Koukourakis Michael I, Simopoulos Constantinos, Polychronidis Alexandros, Perente Sebach, Botaitis Sotirios, Giatromanolaki Alexandra, Sivridis Efthimios
Departments of Radiotherapy-Oncology, Surgery and Pathology, Democritus University of Thrace, Medical School, Alexandroupolis 68100, Greece.
Anticancer Res. 2003 Mar-Apr;23(2C):1673-80.
In this study we describe and discuss the dichotomous effects of docetaxel trastuzumab (Herceptin)/docetaxel therapy on the angiogenic molecular profile in two patients with her-2 + chemo-resistant recurrent breast carcinoma. In the first case, an intensification of angiogenesis occurred following therapy, accompanied by an impressive increase of the cancer cell proliferation index. This tumor did not express HIF1 alpha and shared a HIF-independent VEGF overexpression, which remained unaffected by therapy. An intensified formation of thymidine phosphorylase (TP)-rich stroma, presumably a response to docetaxel, shows a TP-dependent angiogenic response. In the second patient, VEGF and HIF1 alpha were down-regulated in post-treatment biopsies and this was accompanied by a sharp reduction of the vascular density and of the cancer cell proliferation rate. In both cases, c-erbB-2 expression was abrogated by Herceptin. Taking into account that Herceptin down-regulates VEGF through reduction of HIF1 alpha synthesis, this clinical study provides evidence that an anti-angiogenic effect from Herceptin/Docetaxel therapy is expected only in tumors with HIF1 alpha-dependent VEGF overexpression. In contrast, HIF1 alpha-independent VEGF angiogenic activity cannot be abrogated by Herceptin. Docetaxel mediated up-regulation of TP in the tumoral stroma may, on the contrary, result in angiogenesis intersification and rapid tumor relapse. Such an effect should be of clinical importance since Herceptin/Docetaxel-based regimens are currently evaluated for the adjuvant therapy of her-2 + breast cancer patients. Studying the Herceptin-induced phenotypic changes of tumors could lead to the identification of specific molecular profiles that bring about diverging angiogenic responses. Adjustment of the chemotherapy regimen accordingly would prove of clinical importance.
在本研究中，我们描述并讨论了多西他赛联合曲妥珠单抗（赫赛汀）/多西他赛疗法对两名her-2阳性化疗耐药复发性乳腺癌患者血管生成分子谱的二分效应。在第一个病例中，治疗后血管生成增强，同时癌细胞增殖指数显著增加。该肿瘤不表达HIF1α，具有不依赖HIF的VEGF过表达，且不受治疗影响。富含胸苷磷酸化酶（TP）的基质强化形成，推测是对多西他赛的反应，显示出TP依赖性血管生成反应。在第二个患者中，治疗后活检中VEGF和HIF1α下调，同时血管密度和癌细胞增殖率急剧降低。在这两个病例中，赫赛汀均消除了c-erbB-2表达。考虑到赫赛汀通过减少HIF1α合成来下调VEGF，这项临床研究提供了证据，表明仅在具有HIF1α依赖性VEGF过表达的肿瘤中，赫赛汀/多西他赛疗法才有望产生抗血管生成作用。相反，赫赛汀无法消除不依赖HIF1α的VEGF血管生成活性。相反，多西他赛介导的肿瘤基质中TP上调可能导致血管生成增强和肿瘤快速复发。由于目前正在评估基于赫赛汀/多西他赛的方案用于her-2阳性乳腺癌患者的辅助治疗，这种效应应具有临床重要性。研究赫赛汀诱导的肿瘤表型变化可能会导致识别出引起不同血管生成反应的特定分子谱。相应地调整化疗方案将具有临床重要性。
