Synergistic Effect of Methionine‐depleting Total Parenteral Nutrition with 5‐Fluorouracil on Human Gastric Cancer: A Randomized, Prospective Clinical Trial

Goseki, Narihide; Yamazaki, Shigeru; Shimojyu, Katsuo; Kando, Fumio; Maruyama, Michio; Endo, Mitsuo; Koike, Masato; Takahashi, Hirokazu

doi:10.1111/j.1349-7006.1995.tb03082.x

Cited by 74 publications

(50 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Methionine depletion has been attempted by dietary methionine deprivation (18,19) and by the use of methioninase to degrade methionine and deplete circulating methionine levels (8,20). Inhibition of an enzyme critical for methionine production, such as MTHFR, is another means of limiting methionine supply and affecting proliferative potential.…”

Section: Discussionmentioning

confidence: 99%

Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo

Stankova

Shang

Rozen

2005

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisensemediated inhibition of MTHFR on survival of human cancer cells.Experimental Design: We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs.Results: Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of human colon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker.Conclusions: Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.

show abstract

Section: Discussionmentioning

confidence: 99%

Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo

Stankova

Shang

Rozen

2005

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…An even more important observation is the growing evidence that a variety of chemotherapeutic agents appear to be synergistically enhanced by plasma methionine depletion; these include doxirubicin (11), 5-fluorouracil and mitomycin C (13,23), CDDP (19), and nitrosoureas (21,22,30).…”

Section: Discussionmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…[96]. Показано, что перевод пациентов на полное парентеральное питание без метионина в течение 8 дней повышает эффективность 5-фторурацила при раке желудка [97].…”

Section: возможность использования рациона со сниженным содержанием мunclassified

Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy

VS¹,

Davydov²,

Anufrieva³

et al. 2017

Клиническая онкогематология

View full text Add to dashboard Cite

This review presents the characteristics of the cellular metabolism of methionine, as well as known data on the mechanisms of the development of methionine dependence in malignant cells. The possibilities of using a non-methionine diet for the control of the tumor growth in patients with various forms of cancer are considered. The information about methionine Y-lyase, an enzyme providing elimination of methionine from plasma, is provided. Its role as a potential antitumor enzyme is disclosed. Data on cytotoxic activity of the enzyme, obtained from various sources, and information on tumor models and cell cultures, showing methionine dependence are summarised.

show abstract

Synergistic Effect of Methionine‐depleting Total Parenteral Nutrition with 5‐Fluorouracil on Human Gastric Cancer: A Randomized, Prospective Clinical Trial

Cited by 74 publications

References 11 publications

Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo

Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo

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

Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy

Contact Info

Product

Resources

About