Development of Differentiation-directed Cancer Gene Therapy with p21

细胞周期依赖性激酶抑制剂p21在分化过程中被诱导。为了开发一种新的基于基因的抗癌治疗方法，可以诱导癌细胞的良好分化状态，我们研究了p21基因转移对人癌细胞的抗肿瘤效应。重组腺病毒介导的p21在TE-1人食管癌细胞上的瞬时过表达表现出指示分化的形态学变化，例如核增大和扁平形状。此外，p21基因转染后，鳞状细胞分化标志物外皮蛋白的表达上调。我们还发现，视黄酸受体（RAR）的正调控的p21基因转移在DLD-1（结肠），1-11299（肺），H460（肺），TE-13（食管）人癌细胞系。RAR的表达增加诱导RA耐药的DLD-1癌细胞对维甲酸（RA）的敏感性，导致p21基因转移和RA治疗的协同抗肿瘤作用。这些观察结果表明，腺病毒介导的p21基因转移可以诱导人类癌细胞的分化，p21基因具有重要意义的分化导向的分子治疗。

A cycline-dependent kinase inhibitor p21 is induced in thc process of differentiation. To develop a novel gene-based anti-cancer therapy that can induce a welI-differentiated state in cancer cells, we examined antitumor offeet of the p21 gene transfer on human cancer cells. A recombinant adenovirus-mediated transient overexpression of p21 on TE-1 human esophageal cancer cells exhibited morphological changes indicative of differentiation, such as enlarged nuclei and flattened shape. Moreover, expression of involucrin protein, a differentiation marker of squamous cells, was up-regulated after the p21 gene transfer. We also found that retinoic acid receptor (RAR) was positively regulated by the p21 gene transfer in DLD-1 (colon), 1-11299 (lung), H460 (lung), and TE-13 (esophagus) human cancer cell lines. Increased expression of RAR induced the sensitivity to retinoic acid (RA) in RA-resistant DLD-1 cancer cells, resulting in the synergistic antitumor effect of the p21 gene transfer and RA treatment. These observations suggest that adenovirus-mediated p21 gene transfer can induce differentiation in human cancer cells and that the p21 gene has important implications for a differentiation-directed molecular therapy.