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Selective Killing of Transformed Cells by Methotrexate with Histidine Deprivation or with -Amino Alcohols¹

Departments of Biochemistry and Biophysics and of Pharmaceutical Chemistry [E. M. N., D. V. S.] and Division of Clinical Pharmacology, Department of Medicine [D. W. N.], University of California, San Francisco, California 94143

The effects of amino acid deprivation and treatment with amino alcohols upon the growth, viability, and susceptibility to methotrexate (MTX) cytotoxicity were examined in BALB/3T3 cells and their virally transformed counterparts, SV-T2 cells. Cells were deprived of either histidine or tyrosine plus phenylalanine, or they were treated with amino alcohol analogues of histidine and tyrosine (histidinol and tyrosinol).

When incubated in medium lacking histidine and supplemented with dialyzed serum (histidine-deficient medium), the BALB/3T3 cells remained viable for at least 3 days, but they ceased logarithmic growth, and the cell number reached an early plateau. In contrast, the SV-T2 cells continued to divide in histidine-deficient medium. Neither cell line ceased division in medium deficient in both phenylalanine and tyrosine. Incubation of the BALB/3T3 cells with 1.5 mM histidinol or 1.0 mM tyrosinol caused an early plateau similar to the effect of histidine deprivation. SV-T2 cells were not affected by these concentrations of histidinol or tyrosinol, but growth was arrested at higher concentrations.

Any of the conditions used which caused a plateau in the number of BALB/3T3 cells substantially protected the treated cells from cell death caused by MTX. Therefore, pretreatment of BALB/3T3 cells with histidine deprivation, 1.5 mM histidinol, or 1.0 mM tyrosinol protected this cell line against MTX-induced cell death, while the same pretreatment conditions failed to protect SV-T2 cells. (SV-T2 cells were protected by 4.0 mM histidinol.) Thus, the ability of MTX to kill cells in vitro can be selectively modified by conditions which protect cells which retain normal growth control characteristics, but which do not protect virally transformed cells.

¹ This investigation was supported by USPHS Grant CA14266 from the National Cancer Institute.

² Recipient of National Cancer Institute Fellowship F32 CA06573. Present address: Division of Pediatrics, City of Hope Research Institute, 1500 E. Duarte Rd., Duarte, Calif. 91010.

³ Fellow under USPHS Grant GM07546 from the National Institute of General Medical Sciences. Present address: Division of Clinical Pharmacology, Dartmouth Medical School, Hinman Box 7650, Hanover, N. H. 03756.

⁴ To whom requests for reprints should be addressed.

Received 2/10/83. Accepted 7/13/83.