Chinje E C, Williams K J, Telfer B A, Wood P J, van der Kogel A J, Stratford I J
Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Br J Cancer. 2002 Jan 7;86(1):136-42. doi: 10.1038/sj.bjc.6600032.
The putative oestrogen receptor negative human breast cancer cell line MDA231, when grown as tumours in mice continually receiving 17beta-oestradiol, showed substantially increased growth rate when compared to control animals. Further, we observed that 17beta-oestradiol treatment could both increase the growth rate of established MDA231 tumours as well as decreasing the time taken for initiating tumour growth. We have also demonstrated that this increase in growth rate is accompanied by a four-fold increase in nitric oxide synthase activity, which was predominantly the inducible form. Inducible-nitric oxide synthase expression in these tumours was confirmed by immunohistochemical analysis and appeared localized primarily in areas between viable and necrotic regions of the tumour (an area that is presumably hypoxic). Prophylactic treatment with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester resulted in significant reduction in this apparent 17beta-oestradiol-mediated growth promoting effect. Tumours derived from mice receiving 17beta-oestradiol-treatment were characterized by a significantly lower fraction of perfused blood vessels and an indication of an increased hypoxic fraction. Consistent with these observations, 17beta-oestradiol-treated tumours were less radio-responsive compared to control tumours when treated with a single radiation dose of 15 Gy. Our data suggests that long-term treatment with oestrogen could significantly alter the tumour oxygenation status during breast tumour progression, thus affecting response to radiotherapy.
假定的雌激素受体阴性人乳腺癌细胞系MDA231，当在持续接受17β-雌二醇的小鼠体内长成肿瘤时，与对照动物相比，其生长速率显著增加。此外，我们观察到17β-雌二醇处理既能提高已形成的MDA231肿瘤的生长速率，又能缩短肿瘤开始生长所需的时间。我们还证明，这种生长速率的增加伴随着一氧化氮合酶活性增加四倍，且主要是诱导型。通过免疫组织化学分析证实了这些肿瘤中诱导型一氧化氮合酶的表达，且主要定位于肿瘤的存活区和坏死区之间的区域（一个可能缺氧的区域）。用一氧化氮合酶抑制剂硝基-L-精氨酸甲酯进行预防性处理，可显著降低这种明显的17β-雌二醇介导的生长促进作用。接受17β-雌二醇处理的小鼠所产生的肿瘤，其特征是灌注血管的比例显著降低，且缺氧比例增加。与这些观察结果一致，当用15 Gy的单次辐射剂量处理时，17β-雌二醇处理的肿瘤与对照肿瘤相比，对辐射的反应性较低。我们的数据表明，长期雌激素治疗可能会在乳腺肿瘤进展过程中显著改变肿瘤的氧合状态，从而影响放疗反应。
