Schaefer F V, Tonelli Q J, Dickens M S, Custer R P, Sorof S
Cancer Res. 1983 Jul;43(7):3310-5.
Treatment of mouse mammary glands with a high concentration of 7,12-dimethylbenzo(a)anthracene in whole organ culture was reported by Banerjee et al. to transform foci of lobuloalveoli to a hormone-independent state, and to give rise to mammary hyperplastic outgrowths and adenocarcinomas in vivo. In the present study using the identical system, mammary glands of BALB/c mice were exposed to 7,12-dimethylbenzo(a)anthracene or N-2-fluorenylacetamide at low concentrations that bring about maximal incidences of the hormone-independent hyperplastic lobuloalveolar lesions with minimal cytotoxicity. After morphological development of the lobuloalveoli in culture, the glands were enzymatically dissociated into cells and inoculated into gland-free inguinal mammary fat pads of syngeneic mice bearing pituitary gland implants during the initial 8 weeks. After 11 months, fragments of the resultant mammary outgrowths from each mouse were implanted into the gland-free inguinal mammary fat pads of 3 syngeneic mice (not bearing pituitary gland supplements) and were permitted to grow for another 11 months. Mammary outgrowths from the primary and secondary implants were neither neoplastic, anaplastic, nor dysplastic. Also, no hyperplasia in any mammary outgrowth could be attributed to the action of either carcinogen, especially when outgrowths were compared with contralateral outgrowths that arose from the control glands exposed to dimethyl sulfoxide (solvent of the carcinogens) in culture and/or with untreated thoracic mammary glands of the same hosts. One interpretation of these findings is that the hormone-independent, hyperplastic alveolar lesions may not be an appropriate in vitro marker of oncogenic transformation by chemical carcinogens in culture. The great variety of procarcinogens and activated carcinogens that bring about this lesion in vitro and its morphological similarity to presumptive mammary preneoplastic lesions in vivo weigh against this interpretation. A second hypothesis is that high concentrations of procarcinogens, despite their considerable cytotoxicity, complete a multistep process of oncogenic transformation in surviving mammary epithelium, whereas low concentrations optimized to produce the lesions in maximal number do not.
Banerjee等人报告称，在全器官培养中用高浓度的7,12-二甲基苯并(a)蒽处理小鼠乳腺，可使小叶腺泡灶转变为激素非依赖状态，并在体内引发乳腺增生性赘生物和腺癌。在本研究中，使用相同的系统，将BALB/c小鼠的乳腺暴露于低浓度的7,12-二甲基苯并(a)蒽或N-2-芴基乙酰胺，这些低浓度物质能在细胞毒性最小的情况下使激素非依赖型增生性小叶腺泡病变的发生率达到最高。在培养中小叶腺泡完成形态发育后，将腺体酶解成细胞，并接种到在最初8周内植入了垂体的同基因小鼠的无腺体腹股沟乳腺脂肪垫中。11个月后，将每只小鼠产生的乳腺赘生物碎片植入3只同基因小鼠（未植入垂体补充物）的无腺体腹股沟乳腺脂肪垫中，并使其再生长11个月。来自初次和二次植入的乳腺赘生物既不是肿瘤性的、间变的，也不是发育异常的。此外，任何乳腺赘生物中的增生都不能归因于任何一种致癌物的作用，尤其是当将赘生物与在培养中暴露于二甲基亚砜（致癌物的溶剂）的对照腺体产生的对侧赘生物和/或与同一宿主未经处理的胸部乳腺进行比较时。对这些发现的一种解释是，激素非依赖型增生性肺泡病变可能不是化学致癌物在培养中致癌转化的合适体外标志物。在体外导致这种病变的多种前致癌物和活化致癌物及其与体内假定的乳腺癌前病变的形态相似性与这种解释相悖。第二种假设是，高浓度的前致癌物尽管具有相当大的细胞毒性，但能在存活的乳腺上皮细胞中完成致癌转化的多步骤过程，而优化以产生最大数量病变的低浓度前致癌物则不能。
