GAMMA-L-GLUTAMINYL-4-HYDROXYBENZENE, AN INDUCER OF CRYPTOBIOSIS IN AGARICUS-BISPORUS AND A SOURCE OF SPECIFIC METABOLIC-INHIBITORS FOR MELANOGENIC CELLS
A stable phenol .gamma.-L-glutaminyl-4-hydroxybenzene (GHB), is oxidized by tyrosinase in the gill tissues of the mushroom A. bisporus to a quinone and a 2nd oxidation product which together suppress mitochondrial energy production and the synthesis of proteins and nucleic acids in the zygote, thus establishing dormancy in the spores. Brief incubation of cultured murine L1210 leukemia and B-16 melanoma cells with micromolar concentrations of the purified quinone notably prolonged surival times or blocked tumor growth in histocompatible mice inoculated i.p. with high concentrations of the exposed cells. The instability of the quinone precluded in vivo administration. Short incubation of cultured B-16 melanoma cells with millimolar concentrations of GHB prolonged survival times or abolished tumor growth in histocompatible C57BL/6J mice inoculated i.p. with 5 .times. 106 exposed cells. This response did not occur with L1210 leukemia cells, which lack tyrosinase. The survival times of mice bearing B-16 melanoma, but not those with L1210 leukemia, were slightly prolonged by a single injection and were significantly extended by daily i.p. injections of GHB. Normal C57BL/6J mice, given GHB i.p. as single or multiple 400-mg/kg doses, manifested no systemic toxicity but showed depigmentation of the hair after 2-3 wk. These studies provide evidence that GHB exerts cytotoxicity specifically for cells that by their content of tyrosinase convert the phenol to the quinone. This targeted response minimizes systemic toxicity and underscores the potential therapeutic application of this agent to melanocarcinoma.