Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer?

Epner, Daniel E.

doi:10.1080/07315724.2001.10719183

Cited by 38 publications

(26 citation statements)

References 56 publications

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“…These intriguing observations led to an examination of the effect of dietary methionine restriction, including in combination with chemotherapy, on tumor growth in xenograft models of human cancer (13,14). Efficacy was shown in these models, and synergism was produced by adding chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

Yang

Wang²,

Yoshioka

et al. 2004

Clinical Cancer Research

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Pharmacokinetics, methionine depletion, antigenicity, and toxicity of recombinant methioninase (rMETase), which has shown efficacy in achieving cell kill in a broad range of human tumor models, were examined in macaque monkeys. Dose-ranging studies at 1000, 2000, and 4000 units/kg i.v. identified the 4000 units/kg dose as able to reduce plasma methionine to an undetectable level (less than 0.5 M) by 30 min, and the level so remained for 8 h. Pharmacokinetic analysis showed that rMETase was eliminated with a T 1/2 of 2.49 h. A 2-week i.v. administration of 4000 units/kg every 8 h/day for 2 weeks resulted in a steady-state depletion of plasma methionine to less than 2 M. The only manifest toxicity was decreased food intake and slight weight loss. Serum albumin and red cell values declined transiently during treatment, which may be related to extensive blood sampling. Re-challenge on day 28 resulted in anaphylactic shock and death in one animal. Subsequent pretreatment with hydrocortisone prevented the anaphylactic reaction, although vomiting was frequently observed. Re-challenge was carried out at days 66, 86, and 116. Anti-rMETase antibodies (at 10 ؊3 ) were found after the first challenge, and these increased to 10 ؊6 after the fourth challenge and decreased to 10 ؊2 by 2 months post therapy. The main rMETase antibody was IgG, and although it has some in vitro features of being a neutralizing antibody, each challenge dose was effective in depleting plasma methionine levels. Thus, rMETase was able to effectively deplete plasma methionine levels with minimal toxicity in a primate model. These data provide the bases for alteration by polyethyleneglycol conjugation (PEGylation) of the enzyme to increase its duration of effect and reduce its immunogenicity.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

Yang

Wang²,

Yoshioka

et al. 2004

Clinical Cancer Research

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“…In a rat colon cancer model, for example, MR has been shown to inhibit the formation of preneoplastic aberrant crypt foci after the administration of the carcinogen azoxymethane [9]. Data from a phase I clinical trial conducted on 8 patients with metastatic solid tumors by Epner and colleagues indicated for the first time that diet with a reduced Met content is safe and feasible to treat patients with cancer, despite a conclusive lack of sufficient anti-tumor activity [10,11]. A Met-free diet was used in con-junction with other anti-cancer agents in another two Phase I clinical trials [12,13].…”

Section: Methionine Restriction In Aging and Can-cer Studiesmentioning

confidence: 99%

“…In a recent study using fruit fly Drosophila melanogaster, the addition of Met to a CR diet reduced life span and this reduction in life span could be avoided by simply removing Met from the diet [3]. Both nutritional interventions, CR and methionine restriction (MR), do not only simply extend life span, but also forestall the onset of a variety of age-related diseases, such as cancers, obesity, diabetes, hypercholesterolemia and more [3,4,6,[9][10][11]. Since the etiology of many types of diseases involves collapse of epithelial and/or endothelial barriers [4], it is reasonable to speculate that either CR or MR, at least in part, exert their benefits through strengthening barrier functions.…”

Section: Methionine Restriction In Aging and Can-cer Studiesmentioning

confidence: 99%

Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

Wang¹

2012

JEBP

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Abstract:It is well known that caloric restriction leads to an increased longevity by forestalling age-related diseases. Dietary restriction of methionine also renders similar benefits. In this review, we report studies on the effect of methionine restriction on epithelial barrier function in a renal epithelial LLC-PK 1 cell, a rodent gastrointestinal model and a clinical trial using Crohn's patients. In LLC-PK 1 cell culture, a reduction of culture medium methionine by 80% resulted in altered tight junctional claudin composition with improved epithelial barrier function as exemplified by increased transepithelial electrical resistance and decreased paracellular leak to 14 C-D-mannitol. In addition to small but significant reductions in plasma and intracellular colonocyte methionine levels, dietary methionine restriction tightens intestinal epithelium and reduces mannitol permeability in rat colonic, but not ileal tissue. Crohn's patients on methionine-restricted diet reported improved symptoms as demonstrated by a reduced CDAI index, but this diet was not able to significantly reduce the plasma methionine level in patients recruited. An increased urinary lactulose/mannitol ratio was also the result of the regimen in Crohn's patients, suggesting an increased, rather than decreased ileal leakage. Overall, our results showed that reduction in dietary intake of methionine is promising in improving at least some epithelial barriers and this may be through altering tight junctional protein compositions. Methionine restriction might result in contrasting effects depending on the tissue type and possible disease conditions, thus wider range of studies are required.

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“…Levels of cysteine, homocysteine, cysteinyl-glycine and glutathione were determined in plasma from tumour-bearing mice (days 1,3,5,8,10) and from healthy mice (control). Results are presented in Figure 4b.…”

Section: Temporal Evaluation Of Metabolites In Blood Plasmamentioning

confidence: 99%

“…Since this phenotype is unique to cancer cells, it has been proposed as a selective target for cancer therapy. 6,8,9 Although aspects of methionine metabolism have been studied in attempts to identify the underlying mechanism of this metabolic defect, the biochemical mechanism of methionine dependence is not fully understood.…”

mentioning

confidence: 99%

Temporal evaluation of methionine synthase and related metabolites in the MAC15A mouse adenocarcinoma animal model

Blackburn

Bibby

Lucock

et al. 2004

Intl Journal of Cancer

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Methionine dependence is unique to cancer cells and defined as the inability to grow in a methionine-deprived environment even if supplemented with the metabolic precursor homocysteine. Cobalamin-dependent methionine synthase (MS) catalyses the formation of methionine and tetrahydrofolate from homocysteine and methyltetrahydrofolate, thus linking the methionine and folate pathways. The apparent altered methionine metabolism in methionine-dependent cancer cells suggests a role for MS, although results to date are conflicting. We have analysed key metabolites of the MS-associated transmethylation, transsulphuration and folate pathways of the methionine-dependent MAC15A tumour model as a function of tumour progression over a 10-day period. MS activity increased 2-fold from day 1 to day 10. Cysteine, homocysteine, S-adenosylmethionine and Sadenosylhomocysteine levels in tumour cytosolic fractions decreased as a function of tumour progression. Plasma cysteine levels also decreased, whilst the distribution of folates in erythrocytes was altered, with a maximum increase in methyltetrahydrofolate observed by day 5. The increasing MS activity and decreasing cysteine levels suggest an increasing methionine requirement by the tumour, whilst the induction of enzyme activity indicates that MS is not defective in the methionine-dependent MAC15A tumour. The decrease in tumour S-adenosylmethionine and S-adenosylhomocysteine levels suggests that methionine is required for some function other than cellular methylation, e.g., incorporation into protein. Overall, the results support a theory of methionine conservation in response to tumour growth, where the methionine-dependent MAC15A tumour has a higher than normal methionine requirement.

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Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer?

Cited by 38 publications

References 56 publications

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

Temporal evaluation of methionine synthase and related metabolites in the MAC15A mouse adenocarcinoma animal model

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