Enhancement of antitumor activity of ascorbate against Ehrlich ascites tumor cells by the copper:glycylglycylhistidine complex.

Ascorbate in an aqueous solution is easily oxidized by molecular oxygen in the presence of cupric ion, thus producing reactive oxygen species and exhibiting cytotoxicity. In order to increase the antitumor activity of ascorbate, we used the innocuous form of cupric ion complexed with glycylglycylhistidine, a tripeptide designed to mimic the specific Cu(II) transport site of albumin molecule. Although this square planar copper:glycylglycylhistidine complex did not significantly oxidize ascorbate at pH 7.4, it killed Ehrlich ascites tumor cells in vitro in a high concentration of ascorbate. The injections of large doses of ascorbate together with copper: glycylglycylhistidine prolonged the life span of mice inoculated i.p. with Ehrlich tumor cells. The target specificity against tumor cells was primarily attributable to their high peptide-cleaving activity.

[1]  J. S. Burton,et al.  Free Radicals in the Auto-Oxidation of Ascorbic Acid. , 1964 .

[2]  Kazuhiko Ida,et al.  Reaction between Various Copper(II) Complexes and Ascorbic Acid or 3,5-Di-t-butylcatechol , 1980 .

[3]  I. Fridovich,et al.  The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. , 1972, The Journal of biological chemistry.

[4]  H. Maeda,et al.  Mutagenic action of triose reductone and ascorbic acid on Salmonella typhimurium AT 100 strain. , 1978, Journal of nutritional science and vitaminology.

[5]  B. Sylvén,et al.  ON THE CHEMICAL PATHOLOGY OF INTERSTITIAL FLUID. I. PROTEOLYTIC ACTIVITIES IN TRANSPLANTED MOUSE TUMORS. , 1965, Cancer research.

[6]  T. Sakurai,et al.  Interaction of copper(II) and nickel(II) with L-histidine and glycylglycyl-L-histidine as an albumin model , 1980 .

[7]  Horacio A. Mottola,et al.  Absorptiometric determination of hydrogen peroxide in submicrogram amounts with leuco crystal violet and peroxidase as catalyst , 1970 .

[8]  K. Kitagawa,et al.  Mechanism of Inactivation of Bacteriophage J1 by Ascorbic Acid , 1973 .

[9]  S. Bram,et al.  Vitamin C preferential toxicity for malignant melanoma cells , 1980, Nature.

[10]  B. Halliwell,et al.  Ascorbic acid, metal ions and the superoxide radical. , 1976, The Biochemical journal.

[11]  A. Martell,et al.  Metal ion and metal chelate catalyzed oxidation of ascorbic acid by molecular oxygen. I. Cupric and ferric ion catalyzed oxidation. , 1967, Journal of the American Chemical Society.

[12]  L. Oberley,et al.  Superoxide dismutase activity of Ehrlich ascites tumor cells. , 1977, Journal of the National Cancer Institute.

[13]  B. Bielski,et al.  Reaction rates of superoxide radicals with the essential amino acids. , 2008, Ciba Foundation symposium.

[14]  Y. Sugiura.  The production of hydroxyl radical from copper(I) complex systems of bleomycin and tallysomycin: comparison with copper(II) and iron(II) systems. , 1979, Biochemical and biophysical research communications.

[15]  L. Oberley,et al.  The production of hydroxyl radical by bleomycin and iron (II) , 1979, FEBS letters.

[16]  H. Stich,et al.  Enhancement of the chromosome-damaging action of ascorbate by transition metals. , 1979, Cancer research.

[17]  L. Oberley,et al.  Superoxide dismutase activity of normal murine liver, regenerating liver, and H6 hepatoma. , 1978, Journal of the National Cancer Institute.

[18]  T. Kruck,et al.  A peptide molecule mimicking the copper(II) transport site of human serum albumin. A comparative study between the synthetic site and albumin. , 1974, The Journal of biological chemistry.

[19]  L. Benade,et al.  Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-1,2,4,-triazole. , 1969, Oncology.