Biochemical effects and therapeutic potential of tunicamycin in murine L1210 leukemia
Tunicamycin, an antibiotic which specifically inhibits the dolichol-mediated synthesis of glycoproteins, significantly decreased the incorporation of tritiated D-mannose and D-glucosamine into L1210 ascites leukemia cell glycoproteins at concentrations which affected the biosynthesis of proteins minimally. Mice receiving inoculations of L1210 cells pretreated with 10 microM tunicamycin in vitro survived nearly twice as long as did mice receiving implants of untreated tumor cells. A nonlethal dose of X-irradiation (350 rads) to mice 24 hr prior to receiving their inoculation of tunicamycin-treated L1210 cells prevented this increase in life span. Thirty-eight % of the long-term surviving mice which received 1 X 10(5) L1210 cells pretreated with 10 microM tunicamycin in vitro were then resistant to a subsequent challenge with 10(6) untreated L1210 ascites cells. Direct i.p. administration of tunicamycin to mice resulted in potent liver toxicity (50% lethal dose, 2.0 mg/kg) which obviated any therapeutic efficacy when administered to L1210 ascites tumor-bearing mice. The administration of nontoxic levels of D-mannose prior to the administration of tunicamycin decreased the toxicity of the antibiotic in vivo and, when combined with D-mannose in vitro, exhibited cytotoxic additivity in terms of the inhibition of L1210 leukemic cell growth. A therapeutic regimen incorporating a 24-hr infusion of the sugar prior to multiple administrations of tunicamycin gave evidence of a small therapeutic response in terms of the survival of tumor-bearing mice. These results suggest that tunicamycin, an inhibitor of glycoprotein biosynthesis, might be able to alter tumor cell growth and immunogenicity provided that host liver toxicity is diminished.
- Research Organization:
- Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York
- OSTI ID:
- 5762356
- Journal Information:
- Cancer Res.; (United States), Vol. 43:4
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
62 RADIOLOGY AND NUCLEAR MEDICINE
ANTIBIOTICS
BIOLOGICAL EFFECTS
LEUKEMIA
CHEMOTHERAPY
MICE
WHOLE-BODY IRRADIATION
BIOSYNTHESIS
GLUCOPROTEINS
INHIBITION
MANNOSE
SYNERGISM
TRITIUM COMPOUNDS
UPTAKE
X RADIATION
ALDEHYDES
ANIMALS
ANTI-INFECTIVE AGENTS
CARBOHYDRATES
DISEASES
DRUGS
ELECTROMAGNETIC RADIATION
EXTERNAL IRRADIATION
HEMIC DISEASES
HEXOSES
IONIZING RADIATIONS
IRRADIATION
LABELLED COMPOUNDS
MAMMALS
MONOSACCHARIDES
NEOPLASMS
ORGANIC COMPOUNDS
PROTEINS
RADIATIONS
RODENTS
SACCHARIDES
SYNTHESIS
THERAPY
VERTEBRATES
560152* - Radiation Effects on Animals- Animals
550600 - Medicine