Prostate Cancer Vaccines, Fibrin and Selenium: A Conceptual Review

ABSTRACT

Cancer immunotherapy is based on a concept that persistent presence of tumors in cancer patients is a result of immunological breakdown and/or downregulation of the tumor immunogenecity. In view of their limited efficacies, it can be argued that the problem lies not in a particular vaccine, but in tumors themselves. It is known that the rapidly dividing cells express free sulfhydryl groups on the membrane surfaces that can undergo disulfide exchange reactions with thiols of other biomolecules. Under physiological conditions sulfhydryl groups of circulating plasma proteins are engaged in the intramolecular disulfide bridges and are not available for the exchange. However, in neoplastic diseases, particularly in the prostate cancer, such an exchange reaction takes place between fibrinogen and human serum albumin resulting in the formation of a fibrin-like aggregate. A characteristic feature of such an insoluble aggregate is its remarkable resistance to proteolytic degradation not only by plasmin but by active lysosomal proteases as well. As a consequence prostate cancer cells accrue a protective coat of 'self' proteins that is not recognizable by the body's immune system. Moreover, even if some of the unmasked tumor antigens do elicit immune response, the fibrin coat is refractive to degradation by the proteases released by natural killer cells. Consequently, in order to achieve successful immunotherapy the protective barrier of disulfide crosslinked fibrinogen-albumin complex has to be first eliminated. This can be done by the pretreatment with four-valent sodium selenite but not with other chemical forms of selenium. Selenite oxidizes thiols of the tumor cell membranes to disulfides thus making them unavailable for the exchange reaction with partially reduced plasma proteins. Although selenite is known to be toxic to humans when given orally, its body's concentration can be safely increased by the parenteral administration. In conclusion, specific chemical properties of sodium selenite warrant its careful evaluation as a potential improvement of the efficacy of prostate cancer vaccines thus contributing to the reduction of mortality of this deadly form of cancer.