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Vitalethine Modulates Erythropoiesis and Neoplasia¹

School of Medicine, University of New Mexico, Albuquerque, New Mexico 87131 [G. D. K., K. H. L., H. L. F., T. J. S.], and Department of Medicine, Veterans Administration Medical Center, Albuquerque, New Mexico 87108 [D. A. C.]

Novel compounds based upon the thiol N-(carboxy)-ß-alanyl-cysteamine (vitaletheine) have strikingly potent and seemingly diverse biological activities. Concentrations of vitaletheine modulators from 1 femtograms/ml to 100 picograms/ml medium regulate RBC production from progenitors initially deprived of erythropoietin. Similarly, as little as attograms/ml concentrations of the disulfide vitalethine stimulate immunological responses of murine splenocytes toward sheep RBC in a hemolytic plaque assay. Because dosages of vitalethine as low as femtograms/kg substantially diminish tumor size and incidence and increase survival to 80% in mice inoculated with a uniformly fatal melanoma (Cloudman S-91), activities of these compounds have in vivo significance. A preliminary probe of the benzyl derivative of vitalethine in a myeloma model (NS-1) suggests efficacy (100% survival) as well. The high potencies of the vitaletheine modulators, both in cell culture and in vivo, indicate that these or similar regulatory components, if constitutively present, probably occur endogenously at vanishingly small concentrations and may be prone to deficiency resulting from metabolic imbalances, irradiation, aging, diet, pathogenic or parasitic infections, or exposure to environmental pollutants. Pathways for the biosynthesis of vitaletheine are proposed and chemical syntheses of the vitaletheine modulators are described. Possible molecular mechanisms of action, including interactions with peptidyl hormones, other endogenous effectors, and xenobiotic and pharmaceutical compounds, are explored. Indications for the treatment of other diseases are identified.

¹ Early work on this project was funded by NIH Grants HL16796, AM10628, and Basic Research Support Grant SO7RR-05583-25.

² To whom requests for reprints should be addressed, at University of New Mexico, P.O. Box 702, Basic Sciences Building 1, Albuquerque, NM 87131; present address, 3205 Arizona, N. E., Albuquerque, NM 87110.

Received 2/15/94. Accepted 8/25/94.