Biochemical Effects and Therapeutic Potential of Tunicamycin in Murine L1210 Leukemia1

Tunicamycin, an antibiotic which specifically inhibits the dolichol-mediated synthesis of glycoproteins, significantly decreased the incorporation of tritiated o-mannose and o-glucosamine into L1210 ascites leukemia cell glycoproteins at concentrations which affected the biosynthesis of proteins minimally. Mice re ceiving inoculations of LI 210 cells pretreated with 10 ^M 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 105 L1210 cells pretreated with 10 U.M tunicamycin in vitro were then resistant to a subsequent chal lenge with 106 untreated L1210 ascites cells. Direct i.p. admin istration 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 o-mannose prior to the administration of tunicamycin decreased the toxicity of the anti biotic in vivo and, when combined with o-mannose in vitro, exhibited cytotoxic additivity in terms of the inhibition of L1210 leukemic cell growth. A therapeutic regimen incorporating a 24hr 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 sug gest that tunicamycin, an inhibitor of glycoprotein biosynthesis, might be able to alter tumor cell growth and immunogenicity provided that host liver toxicity is diminished.