Nettesheim P, Barrett J C, Mass M J, Steele V E, Gray T E
IARC Sci Publ. 1984(56):109-27.
Studies were carried out to examine the susceptibility of normal and initiated tracheal epithelial cells of rats to known tumour-promoting agents. The ability of normal rat tracheal epithelial cells to form colonies in cultures was enhanced markedly by addition of known tumour promoters to the medium. Several retinoids were shown to reduce the ability of these cells to form colonies in culture and to inhibit this effect of 12-O-tetradecanoylphorbol-13-acetate (TPA). A transformation assay of tracheal epithelial cells was used to study promotional effects of TPA in cultures initiated with N-methyl-N'-nitro-N-nitrosoguanidine. In this assay, four stages of transformation are recognized. TPA did not affect measurably the first two transformation stages, i.e., the development of transformed colonies (enhanced growth variants) and the 'immortalization' of enhanced growth variant-derived subcultures. However, treatment of cultures with TPA during the early post-initiation period resulted in a marked enhancement of the appearance of the third transformed phenotype, which is characterized by anchorage independence of growth. The findings of these in-vitro initiation-promotion studies paralleled, in all major respects, the results obtained in in-vivo - in-vitro studies. Tracheas exposed in vivo to initiator and promoter were shown to develop the same transformants observed in the in-vitro assay. TPA affected primarily the late anchorage-independence phenotype. Parallel tumour induction studies showed that TPA increased markedly the incidence of tracheal carcinomas following initiation with a low dose of 7,12-dimethylbenz[a]anthracene. The studies thus demonstrate that TPA is an effective tumour promoter for rat tracheal epithelium, causing an increase in tracheal carcinomas. They further suggest that the action of TPA on an early transformed cellular phenotype enhances the development of later phenotypes, including neoplastic cell variants.
开展了多项研究，以检测大鼠正常和已启动的气管上皮细胞对已知肿瘤促进剂的敏感性。向培养基中添加已知的肿瘤促进剂后，正常大鼠气管上皮细胞在培养物中形成集落的能力显著增强。结果表明，几种类视黄醇可降低这些细胞在培养物中形成集落的能力，并抑制12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）的这种作用。采用气管上皮细胞转化试验来研究TPA对用N - 甲基 - N'- 硝基 - N - 亚硝基胍启动的培养物的促进作用。在该试验中，可识别出转化的四个阶段。TPA对前两个转化阶段没有明显影响，即转化集落（生长增强变体）的形成以及生长增强变体衍生的亚培养物的“永生化”。然而，在启动后的早期阶段用TPA处理培养物，会导致第三种转化表型的出现显著增加，其特征是生长不依赖贴壁。这些体外启动 - 促进研究的结果在所有主要方面都与体内 - 体外研究获得的结果相似。体内暴露于启动剂和促进剂的气管显示出与体外试验中观察到的相同转化体。TPA主要影响后期不依赖贴壁的表型。平行的肿瘤诱导研究表明，TPA显著增加了低剂量7,12 - 二甲基苯并[a]蒽启动后气管癌的发生率。因此，这些研究表明TPA是大鼠气管上皮的一种有效肿瘤促进剂，可导致气管癌增加。它们进一步表明，TPA对早期转化细胞表型的作用会增强后期表型的发展，包括肿瘤细胞变体。
