Antitumor effects of recombinant human adenovirus-p53 against human cutaneous squamous cell carcinoma in mice
Yuanchao Li1, Wei He1, Rupeng Wang1
1Department of Dermatology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
Abstract:
The present study was conducted to identify the anti-tumor effects of rAd/p53, which is a recombinant human serotype 5 adenovirus, in cutaneous squamous cell carcinoma (cSCC). Mouse models of human cSCC were constructed by injecting human cutaneous squamous cell carcinoma cells into both flanks of nude mice. Subsequently, the 75 nude mice with cSCC xenograft tumors were randomly divided into recombinant human serotype 5 adenovirus (rAd)/p53, rAd/p53 + 5-fluorouracil (5-Fu) and 5-Fu groups. One side of the tumors was administered the therapeutic agents as the therapeutic group, whereas the remaining side was treated with medical saline as the control. At 24, 48, 72, 120 and 168 h post-intratumoral injection, alterations in tumor volume, tumor necrosis and the expression of several tumor-associated genes, including Smad4, Brca1 and matrix metalloproteinase (MMP-2), were analyzed. Compared with its control group, the rAd/P53 group exhibited a significantly increased tumor necrosis ratio. In addition, Smad4 and Brca1 expression levels increased significantly at various time points (P<0.05), and MMP-2 expression decreased significantly (P<0.05). In the rAd/p53 + 5-Fu group, the tumor necrosis ratio, and Smad4 and Brca1 expression levels also significantly increased at various time points (P<0.05). MMP-2 gene transcription gradually decreased, high expression of Smad4 was prolonged, and high expression of Brca1 was observed in the early period following treatment compared with the rAd/P53 group. In addition, p53 expression exhibited a positive correlation with the tumor necrosis ratio and Smad4 expression, and showed a negative correlation with MMP-2 gene transcription (P<0.05). These findings indicate that rAd/p53 has a potent anti-tumor effect in cSCC via the promotion of tumor necrosis and regulating the expression of various tumor-associated genes.
Insights
Recombinant adenovirus (rAd)/p53 shows significant anti-tumor effects in cutaneous squamous cell carcinoma (cSCC) by increasing tumor necrosis and regulating key gene expressions. This therapy holds promise for cSCC treatment.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer with various treatment challenges.
- Gene therapy using oncolytic viruses like recombinant adenovirus (rAd)/p53 offers a novel therapeutic strategy.
- Understanding the molecular mechanisms underlying rAd/p53's anti-tumor activity is crucial for its clinical application.
Purpose of the Study:
- To investigate the anti-tumor efficacy of rAd/p53 in mouse models of human cSCC.
- To analyze the effects of rAd/p53, alone and in combination with 5-fluorouracil (5-Fu), on tumor growth and associated gene expression.
- To elucidate the correlation between p53 expression and tumor-associated gene modulation.
Main Methods:
- Construction of cSCC xenograft mouse models.
- Randomized treatment of tumors with rAd/p53, rAd/p53 + 5-Fu, or 5-Fu.
- Intratumoral injections and subsequent analysis of tumor volume, necrosis, and expression of Smad4, Brca1, and MMP-2 at various time points.
Main Results:
- rAd/p53 significantly increased tumor necrosis and upregulated Smad4 and Brca1 expression while downregulating MMP-2 expression.
- The combination therapy (rAd/p53 + 5-Fu) demonstrated enhanced anti-tumor effects, prolonging Smad4 expression and increasing Brca1 expression.
- p53 expression positively correlated with tumor necrosis and Smad4 expression, and negatively correlated with MMP-2 transcription.
Conclusions:
- rAd/p53 exhibits potent anti-tumor activity against cSCC by promoting tumor necrosis.
- rAd/p53 effectively regulates the expression of tumor-associated genes, including Smad4, Brca1, and MMP-2.
- The findings support rAd/p53 as a promising therapeutic agent for cSCC, potentially enhanced by combination with chemotherapy.
