Spratlin Jennifer, Sangha Randeep, Glubrecht Darryl, Dabbagh Laith, Young James D, Dumontet Charles, Cass Carol, Lai Raymond, Mackey John R
University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
Clin Cancer Res. 2004 Oct 15;10(20):6956-61. doi: 10.1158/1078-0432.CCR-04-0224.
Gemcitabine monotherapy is the standard palliative chemotherapy for pancreatic adenocarcinoma. Gemcitabine requires plasma membrane nucleoside transporter proteins to efficiently enter cells and exert it cytotoxicity. In vitro studies have demonstrated that deficiency of human equilibrative nucleoside transporter 1 (hENT1), the most widely abundant and distributed nucleoside transporter in human cells, confers resistance to gemcitabine toxicity, but the distribution and abundance of nucleoside transporters in normal and malignant pancreatic tissue is unknown.
We studied tumor blocks from normal pancreas and 21 Alberta patients with gemcitabine-treated pancreatic cancer. Immunohistochemistry on the formalin-fixed, paraffin-embedded tissues was performed with specific hENT1 and human Concentrative Nucleoside Transporter 3 monoclonal antibodies and scored by a pathologist blinded to clinical outcomes.
hENT1 was detected in normal Langerhan cells and lymphocytes but not in normal glandular elements. Patients in whom all adenocarcinoma cells had detectable hENT1 had significantly longer median survivals from gemcitabine initiation than those for whom hENT1 was absent in a proportion (10 to 100%) of adenocarcinoma cells (median survival, 13 versus 4 months, P = 0.01). Immunohistochemistry for human Concentrative Nucleoside Transporter 3 revealed moderate to high-intensity staining in all adenocarcinoma tissue samples.
Patients with pancreatic adenocarcinoma with uniformly detectable hENT1 immunostaining have a significantly longer survival after gemcitabine chemotherapy than tumors without detectable hENT1. Immunohistochemistry for hENT1 shows promise as a molecular predictive assay to appropriately select patients for palliative gemcitabine chemotherapy but requires formal validation in prospective, randomized trials.
吉西他滨单药治疗是胰腺腺癌的标准姑息化疗方法。吉西他滨需要通过质膜核苷转运蛋白才能有效进入细胞并发挥其细胞毒性作用。体外研究表明，人平衡核苷转运体1（hENT1）是人类细胞中分布最广泛且含量最多的核苷转运体，其缺乏会导致对吉西他滨毒性产生耐药性，但核苷转运体在正常胰腺组织和胰腺恶性肿瘤组织中的分布及含量尚不清楚。
我们研究了来自正常胰腺的肿瘤组织块以及21例接受吉西他滨治疗的艾伯塔省胰腺癌患者的肿瘤组织块。对福尔马林固定、石蜡包埋的组织进行免疫组织化学检测，使用特异性hENT1和人浓缩核苷转运体3单克隆抗体，并由对临床结果不知情的病理学家进行评分。
在正常朗格汉斯细胞和淋巴细胞中检测到hENT1，但在正常腺细胞成分中未检测到。所有腺癌细胞均能检测到hENT1的患者，从开始使用吉西他滨起的中位生存期明显长于部分（10%至100%）腺癌细胞中不存在hENT1的患者（中位生存期分别为13个月和4个月，P = 0.01）。人浓缩核苷转运体3的免疫组织化学检测显示，所有腺癌组织样本均有中度至高强度染色。
胰腺腺癌患者中，hENT1免疫染色均能检测到的患者在接受吉西他滨化疗后的生存期明显长于hENT1检测不到的肿瘤患者。hENT1免疫组织化学检测有望作为一种分子预测检测方法，用于合理选择适合接受吉西他滨姑息化疗的患者，但需要在前瞻性随机试验中进行正式验证。
