The objective of this proposal is to test the effects on tumor growth and normal physiology of active immunization and passive immunization to transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF). This proposal is an extension of work which I have done which has shown that active immunization with LHRH-foreign protein conjugates results in active-immunity to LHRH, a perturbation of the hormonal milieu, and an inhibition of the growth of DMBA induced mammary tumors in the rat. Can this strategy of active immunization to endogenous peptides be used to inhibit the growth of autocrine peptide dependent tumors? Active immunization with beta-HCG conjugated to tetanus toxoid has been used successfully in human contraception trials. Passive immunization to endogenous peptides has been used in exploring the role of bombesin (gastrin releasing peptide) in the autocrine stimulation of the growth of human lung cancers, and in demonstrating the role of nerve growth factor (NGF), in the development and maintenance of the sympathetic nervous system. In the initial stages of the work, the ability to achieve in rodents consistently high immunoneutralizing titers of antibodies to TGF-alpha and EGF will be assessed. The immunogens to be used will be intact endogenous growth factors, as well as peptide fragments from them, conjugated to foreign proteins. Because passive immunization has some potential advantages in some situations, the stage will also be set for studies of passive immunization, by using lymphocytes from some of the actively immunized animals for preparation of monoclonal antibodies. The central part of the work will then be to observe in rodents the effects of active and passive immunization to growth factors on tumor growth and normal physiology. Two of the hypothesis to be tested are that: 1) TGF-alpha plays an important role in tumor progression, and 2) EGF, but not TGF-alpha, plays an important role in normal adult physiology. This work will provide a foundation for studies of active and passive immunization to TGF-alpha, and potentially other peptide hormones, as a strategy for treatment of cancer in humans.
