Crane Christopher H, Mason Kathy, Janjan Nora A, Milas Luka
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Am J Clin Oncol. 2003 Aug;26(4):S81-4. doi: 10.1097/00000421-200308002-00009.
Pancreatic cancer is a lethal disease that is resistant to chemotherapy and radiotherapy. Gemcitabine has recently been shown to be an improvement over 5-fluorouracil in patients with advanced disease. It is also a potent radiosensitizer, which has led to the investigation of gemcitabine with concurrent radiotherapy. However, preliminary results indicate that there are significant limitations to this approach in this challenging disease. Pancreatic cancer cells have alterations in many molecular signaling pathways that may be responsible for their resistance to cytotoxic therapy and aggressive behavior. Cyclooxygenase-2 (COX-2) is commonly overexpressed in pancreatic tumors, and preclinical evidence indicates that selective COX-2 inhibition enhances both chemotherapy and radiotherapy response, without affecting normal tissue damage. We have initiated preclinical studies as well as a phase I clinical protocol evaluating the combination of gemcitabine and celecoxib (Celebrex) with radiotherapy. In preclinical studies, celecelecoxib strongly enhanced the antitumor efficacy of chemoradiation. However, preliminary observations from both the preclinical experiments as well as the clinical protocol have revealed more toxicity with this combination than with gemcitabine and radiotherapy alone. These observations require further study, but are cause for concern when combining gemcitabine, radiotherapy, and celecoxib.
胰腺癌是一种对化疗和放疗具有抗性的致命疾病。最近研究表明，对于晚期疾病患者，吉西他滨比5-氟尿嘧啶疗效更佳。它还是一种有效的放射增敏剂，这促使人们对吉西他滨与同步放疗联合使用展开研究。然而，初步结果表明，在这种具有挑战性的疾病中，这种方法存在显著局限性。胰腺癌细胞在许多分子信号通路中存在改变，这可能是其对细胞毒性疗法产生抗性以及具有侵袭性的原因。环氧合酶-2（COX-2）在胰腺肿瘤中通常过度表达，临床前证据表明，选择性COX-2抑制可增强化疗和放疗反应，且不影响正常组织损伤。我们已启动临床前研究以及一项I期临床方案，评估吉西他滨和塞来昔布（西乐葆）与放疗联合使用的效果。在临床前研究中，塞来昔布显著增强了放化疗的抗肿瘤疗效。然而，临床前实验和临床方案的初步观察结果显示，这种联合用药比单独使用吉西他滨和放疗毒性更大。这些观察结果需要进一步研究，但在联合使用吉西他滨、放疗和塞来昔布时令人担忧。
