Modulation of the tissue disposition of methylglyoxal bis(guanylhydrazone) in mice by polyamine depletion and by polyamine administration

Abstract

Treatment of mice with DL-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a significant spermidine depletion in liver, small intestine, and bone marrow among eight tissues studied. The accumulation of methylglyoxal bis(guanylhydrazone) (MGBG) was selectively enhanced in small intestine and in bone marrow cells in response to a prior DFMO treatment. In other tissues studied, i.e., brain, skeletal and cardiac muscle, liver, kidney, and spleen, a preceding treatment with DFMO had no effect on the accumulation of subsequently injected MGBG. When mice, primed with DFMO and then treated with a single injection of MGBG, were given nontoxic doses of spermidine or putrescine through a gastric tube, high concentrations of MGBG in the small intestine and in bone marrow cells were effectively reduced. In spite of the route of administration, bone marrow cells appeared to be more sensitive than intestinal tissue as regards the prevention of the tissue accumulation of MGBG by the polyamines. The different sensitivity of various tissues to the natural polyamines in this respect may offer a means to develop a tissue-specific "polyamine rescue concept" to be used in connection with MGBG treatment.