p53 therapy in a patient with Li-Fraumeni syndrome
p53 therapy in a patient with Li-Fraumeni syndrome
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DOI：
10.1158/1535-7163.mct-07-0125
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发表时间：
2007-05-01
影响因子：
5.7
通讯作者：
Chada, Sunil
中科院分区：
文献类型：
--
作者：
Senzer, Neil;Nemunaitis, John;Chada, Sunil
Li-Fraumeni综合征是一种常染色体显性遗传性疾病，极大地增加了患多种癌症的风险。大多数Li-Fraumeni综合征家系都含有p53肿瘤抑制基因的胚系突变。我们描述了一个难治性的，进展性的Li-Fraumeni综合征胚胎癌的治疗，用针对这种综合征潜在的分子缺陷的p53疗法(Advexin)。通过荧光脱氧葡萄糖正电子发射断层扫描，P53治疗导致注射的病变完全和持久的缓解，并改善了肿瘤相关症状。在分子标志物方面，患者的肿瘤有异常的P53，表达的柯萨奇腺病毒受体具有低Hdm2和bcl2特征，有利于腺病毒P53的活性。P21和裂解caspase-3检测显示，P53处理可诱导细胞周期停滞和细胞凋亡。重复治疗后，腺病毒抗体滴度增加并不抑制腺病毒P53的活性，也不会导致病理后遗症。这些临床、放射学和分子标志物之间的关系可能被证明对指导未来P53肿瘤抑制治疗的应用是有用的。
Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy.