Generation of 5-fluorouracil from 5-fluorocytosine by monoclonal antibody-cytosine deaminase conjugates

Bioconjug Chem. 1991 Nov-Dec;2(6):447-51. doi: 10.1021/bc00012a012.

Abstract

Cytosine deaminase (CDase) catalyzes the conversion of cytosine to uracil and is also able to convert the clinically used antifungal agent 5-fluorocytosine (5FC) into the anticancer drug 5-fluorouracil (5FU). The enzyme was purified from bakers' yeast in a six-step procedure. Studies indicated that bakers' yeast CDase had a molecular weight of approximately 32 kDa and was composed of two subunits of equal molecular weights. Monoclonal antibodies were covalently attached to CDase, forming conjugates that could bind to antigens on tumor cell surfaces. The combination of L6-CDase and 5FC was equivalent in cytotoxic activity to 5FU when tested against the H2981 human lung adenocarcinoma cell line (L6 positive, 1F5 negative). 5FC alone was noncytotoxic. The activation of 5FC was immunologically specific since 1F5-CDase did not enhance 5FC activity.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / immunology
  • Antibodies, Monoclonal*
  • Antigens, Neoplasm / immunology*
  • Cytosine Deaminase
  • Electrophoresis, Polyacrylamide Gel
  • Flucytosine / metabolism*
  • Fluorouracil / metabolism*
  • Fluorouracil / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Macromolecular Substances
  • Molecular Weight
  • Nucleoside Deaminases / chemistry
  • Nucleoside Deaminases / isolation & purification
  • Nucleoside Deaminases / metabolism*
  • Saccharomyces cerevisiae / enzymology
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Macromolecular Substances
  • Flucytosine
  • Nucleoside Deaminases
  • Cytosine Deaminase
  • Fluorouracil