Harris M P, Sutjipto S, Wills K N, Hancock W, Cornell D, Johnson D E, Gregory R J, Shepard H M, Maneval D C
Canji Incorporated, San Diego, California 92121, USA.
Cancer Gene Ther. 1996 Mar-Apr;3(2):121-30.
Human malignancies are often characterized by mutations of the p53 tumor suppressor gene. In a large proportion of cases, the mutation results in production of an altered protein that can bind and inactivate the wild-type gene product. This "dominant-negative" activity of mutant p53 molecules may limit the utility of p53 gene therapy of cancer. Using replication-deficient recombinant adenoviruses (rAd-p53) as a p53 gene delivery system, we evaluated the effects of p53 reintroduction on a series of 45 human cell lines containing wild-type, mutated, or no p53 protein. Results indicate a p53-specific, dose-dependent, and promoter-specific growth inhibition of a majority of p53-altered cell lines that correlates with the degree of adenovirus transgene expression. Similar effects were not observed on cells containing wild-type p53. rAd-p53 inhibited the growth of cells expressing various mutant p53 proteins including those characterized as "dominant negative mutants", and the antiproliferative effects were not abrogated by high levels of endogenous mutated p53 protein. In vivo, rAd-p53 also suppressed tumor growth and increased survival of nude mice bearing tumors that express mutant p53. These results support a role for p53 gene therapy of cancer, including malignancies harboring mutations in this tumor suppressor gene.
人类恶性肿瘤通常以p53肿瘤抑制基因的突变为特征。在很大一部分病例中，这种突变导致产生一种改变的蛋白质，该蛋白质能够结合并使野生型基因产物失活。突变型p53分子的这种“显性负性”活性可能会限制p53基因治疗癌症的效用。我们使用复制缺陷型重组腺病毒（rAd-p53）作为p53基因递送系统，评估了重新导入p53对一系列45种含有野生型、突变型或无p53蛋白的人类细胞系的影响。结果表明，大多数p53改变的细胞系呈现出p53特异性、剂量依赖性和启动子特异性的生长抑制，这与腺病毒转基因表达程度相关。在含有野生型p53的细胞上未观察到类似效果。rAd-p53抑制表达各种突变型p53蛋白的细胞生长，包括那些被表征为“显性负性突变体”的蛋白，并且高水平的内源性突变型p53蛋白不会消除其抗增殖作用。在体内，rAd-p53还抑制了表达突变型p53的荷瘤裸鼠的肿瘤生长并提高了其生存率。这些结果支持p53基因治疗癌症的作用，包括在这种肿瘤抑制基因中存在突变的恶性肿瘤。
