The primary goal of this study is to develop new therapies for the treatment of squamous cell carcinoma of the head and neck (SCCHN) which exploit the production of prostaglandins (PG) and other arachidonic acid (AA) metabolites by squamous cell carcinoma.
Specific aims are: 1) to determine the prognostic significance of PG production in SCCHN, 2) to determine the mechanism of immunosuppression by SCCHN, 3) to demonstrate the effectiveness and mechanism of anti-PG therapy in the treatment of SCCHN. The establishment of in vitro cultures of SCCHN and the development of a suitable animal model enable us to pursue these aims. We anticipate that investigations of PG production by cultured SCCHN in vitro and the development of new therapeutic approaches in an animal model will lead directly to innovative clinical trials in our patient population. PGE2, a major metabolite of PG, has been implicated as an immunosuppressive factor in patients with SCCHN. PGE2 has been demonstrated to have multiple immunosuppressive effects in vitro and in animal models which are reversible with PG inhibitors such as indomethacin (INDO). Elevated PG levels have been noted in tumor tissues of patients with SCCHN. Although PG are produced by monocytes/macrophages, the source of the inhibitory PG is not entirely clear. Our studies, employing in vitro cultures of SCCHN, have demonstrated that SCCHN are a significant source of PGE2, and that the tumor supernatant markedly inhibits lymphocyte proliferation and LAK cell generation, and that PGE2 production is associated with an increased incidence of cervical metastases (P = 0.03). The goals of this proposal will be achieved using SCCHN cultures as a model for the production of PG by tumor cells. Levels of PGE2 in tumor supernatant will be determined by radioimmunoassay (RIA) and be used to determine the prognostic significance of elevated PG production in SCCHN. The source of PG will be investigated by separating tumor-infiltrating lymphocytes from fresh tumor biopsies and measuring PGE2 production. Mechanisms of immunosuppression by SCCHN will be investigated in vitro using the cell lines. Tumors derived from SCCHN cultures using immunocompromised and immunocompetent mouse models will allow us to investigate the effectiveness and mechanism of action of therapy directed against PG production. If significant tumor inhibition with PG inhibitors is demonstrated, possible synergism of PG inhibitors and biologic response modifiers (IL1, IL2) will be investigated using this model.
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