Antineoplastic activity of lipid-soluble dialkyl esters of methotrexate

Johns, D. G.; Farquhar, David; Ba, Chabner; Wolpert, M. K.; Adamson, Richard H.

doi:10.1007/bf01946745

Cited by 20 publications

(15 citation statements)

References 3 publications

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“…The majority of these studies have been concerned with the pteridine moiety of the substrate or inhibitor, though the binding of NHjBzGlu has been recognized for a number of years (Baker et al, 1966). While it is true that the major part of the very considerable binding energy of methotrexate and related compounds (IF0 = -12 to -15 kcal/mol) is attributable to the pteridine ring, significant variations in affinity are seen with changes in the NHiBzGlu moiety (Baker et al, 1964;Blakley, 1969;Johns et al, 1973).…”

Section: Discussionmentioning

confidence: 99%

“…A number of earlier experiments have indicated the importance of the glutamate residue for the binding of substrate analogs to dihydrofolate reductase (Baker el al., 1964(Baker el al., , 1966; Morales and Greenberg, 1964;Greenberg et al, 1966;Plante et al, 1967). Recently Johns et al (1973), have reported that the dimethyl ester of methotrexate (in which both carboxylate groups of the glutamate residue are blocked) has a strikingly lower affinity (almost 100-fold) for L1210 dihydrofolate reductase than does methotrexate itself.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear magnetic resonance studies of the binding of substrate analogs and coenzyme to dihydrofolate reductase from Lactobacillus casei

Roberts¹,

Feeney²,

Burgen³

et al. 1974

Biochemistry

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The interactions of the coenzyme, NADPH, and of /7-aminobenzoyl-L-glutamate, a fragment of the substrate, with Lactobacillus casei dihydrofolate reductase have been studied by nuclear magnetic resonance spectroscopy. The aromatic proton resonances of p-aminobenzoyl-L-glutamate shift upfield in the presence of the enzyme by 0.41 and 0.58 ppm (protons ortho and meta to the glutamate moiety, respectively); the binding constant is 1.05 X 103 M~'. Similar chemical-shift changes on binding are observed with p-nitrobenzoyl-L-glutamate, but with p-aminobenzoyl-D-glutamate, no changes in chemical shift of the aromatic protons are observed, although it binds to the same site with a binding constant of 0.34 X 103 M~'. In the presence of NADPH, all three compounds bind approximately 3.5-fold more tightly, and the shifts of the aromatic protons of p-aminobenzoyl-and p-nitrobenzoyl-L-gluta-Dihydrofolate reductase(5,6,7,8-tetrahydrofolate:NADP oxidoreductase, EC 1.5.1.3) catalyzes the reduction of dihydrofolate to tetrahydrofolate. This reaction is of considerable importance in one-carbon metabolism, notably in thymidylate biosynthesis. Dihydrofolate reductases are also the target of a potent and important group of inhibitors of considerable chemotherapeutic interest (Blakley, 1969; Hitchings and Burchall, 1965). In order to improve our understanding of the mode of action of these folate antagonists at the molecular level, we are undertaking a detailed study of ligand binding to dihydrofolate reductase from a methotrexate-resistant strain of Lactobacillus casei.We have begun by studying the binding of p-aminobenzoyl-L-glutamate (NHaBzGlu),* 1 a fragment of the substrate molecule, by high-resolution nmr spectroscopy. Both dihydrofolate and inhibitors such as methotrexate bind very tightly to dihydrofolate reductase (Kd ce. 10s-1010 M_l) and are thus in slow exchange on the nmr time scale. Fragments such as L-NH2BzG1u, however, bind much more weakly, are in rapid exchange, and can thus be studied much more conveniently. The low molecular weight of L. casei dihydrofolate reductase (17,500;Dann et al., 1974) has made it possible to study the nmr spectrum of the protein as well as the ligand in some detail.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nuclear magnetic resonance studies of the binding of substrate analogs and coenzyme to dihydrofolate reductase from Lactobacillus casei

Roberts¹,

Feeney²,

Burgen³

et al. 1974

Biochemistry

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“…Because this new type of ester is lipophilic and differs markedly in physiochemical properties from the parent alkylating acid, it might be expected that the drug remains unaltered for a sufficient length of time to reach tumour sites that are inaccessible to the lipophobic free acid (5). The main reason for employing a corticosteroid as a carrier is to obtain a selective distribution, by localizing the alkylating agent in a higher concentration within the malignant cells, and in this way reduce the systemic toxicity.…”

mentioning

confidence: 99%

Therapeutic Effect of Leo 1031, an Alkylating Corticosteroid Ester, in Lymphoproliferative Disorders

Brandt¹,

Könyves²,

Tr³

1975

Journal of Internal Medicine

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Leo 1031, a chlorambucil ester of pred nisolone, has been administered orally to 15 patients with chronic lymphocytic leukaemia (CLL) continuously for 1–29 months (mean 12.5). Seven patients were previously untreated and eight had been treated with prednisolone, radiotherapy and/or alkylating agents. The initial daily dose was generally 8–16 mg and the maintenance dose was 6–8 mg. Allopurinol was given concurrently. In 14 of 15 patients a reduction of the leucocyte count was observed and a reduction, in most instances, of lymphadenopathy or splenomegaly, or both. In seven patients the Hb concentration was improved. Significant toxic effects on bone marrow function have been observed in one patient. Two patients developed urticaria. Our study suggests that the drug is effective in the treatment of CLL.

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“…Diesters and monoesters of MTX have been studied actively in this laboratory [2,8,20,22,25,26] and others [I0, 13,14] for a number of years. Interest in these compounds arose from the idea that decreasing the polar character of the glutamate side-chain in MTX might give rise to favorable changes in biological activity [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Although MTX diesters prolong the life of mice with L1210 leukemia, this has been ascribed to rapid in vivo hydrolysis to MTX [10,13,14,20]. Since the diesters inhibit dihydrofolate reductase less effectively than MTX by as much as two orders of magnitude, direct antitumor action by these compounds in the murine L121t) system was judged to be unimportant.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic studies on the dibutyl and ?-monobutyl esters of methotrexate in the rhesus monkey

Rosowsky

Abelson

Beardsley

et al. 1982

Cancer Chemother. Pharmacol.

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The pharmacokinetics and metabolism of dibutyl methotrexate (DBMTX) and gamma-monobutyl methotrexate (gamma-MBMTX) were studied in Rhesus monkeys. When a bolus IV dose of either [3H]DBMTX or [3H] gamma-MBMTX was given, the principal species in serum for up to 1 h was the monoester, with MTX accounting for less than 10% of the total radioactivity. Products other than gamma-MBMTX and MTX were formed in substantial amounts with DBMTX, but not with gamma-MBMTX. Total radioactivity recovered in the bile 5 h after [3H]DBMTX injection accounted for 32% of the administered dose, indicating high hepatic extraction for this lipophilic compound. Serum and CSF levels of unchanged gamma-MBMTX, as well as of MTX arising via esterase cleavage, were measured by HPLC after IV infusion of gamma-MBMTX (10 g/m2). Efflux of monoester from CSF was slower than disappearance from serum. However, gamma-MBMTX levels in CSF were no higher than could be attained by infusing MTX itself at the same dose rate. While CSF/serum ratios were ca. 10-fold higher for gamma-MBMTX than for MTX, this difference could be explained on the basis of the very different affinities of the two compounds for serum proteins. HPLC analysis of serum processed by methanol precipitation as opposed to ultrafiltration of the proteins showed gamma-MBMTX to be greater than 99% bound, whereas for MTX this value was 50% or less. When gamma-MBMTX and MTX levels measured after ultrafiltration were corrected for this difference in serum protein binding the total amount of the two drugs in serum became almost equivalent.

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Antineoplastic activity of lipid-soluble dialkyl esters of methotrexate

Cited by 20 publications

References 3 publications

Nuclear magnetic resonance studies of the binding of substrate analogs and coenzyme to dihydrofolate reductase from Lactobacillus casei

Nuclear magnetic resonance studies of the binding of substrate analogs and coenzyme to dihydrofolate reductase from Lactobacillus casei

Therapeutic Effect of Leo 1031, an Alkylating Corticosteroid Ester, in Lymphoproliferative Disorders

Pharmacologic studies on the dibutyl and ?-monobutyl esters of methotrexate in the rhesus monkey

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