GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426, USA.
BMC Cancer. 2012 Sep 11;12:405. doi: 10.1186/1471-2407-12-405.
Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R) agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues.
Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and for TPO-R protein expression by immunohistochemistry (IHC). Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot.
MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43%) and malignant (3-17%) breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines.
Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and megakaryocyte precursors.
许多有效的化疗方案可能导致血小板减少症。血小板生成素受体 (TPO-R) 激动剂，如艾曲波帕，代表了治疗化疗诱导的血小板减少症的一种新方法。TPO-R MPL 表达于巨核细胞和巨核细胞前体，但对其在其他组织中的表达知之甚少。
通过微阵列和/或定量逆转录聚合酶链反应 (qRT-PCR) 分析乳腺癌、肺癌和卵巢肿瘤样本的 MPL 表达，并通过免疫组织化学 (IHC) 分析 TPO-R 蛋白表达。细胞系增殖测定用于分析艾曲波帕对乳腺癌、肺癌和卵巢肿瘤细胞增殖的体外影响。还通过 Western blot 分析肺癌细胞系的 TPO-R 蛋白表达。
微阵列分析未在 118 例乳腺癌肿瘤中检测到 MPL mRNA，在 29 例研究的肺癌肿瘤中仅在 48%的肿瘤中检测到很低水平的 MPL mRNA。通过 qRT-PCR，在一些正常（14-43%）和恶性（3-17%）的乳腺、肺和卵巢组织中可检测到低但可检测到的 MPL mRNA 水平。将 MPL 与 EPOR、ERBB2 和 IGF1R mRNA 进行比较表明，在相同组织中，MPL mRNA 水平远低于 EPOR 和 ERBB2 mRNA 水平。IHC 分析显示肿瘤组织中 TPO-R 蛋白表达可忽略不计，这与 mRNA 分析结果一致。乳腺癌、肺癌和卵巢癌细胞系的培养显示，在与艾曲波帕孵育后，增殖没有增加，实际上减少了。Western blot 分析显示肺癌细胞系中未检测到 TPO-R 蛋白表达。
对乳腺癌、肺癌和卵巢肿瘤样本和/或细胞系进行的多项分析均未显示 MPL mRNA 或 TPO-R 蛋白表达的证据。艾曲波帕在可能对巨核细胞和巨核细胞前体发挥作用的剂量下，不会刺激乳腺癌、肺癌或卵巢肿瘤细胞系的生长。
