Department of Radiotherapy and Radiation Oncology, University of Rostock, Südring 75, 18059 Rostock, Germany.
Med Oncol. 2012 Sep;29(3):2276-83. doi: 10.1007/s12032-011-0041-7. Epub 2011 Aug 14.
Panitumumab is the first fully human monoclonal antibody targeting the epidermal growth factor receptor whose clinical use is limited to patients with a non-mutated KRAS status. The aim of this in vitro study was to evaluate whether the KRAS status might influence the cytotoxic and radiosensitizing efficacy of Panitumumab. Exponentially growing cancer cells (HT-29: KRAS wild-type, A549: KRAS mutant) were either treated with the monoclonal antibody alone in growth and proliferation assays or in combination with radiation in metabolic and colony-forming assays. For the assessment of ionizing radiation-induced DNA damage and to evaluate Panitumumab's influence on DNA damage repair, the γH2AX foci assay was performed. Treatment with Panitumumab resulted in a concentration-independent growth inhibition as well as a cytotoxic effect only in the KRAS-mutated cell line A549. BrdU assay confirmed an antiproliferative influence of Panitumumab. When combined with irradiation, incubation with the antibody was found to result in an enhanced radiosensitivity. Contrary to expectations, Panitumumab had no influence on the cell growth, LDH release or clonogenic survival of KRAS wild-type cells HT-29. Our results suggest that response to Panitumumab treatment is not only controlled by the KRAS status but may also be essentially influenced by other regulating factors.
帕尼单抗是首个针对表皮生长因子受体的全人源单克隆抗体，其临床应用仅限于 KRAS 无突变状态的患者。本体外研究旨在评估 KRAS 状态是否会影响帕尼单抗的细胞毒性和放射增敏作用。在生长和增殖测定中，将处于指数生长期的癌细胞（HT-29：KRAS 野生型，A549：KRAS 突变型）单独用单克隆抗体处理，或在代谢和集落形成测定中与放射联合处理。为了评估电离辐射诱导的 DNA 损伤，并评估帕尼单抗对 DNA 损伤修复的影响，进行了 γH2AX 焦点测定。帕尼单抗的处理导致浓度非依赖性的生长抑制和仅在 KRAS 突变细胞系 A549 中的细胞毒性作用。BrdU 测定证实了帕尼单抗的抗增殖作用。当与照射联合时，发现与抗体孵育可导致放射增敏作用增强。出乎意料的是，帕尼单抗对 KRAS 野生型细胞 HT-29 的细胞生长、LDH 释放或集落形成存活没有影响。我们的结果表明，对帕尼单抗治疗的反应不仅受 KRAS 状态控制，还可能受其他调节因子的重要影响。
