Effect of Methionine-Deprived Nutrition on Cell Growth and Cell Kinetics in Cell Cultures and Experimental Tumors

Abstract

The effect of methionine-deprived nutrition on cell growth and cell kinetics was investigated in cell cultures and in tumor-bearing rats using the total parenteral nutrition (TPN) technique. A simultaneous flow cytometric measurement of the cellular DNA content and the amount of 5-bromodeoxyuridine incorporated into cellular DNA was performed for analysis of cell kinetics. The methionine-free medium demonstrated a cytocidal effect on the growth of SLC cells after 6 hours of culturing. It decreased viability from 80% in the control medium to 23%, and it decreased the S phase and increased the G₀/G₁ phase of the cell cycles. The methionine-deprived medium showed a concentration-dependent inhibition in cellular growth. Methionine-deprived TPN was seen to inhibit AH109A and SLC tumor growth compared with conventional TPN and decreased the S phase and increased the Go/ G₁ phase of cell cycles. These results confirm that methionine deprivation blocks cells from processing into the G₁ phase and recycling, and that it is effective in inhibiting tumor growth in cultures and in vivo. (Journal of Parenteral and Enteral Nutrition 15: 540-545, 1991)

Get full access to this article

View all access options for this article.

References

Usami M. , Ishimoto S. , Nishijima M. , et al: Effect of total parenteral nutrition (TPN) on the immunological status and tumor growth of tumor bearing rats and cancer patients. IN Proceedings of the Fifth Asian Congress of Nutrition . Center for Academic Publications, Tokyo, Japan, 1987, p 481

Ford JH , Dudan RC , Bennett JS : Parenteral hyperalimentation in gynecologic oncology patients. Gynecol Oncol 1:70-75, 1972

Steiger E. , Oram-Smith J. , Miller E. , et al: Effects on tumor growth and tolerance to chemotherapy. J Surg Res 18:455-461, 1975

Cameron IL , Pavalot WA : Stimulation of growth of a transplant-able hepatoma in rats by parenteral nutrition. J Natl Cancer Inst 56:597-601, 1976

Tachibana K. , Mukai K. , Hiraoka I. , et al: Evaluation of the effect of arginine-enriched amino acid solution on tumor growth (in Japanese) . JPEN 9:428-434, 1985

Kawaura Y. , Ohmura K. , Hashizume Y. , et al: The treatment of advanced cancer with amino acid imbalance solution (in Japanese). J Jpn Soc Cancer Ther 20:1093-1097, 1985

Elvehjem CA : Amino acid imbalance. Fed Proc 15:965-970, 1956

Sugimura T. , Birnbaum SM , Winitz M. , et al: Quantitative nutritional studies with water soluble, chemically defined diets: The forced feeding of diets each lacking in one essential amino acid. Arch Biochem Biophys 81:448-455, 1959

Kreis W. , Hession C. : Biological effects of enzymatic deprivation of L-methionine in cell culture and experimental tumor. Cancer Res 33:1866-1869, 1973

10.

Chello PL , Bertino JR : Dependence of 5-methyltetrahydrofolate utilization by L5178 murine leukemia cells in vitro on the presence of hydroxycobalamin and transcobalamine . Cancer Res 33:1898-1904, 1973

11.

Kreis W. : Tumor therapy by deprivation of L-methionine: Rationale and results . Cancer Treat Rep 63:1069-1072, 1979

12.

Goseki N. , Onodera T. , Koike M. , et al: Inhibitory effect of L-methionine-deprived amino acid imbalance using total parenteral nutrition on growth of ascites hepatoma in rats. Tohoku J Exp Med 151:191-200, 1987

13.

Mori K. : Induction of pulmonary tumors in rats by subcutaneous injections of 4-nitroquinoline 1-oxide. Gann 53:303, 1962

14.

Nakamura K. : Studies on the ascites hepatoma (8). Difference of chromosome numbers among tumor cells constituting the same "island" of the ascites hepatoma. Gann 46:196-199, 1955

15.

Steiger F. Vars HM Dudrich SJ : A technique for long term intravenous feeding in unrestrained rats . Arch Surg 104:330-332, 1972

16.

Dolbeare F. Gratzner H. Pallavicini MG et al: Flow cytometric measurement of total DNA content and incorporated bromodeoxyuridine. Proc. Natl. Acad. Sci. USA 80:5573-5577, 1983

17.

Tsukada K. , Maruyama I. , Aoi S. : Metabolism of methionine and S-adenosylmethionine in rat hepatoma cells (in Japanese). Jpn J Surg Metab Nutr 21:9-15, 1987

18.

Vaughn MH , Pawlowski PJ , Forchhammer J. : Regulation of protein synthesis inhibition in HeLa cells deprived of single essential amino acids. Proc. Natl. Acad. Sci. USA 68:2057-2061, 1971

19.

Hoffman RM , Jacobsen SJ : Reversible growth arrest in simian virus 40-transformed human fibroblasts . Proc. Natl. Acad. Sci. USA 77:7306-7310, 1980

20.

Ishimoto S. , Usami M. , Nishimatsu S. , et al: Inhibition in tumor growth by amino acid imbalance analyzed using flow-cytometry (in Japanese) . J Jpn Surg Soc 90(suppl):248, 1989

21.

Takizawa T. , Sato M. , Isono T. , et al: Total parenteral nutrition (TPN) using imbalanced (methionine deprived) amino acids solution in chemotherapy for ovarian cancer. IN Proceedings of the Fifth Asian Congress of Nutrition . Center for Academic Publications, Tokyo, Japan, 1987, p 482

22.

Hoffman RM : Methionine dependence in cancer cells: A review. In Vitro 18:421-428, 1982

23.

Tisdale MJ : Effect of methionine deprivation on methylation and synthesis of macromolecules . Br J Cancer 42:121-128, 1980

24.

Ishiwaki K. , Ido T. , Abe Y. , et al: Tumor uptake studies of S-adenosyl-L-[methyl-11] methionine and L-[methyl-11C] methionine . Nucl Med Biol 5:123-126, 1988