Milenic Diane E, Garmestani Kayhan, Brady Erik D, Albert Paul S, Abdulla Alia, Flynn Joseph, Brechbiel Martin W
Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch and Biometric Research Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Clin Cancer Res. 2007 Mar 15;13(6):1926-35. doi: 10.1158/1078-0432.CCR-06-2300.
Recent studies from this laboratory with (212)Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb as an in vivo generator of (212)Bi. The objective of the studies presented here was improvement of the efficacy of alpha-particle radioimmunotherapy using a chemotherapeutic agent.
In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by (212)Pb radioimmunotherapy.
In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 muCi (212)Pb-trastuzumab. Improvement in median survival was observed at 5 microCi (212)Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 microCi versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single (212)Pb radioimmunotherapy (10 microCi) administration was then evaluated. Mice received three doses of gemcitabine: one before (212)Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P < 0.001), specifically attributable to (212)Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 microCi (212)Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 microCi (212)Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before (212)Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before (212)Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because (212)Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine).
Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.
本实验室近期关于（212）Pb-曲妥珠单抗的研究表明，以（212）Pb作为体内（212）Bi发生器，靶向治疗播散性腹膜疾病具有可行性。本文所述研究的目的是使用化疗药物提高α粒子放射免疫疗法的疗效。
在一系列实验中，系统制定了一种治疗方案，即给腹腔内接种LS-174T异种移植物的无胸腺小鼠腹腔注射50mg/kg吉西他滨，随后进行（212）Pb放射免疫治疗。
在一项初步研究中，给荷瘤小鼠注射吉西他滨，24至30小时后，再注射5或10μCi（212）Pb-曲妥珠单抗。在未使用（31天）或使用（51天）吉西他滨的情况下，5μCi（212）Pb-曲妥珠单抗可使中位生存期延长：10μCi时为45天和70天，而未治疗小鼠为16天（P<0.001）。然后评估了多剂量吉西他滨联合单次（212）Pb放射免疫治疗（10μCi）的效果。小鼠接受三剂吉西他滨：一剂在（212）Pb-曲妥珠单抗之前，两剂在之后。接受放射免疫治疗前单次使用吉西他滨的小鼠中位生存期为54天，而接受三剂吉西他滨的小鼠中位生存期为63天（P<0.001），这特别归因于（212）Pb-曲妥珠单抗（P=0.01）。扩展这些发现，比较了一个与两个治疗周期。一个周期包括依次用吉西他滨、10μCi（212）Pb放射免疫治疗，然后再用一或两剂吉西他滨。在第一个周期中，三剂吉西他滨使中位生存期从未治疗小鼠的21天延长至90天。接受10μCi（212）Pb-曲妥珠单抗和两剂吉西他滨的小鼠在第2个周期后获益最大，中位生存期为196.5天（P=0.005）。还评估了在（212）Pb放射免疫治疗前给荷瘤小鼠注射两剂吉西他滨的情况，吉西他滨在（212）Pb-曲妥珠单抗前72小时和24小时注射。一剂和两剂吉西他滨的中位生存期分别为56天和76天，而未使用吉西他滨的为49天。这种作用可能并非完全特异于曲妥珠单抗，因为两剂吉西他滨联合（212）Pb-人免疫球蛋白的中位生存期为66天（未使用吉西他滨时为34天）。
将化疗药物与高LET靶向治疗相结合的治疗方案在癌症患者的管理和治疗中可能具有巨大潜力。
Zotero 插件