The vitalethine modulators are novel compounds based upon the thiol N- (carboxy)-BETA-alanylcysteamine that exhibit potent biologic activity with a lack of toxicity. They have been shown to stimulate antibody production in vivo and in vitro and, more importantly, to modulate both erythropoiesis and neoplasia. Because direct cytotoxicity to tumor cells has not been seen, the mechanism for the anticancer effect of the vitalethine modulators is hypothesized to involve altered immunoregulation. We propose to examine the activity of a stable derivative of vitalethine, benzyl vitalethine, on immune cells. The activation status of benzyl vitalethine treated T-cells will be assessed using the CD69 activation marker, cell cycle analysis, the production of second messengers including DAG and IP3, and calcium mobilization. Another important component of T-cell activation to be measured is expression of members of the beta-integrin family. Along with upregulation of ICAM on endothelial cells, an increase in beta-integrins can result in increased lymphocyte adhesion and localization to tumor sites. Further, we will examine benzyl vitalethine activity on macrophages in terms of nitric oxide production, MHC expression, and presentation of the MART-1 and MAGE-3 melanoma antigens. Together, these analyses should contribute to delineating the usefulness of the vitalethine modulators as antitumor immunotherapeutic agents.
An understanding of the mechanism of action of the vitalethine modulators will facilitate their use as antineoplastic agents. Their potency and lack of toxicity also make them attractive as adjuvants in tumor vaccinations, adoptive immunotherapies, and combination therapy for cancer. Other potential uses including immunodeficiency states and infectious disease states further increase their potential long-term commercial applications.
