EFFECTS OF RECOMBINANT NEUTRAL ENDOPEPTIDASE (EC 3.4.24.11) ON THE GROWTH OF LUNG-CANCER CELL-LINES IN-VITRO AND IN-VIVO

Many lung cancers are stimulated by an autocrine/paracrine system of n euroendocrine peptide hormones. Attempts to block this autocrine growt h pathway by interactions with specific ligand-receptor binding using monoclonal antibodies and peptide-specific antagonists have been large ly unsuccessful because of the heterogeneity of hormone production and receptor expression. In the normal lung, neutral endopeptidase (NEP; CD10, CALLA, enkephalinase, and EC 3.4.24.11) plays a physiological ro le in degrading biologically active peptides, including all peptides i mplicated in autocrine growth stimulation of lung cancer. Cigarette sm oke decreases the activity of NEP, indicating that the lack of NEP con tributes to the dysregulation of the peptide autocrine system. The clo ning of the human NEP gene allowed for production of sufficient quanti ties of recombinant NEP (rNEP) to evaluate its role in inhibiting the growth of lung cancer cells. In this study, we evaluated the ability o f rNEP to inactivate the peptides involved in lung cancer signal trans duction and to inhibit the growth of lung cancer cells as well as norm al lung cells in vitro and in vivo in athymic nude mice. We showed tha t the growth inhibition of lung cancer cells by rNEP was related to th e dose and schedule. Continuous exposure to high doses was required fo r growth inhibition. These studies confirm the importance of NEP in th is autocrine pathway.