possible Mechanism of Chronic Toxicity to the Drug

Changes in Liver Histology during Methotrexate Therapy of Psoriasis Correlated to the Concentration of Methotrexate and Folate in Erythrocytes

A synthetic approach to poly(.gamma.-glutamyl) conjugates of methotrexate

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