Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell death: Potential application of gene therapy to endometrial cancer

Papillary serous endometrial carcinoma is an aggressive tumor characterized by late-stage presentation, i.p. spread, and poor prognosis. It is histolo gically similar to serous papillary carcinoma of the ovary. Preclinical stu dies have shown that adenovirus-mediated expression of p53 in ovarian cance r cell lines causes growth inhibition and apoptosis in vitro and in vivo. S uch studies provide the rationale for Phase I Adp53 gene therapy clinical t rials in ovarian cancer, In the present study, we compared the efficacy of adenoviral vectors containing p53 (Adp53) or p21 (Adp21) in a papillary ser ous endometrial tumor cell line (SPEC-2) that contains mutated p53, Growth assays revealed that both Adp53 and Adp21 were efficacious in decreasing ce ll proliferation as assessed by anchorage-dependent and anchorage-independe nt growth assays. However, as compared with Adp53, the effects of Adp21 ten ded to be more transient and less marked. Strikingly, Adp21, but not Adp53, induced a G(1) arrest in SPEC-2 endometrial adenocarcinoma cells, In contr ast, as assessed by induction of hypodiploid peaks, free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay, and annexin V posit ivity, p53 was more effective than p21 in inducing cell death by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53, but not Adp21, induced a marked increase in expression of the preapoptotic molecule BAX without a concomitant change in expression of the antiapoptotic mediat or Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle progres sion and apoptosis may be related to the reversibility of p21-induced cell cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at lea st in the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 ma y be more effective than Adp21 as a gene therapeutic. Nevertheless, these p reclinical studies suggest that papillary serous endometrial carcinoma is a potential target for p53- or p21-mediated gene therapy.