Effects of recombinant neutral endopeptidase (EC 3.4.24.11) on the growth of lung cancer cell lines in vitro and in vivo

Clin Cancer Res. 1998 Nov;4(11):2849-58.

Abstract

Many lung cancers are stimulated by an autocrine/paracrine system of neuroendocrine peptide hormones. Attempts to block this autocrine growth pathway by interactions with specific ligand-receptor binding using monoclonal antibodies and peptide-specific antagonists have been largely 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 role in degrading biologically active peptides, including all peptides implicated in autocrine growth stimulation of lung cancer. Cigarette smoke decreases the activity of NEP, indicating that the lack of NEP contributes to the dysregulation of the peptide autocrine system. The cloning of the human NEP gene allowed for production of sufficient quantities of recombinant NEP (rNEP) to evaluate its role in inhibiting the growth of lung cancer cells. In this study, we evaluated the ability of rNEP to inactivate the peptides involved in lung cancer signal transduction and to inhibit the growth of lung cancer cells as well as normal lung cells in vitro and in vivo in athymic nude mice. We showed that the growth inhibition of lung cancer cells by rNEP was related to the dose and schedule. Continuous exposure to high doses was required for growth inhibition. These studies confirm the importance of NEP in this autocrine pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / pathology
  • Cell Division / drug effects
  • Cell Line
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects
  • Humans
  • Lung / drug effects
  • Lung / pathology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neprilysin / biosynthesis
  • Neprilysin / metabolism
  • Neprilysin / therapeutic use*
  • Neuropeptides / metabolism
  • Neuropeptides / pharmacology
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured

Substances

  • Neuropeptides
  • Recombinant Proteins
  • Neprilysin