Zagon I S, Hytrek S D, McLaughlin P J
Department of Neuroscience and Anatomy, Pennsylvania State University, College of Medicine, Hershey 17033, USA.
Am J Physiol. 1996 Sep;271(3 Pt 2):R511-8. doi: 10.1152/ajpregu.1996.271.3.R511.
Native opioid peptides serve as growth factors in a number of normal and neoplastic cells and tissues, including the prevention and delayed growth of human colon cancer xenografts in nude mice. This study examined the hypothesis that opioids exert a direct inhibitory influence on tumor cell growth by the use of a tissue culture model. The naturally occurring pentapeptide [Met5]enkephalin depressed growth of HT-29 human colon cancer cells from 17 to 41% at 12-72 h after administration of 10(-6)M concentration; consistent with previously defined nomenclature, this peptide was termed opioid growth factor (OGF). OGF action exhibited a dose-response relationship, was reversible and not cytotoxic, and was opioid receptor mediated. Growth inhibition by OGF was not dependent on serum, and was noted in the two other human colon cancer cell lines examined WiDr and COLO 205. This peptide continually repressed growth because an increase in cell number was noted when cells were exposed to the potent opioid antagonist naltrexone or an antibody to OGF. Both OGF and its receptor, zeta (zeta), were found in colon cancer cells by immunocytochemistry, and receptor binding assays revealed a nuclear-associated receptor with a dissociation constant of 8.9 nM and a maximum binding capacity of 43 fmol/mg of protein. OGF was produced and secreted by the tumor cells. These results lead to the suggestion that OGF has a direct, tonic, inhibitory action on the growth of human colon cancer cells and contribute to our understanding of the mechanisms underlying the marked antitumor effect of this peptide in nude mice inoculated with human colon cancer cells.
内源性阿片肽在许多正常和肿瘤细胞及组织中作为生长因子发挥作用，包括对裸鼠体内人结肠癌异种移植瘤生长的预防和延缓。本研究通过使用组织培养模型检验了阿片类物质对肿瘤细胞生长有直接抑制作用这一假说。天然存在的五肽[Met5]脑啡肽在给予10(-6)M浓度后12 - 72小时，使HT - 29人结肠癌细胞的生长降低了17%至41%；根据先前定义的命名法，该肽被称为阿片生长因子（OGF）。OGF的作用呈现剂量反应关系，是可逆的且无细胞毒性，并且是由阿片受体介导的。OGF对生长的抑制不依赖于血清，在另外两种检测的人结肠癌细胞系WiDr和COLO 205中也观察到了这种抑制作用。当细胞暴露于强效阿片拮抗剂纳曲酮或抗OGF抗体时，细胞数量增加，这表明该肽持续抑制生长。通过免疫细胞化学在结肠癌细胞中发现了OGF及其受体ζ（zeta），受体结合试验显示存在一种与细胞核相关的受体，其解离常数为8.9 nM，最大结合容量为43 fmol/mg蛋白质。OGF由肿瘤细胞产生并分泌。这些结果表明OGF对人结肠癌细胞的生长具有直接、持续性的抑制作用，并有助于我们理解该肽在接种人结肠癌细胞的裸鼠中显著抗肿瘤作用的潜在机制。
