Product Research Department, Chugai Pharmaceuticals Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
Cancer Chemother Pharmacol. 2010 Jul;66(2):269-76. doi: 10.1007/s00280-009-1160-0. Epub 2009 Nov 11.
The clinical relevance of prolonged trastuzumab administration in combination therapy beyond progressive disease (PD) has been suggested. Here, we examined whether trastuzumab treatment is effective in combination after failing to show antitumor activity as monotherapy in HER2-positive human breast cancer xenograft models.
We established trastuzumab PD models with HER2-positive breast cancer xenograft models and compared the antitumor activity of trastuzumab in combination with a taxane versus monotherapy with a taxane in the models subsequent to tumor progression under trastuzumab monotherapy.
We established trastuzumab PD model using the HER2-positive human breast cancer line MDA-MB-361 and KPL-4 in in vivo. In these models, trastuzumab at the same dose as the initial treatment showed no significant antitumor activity at 3 weeks after start of treatment. Re-inoculated tumor tissues showing PD regained sensitivity to trastuzumab. In the trastuzumab PD models, the HER2 status of the tumor tissues did not decrease. Also, the pAKT level continued to decrease, as with the initial treatment, and IGF-1R was not found to be up-regulated. Instead, differences were observed in the gene-expression profiles of the tumor tissues showing PD. Trastuzumab in combination with G-CSF, which is expected to enhance antibody-dependent cellular cytotoxicity (ADCC), showed significant antitumor activity, even though the single agents alone showed no antitumor activity in the PD model. In the MDA-MB-361 trastuzumab PD model, the combination of trastuzumab with paclitaxel showed significantly more potent antitumor activity compared with paclitaxel or docetaxel monotherapy. In the KPL-4 trastuzumab PD model as well, trastuzumab showed significant antitumor activity in combination with taxanes or capecitabine after PD had developed in response to trastuzumab monotherapy.
We established in vivo trastuzumab PD models, in which trastuzumab monotherapy ceases to have antitumor activity during the treatment. The mechanisms of PD with trastuzumab are considered to involve both reversible changes in the gene expression profiles in tumor tissues and a decrease of ADCC activity in the host. Our present results demonstrated that trastuzumab showed antitumor activity in combination with taxanes or capecitabine even though it showed no antitumor activity as a monotherapy, suggesting a clinical relevance of treatment with trastuzumab as a combination therapy beyond PD.
有研究表明，曲妥珠单抗联合治疗中在疾病进展（PD）后继续应用曲妥珠单抗具有临床意义。在这里，我们研究了在曲妥珠单抗单药治疗作为单一药物治疗后显示出抗肿瘤活性的 HER2 阳性人乳腺癌异种移植模型中，曲妥珠单抗联合治疗是否有效。
我们建立了曲妥珠单抗 PD 模型，使用 HER2 阳性乳腺癌异种移植模型，并比较了在曲妥珠单抗单药治疗后肿瘤进展时，曲妥珠单抗联合紫杉醇与紫杉醇单药治疗的抗肿瘤活性。
我们在体内使用 HER2 阳性人乳腺癌 MDA-MB-361 细胞系和 KPL-4 建立了曲妥珠单抗 PD 模型。在这些模型中，曲妥珠单抗在初始治疗相同剂量下，在治疗开始后 3 周时没有显著的抗肿瘤活性。重新接种 PD 肿瘤组织恢复对曲妥珠单抗的敏感性。在曲妥珠单抗 PD 模型中，肿瘤组织的 HER2 状态没有下降。此外，pAKT 水平持续下降，与初始治疗相同，并且没有发现 IGF-1R 上调。相反，在显示 PD 的肿瘤组织的基因表达谱中观察到差异。曲妥珠单抗与 G-CSF 联合使用，有望增强抗体依赖性细胞毒性（ADCC），显示出显著的抗肿瘤活性，即使单药在 PD 模型中没有抗肿瘤活性。在 MDA-MB-361 曲妥珠单抗 PD 模型中，与紫杉醇单药或多西他赛单药相比，曲妥珠单抗与紫杉醇联合具有更强的抗肿瘤活性。在 KPL-4 曲妥珠单抗 PD 模型中，曲妥珠单抗单药治疗后出现 PD 时，与紫杉醇或卡培他滨联合使用也显示出显著的抗肿瘤活性。
我们建立了曲妥珠单抗 PD 模型，在该模型中，曲妥珠单抗单药治疗在治疗过程中停止具有抗肿瘤活性。曲妥珠单抗 PD 的机制被认为既涉及肿瘤组织中基因表达谱的可逆变化，也涉及宿主 ADCC 活性的降低。我们的研究结果表明，即使作为单一药物治疗时没有抗肿瘤活性，曲妥珠单抗与紫杉醇或卡培他滨联合使用也具有抗肿瘤活性，提示曲妥珠单抗联合治疗在 PD 后具有临床意义。
