The laboratory has been investigating the role of endogenous cytokines as potential mediators of clinical conditions that are important in the management of cancer patients. In addition the laboratory has been evaluating the efficacy of tumor necrosis factor (TNF), hyperthermia, and chemotherapy in the treatment of cancer. The laboratory has characterized the contribution of D-factor, also known as leukemia inhibitory factor, in acute and chronic inflammatory conditions. We have shown that passive immunization against D-factor will improve survival time in mice subjected to a clinically relevant model of gram negative sepsis, cecal ligation and puncture (CLP). Circulating D-f actor levels have been detected in mice after CLP and following passive immunization against D-factor serum IL-6 levels in septic mice are markedly attenuated suggesting that the salutory effect of the D-factor antibody may be related to modulation of other inflammatory mediators. The laboratory has also identified D-factor as a potentially important tumor product that may mediate deleterious effects in the cancer bearing host. In vitro co-cultivation of murine or human tumors with macrophages or monocytes from the same species will result in an increase in D-factor and IL-6 production by tumor. This tumor activation by inflammatory host cells appears to be mediated by TNF or IL-1. In vitro we have shown that D-factor and TNF act synergistically to inhibit lipoprotein lipase (LPL) activity in adipocytes which is one of the fundamental metabolic alterations present in cancer cachexia. Together these findings indicate that critical cellular interactions between a tumor and infiltrating host cells may result in augmented cytokine levels that are deleterious to the host. The laboratory has also evaluated the cytotoxic effects of TNF, cisplatin, and hyperthermia against gastrointestinal cell lines. TNF markedly augments the cytotoxic effects of platinum against these cell lines and is associated with an increase platinum levels in tumor DNA. The synergistic interaction occurs at relatively brief exposure intervals, a level of hyperthermia, and concentrations of TNF and cisplatin that can be achieved clinically. These experiments have provided the preclinical basis for current ongoing clinical trials in the Surgery Branch.
