Efficacy of Methionine-Restricted Diets on Cancers In Vivo

  • Robert M. HoffmanEmail author
  • Yasunori Hoshiya
  • Weiyan Guo
Part of the Methods in Molecular Biology book series (MIMB, volume 1866)


Methionine (MET) dependence is the elevated requirement of cancer cells for MET. Cancer cells are arrested when MET is restricted in late S/G2 phase of the cell cycle. MET dependence may be the only known general metabolic defect in cancer. This chapter reviews the in vivo efficacy of dietary MET restriction (MR) to arrest human-cancer cell-line tumors and mouse tumors in nude mice. Human cancer xenografts in nude mice, when fed a MET-free diet, had greatly inhibited tumor growth. The body weight of mice on the MET-free diet was found to be maintainable by once-per-week administration of MET. These results suggested that MET dependence can be an important target for human cancer treatment. Yoshida sarcoma in nude mice on a MET-depleted diet regressed. MET depletion resulted in the extended survival of the tumor-bearing mice. These experiments are a prelude to further clinical studies of the efficacy of MR diets on cancer patients.

Key words

Methionine dependence Human cancer Sarcoma Cell lines Yoshida sarcoma Nude mice Methionine-free diet Tumor growth inhibition 


  1. 1.
    Hoffman RM (2015) Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15:21–31CrossRefGoogle Scholar
  2. 2.
    Hoffman RM (1984) Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis: a review and synthesis. Biochim Biophys Acta 738:49–87PubMedGoogle Scholar
  3. 3.
    Stern PH, Hoffman RM (1984) Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20:663–670CrossRefGoogle Scholar
  4. 4.
    Hoffman RM, Jacobsen SJ (1980) Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci U S A 77:7306–7310CrossRefGoogle Scholar
  5. 5.
    Guo HY, Lishko VK, Herrera H, Groce A, Kubota T, Hoffman RM (1993) Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res 53:5676–5679PubMedGoogle Scholar
  6. 6.
    Mecham JO, Rowitch D, Wallace CD, Stern PH, Hoffman RM (1983) The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun 117:429–434CrossRefGoogle Scholar
  7. 7.
    Guo HY, Herrera H, Groce A, Hoffman RM (1993) Expression of the biochemical defect of methionine dependence in fresh patient tumors in primary histoculture. Cancer Res 53:2479–2483PubMedGoogle Scholar
  8. 8.
    Goseki N, Yamazaki S, Endo M (1992) Antitumor effect of methionine-depleting total parenteral nutrition with doxorubicin administration on Yoshida sarcoma-bearing rats. Cancer 69:1865–1872CrossRefGoogle Scholar
  9. 9.
    Breillout F, Hadida F, Echinard-Darin P, Lascaux V, Poupon M-F (1987) Decreased rat rhabdomyosarcoma pulmonary metastases in response to a low methionine diet. Anticancer Res 7:861–867PubMedGoogle Scholar
  10. 10.
    Breillout F, Antoine E, Poupon M-F (1990) Methionine dependency of malignant tumors: a possible approach for therapy. J Natl Cancer Inst 82:1628–1632CrossRefGoogle Scholar
  11. 11.
    Hoshiya Y, Guo H, Kubota T, Inada T, Asanuma F, Yamada Y, Koh J, Kitajima M, Hoffman RM (1995) Human tumors are methionine dependent in vivo. Anticancer Res 15:717–718PubMedGoogle Scholar
  12. 12.
    Nawara H, Bronzert D, Lippman ME (1981) Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J Biol Chem 256:5016–5021Google Scholar
  13. 13.
    Kubota T, Kubouchi K, Koh J, Enomoto K, Ishibiki K, Abe O (1983) Human breast carcinoma (MCF-7) serially transplanted into nude mice. Jpn J Surg 13:381–384CrossRefGoogle Scholar
  14. 14.
    Fukutomi T, Kubota T, Ikeda T, Isobe Y, Kikuyama S, Shimada A, Nakamura A, Nishiumi T, Enomoto K, Ishibiki K, Abe O (1986) Experimental combined hormone therapy on human breast carcinomas serially transplanted into nude mice. Jpn J Cancer Res 77:92–97PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Robert M. Hoffman
    • 1
    • 2
    Email author
  • Yasunori Hoshiya
    • 3
  • Weiyan Guo
    • 1
  1. 1.AntiCancer, Inc.San DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of SurgeryKeio UniversityTokyoJapan

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