CELL DEATH, CHALONES, AND CYTOTOXIC METABOLITES

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During experiments on the mechanisms of regulation of embryonal carcinoma cells by the blastocyst, a soluble factor in blastocele fluid was identified that causes programmed cell death of some embryonal carcinoma and inner cell mass cells each with the potential to differentiate into trophectoderm. Preliminary data obtained with the cyst fluid from blastocyst-like embryoid bodies of the ascites form of a teratocarcinoma suggest that cytotoxic polyamine metabolites, generated by the activities of amine oxidases, kill the target cells during programmed cell death. During these experiments it became apparent that the effect of selective cell death on a stem cell population is often perceived as inhibition of proliferation, thus these metabolites appeared to produce chalone-like activity in vitro. Historically chalone activity has been difficult to separate from polyamine toxicity. Thus, the hypothesis of this proposal is that cytotoxic polyamine metabolites kill cells during programmed cell death and thereby act as a chalone in renewing stem cell populations of the adult. This proposal will test three predictions of the hypothesis: antibodies against amine oxidases and polyamines will co-localize in areas of programmed cell death in embryonic and adult tissues, enzyme inhibitors of amine oxidase will prevent programmed cell death, and chalones exert their effects via polyamine/amine oxidase biochemistry. The data will impact upon the understanding of selective cell death via oxidative damage (including drug- and radiation-induced), morpho- and histogenesis of the embryo, and aberrations of tissue renewal in the adult.