Bunn P A, Helfrich B A, Brenner D G, Chan D C, Dykes D J, Cohen A J, Miller Y E
Division of Medical Oncology, University of Colorado Cancer Center, Denver 80262, USA.
Clin Cancer Res. 1998 Nov;4(11):2849-58.
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.
许多肺癌是由神经内分泌肽激素的自分泌/旁分泌系统刺激引起的。由于激素产生和受体表达的异质性，试图通过使用单克隆抗体和肽特异性拮抗剂与特定配体-受体结合来阻断这种自分泌生长途径的尝试大多未成功。在正常肺组织中，中性内肽酶（NEP；CD10、CALLA、脑啡肽酶和EC 3.4.24.11）在降解生物活性肽方面发挥生理作用，这些生物活性肽包括所有与肺癌自分泌生长刺激有关的肽。香烟烟雾会降低NEP的活性，这表明NEP的缺乏导致了肽自分泌系统的失调。人NEP基因的克隆使得能够生产足够数量的重组NEP（rNEP），以评估其在抑制肺癌细胞生长中的作用。在本研究中，我们评估了rNEP使参与肺癌信号转导的肽失活以及在体外和无胸腺裸鼠体内抑制肺癌细胞以及正常肺细胞生长的能力。我们发现rNEP对肺癌细胞的生长抑制与剂量和给药方案有关。需要持续高剂量暴露才能抑制生长。这些研究证实了NEP在这条自分泌途径中的重要性。
