Adenovirus-mediated wild-type p53 overexpression reverts tumourigenicity of human mesothelioma cells

Our plain-English summary of Adenovirus-mediated wild-type p53 overexpression reverts tumourigenicity of human mesothelioma cells, by M. Giuliano, A. Catalano, L. Strizzi, et al (International Journal of Molecular Medicine, 2000).

The study

• Authors: M. Giuliano, A. Catalano, L. Strizzi, G. Vianale, M. Capogrossi, A. Procopio
• Journal: International Journal of Molecular Medicine
• Published: 2000;5(6):591-6
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pleural malignant mesothelioma (MM) shows poor survival, regardless of tumour stage at diagnosis. MM is unresponsive to present treatment regimens and new protocols are desperately needed. The localised nature, the potential accessibility, and the relative lack of distant metastases make MM a particularly attractive candidate for somatic gene therapy. A common target for cancer gene therapy is the tumour suppressor protein p53. p53 does not seem to be mutated or deleted in MM, but it can be inactivated by binding to other proteins, like mdm2 and SV40 large T antigen. We tested the effects of a replication-deficient adenoviral vector carrying wild-type p53 cDNA in human MM cells. Our results show that >95% of MM cells were efficiently infected with 25 multiplicity of infection (MOI) of vector. Wild-type p53 was effectively expressed resulting in >80% inhibition of proliferation in MM cells. AdCMV.p53 infection induced apoptosis while controls did not show any evident morphological alterations. Ex vivo p53 gene transfer experiments inhibited tumourigenesis in nude mice. In vivo, direct intratumour injection of AdCMV.p53 arrested tumour growth and prolonged survival of treated mice. These results indicate that p53-gene therapy should be strongly exploited for clinical trials in MM patients.

In plain English

This laboratory and animal study tested a gene therapy for malignant mesothelioma; it did not study asbestos exposure. The authors used a disabled adenovirus to carry a normal (wild-type) copy of the p53 tumour suppressor gene into four human mesothelioma cell lines. At 25 multiplicity of infection, more than 95% of cells took up a marker version of the virus. Cells given the p53 virus made more p53 protein as the dose rose, and their growth was inhibited by more than 80% at that dose. An empty control virus did not affect growth. Only p53-treated cells showed microscopic signs of apoptosis (programmed cell death). In female nude mice, cells treated with the p53 virus before injection under the skin produced no measurable tumours for more than 40 days, while control cells formed tumours within days. In mice with mesothelioma cells injected into the abdomen, the authors reported that the p53 virus significantly reduced tumour growth and prolonged survival, followed up to 120 days, compared with controls. The authors concluded that p53 gene therapy may be a promising new approach for mesothelioma and called for clinical trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human mesothelioma cell lines plus experiments in mice (animal experiment) testing adenovirus-delivered wild-type p53 gene therapy
• Who was studied: Four human malignant mesothelioma cell lines: biphasic MM-B1, fibrosarcomatous MM-F1, epithelioid MM-E1, and the commercially available epithelioid line HM. Animal experiments used four- to eight-week-old female nude mice, 10 per group, injected with HM cells. The work was done in Italy.
• Exposure: No asbestos exposure was studied. The treatment tested was a replication-deficient adenovirus carrying wild-type p53 (AdCMV.p53). Comparisons were made with a LacZ marker virus (AdCMV.ßGal), an empty virus (AdCMV.null), uninfected cells or saline.
• Main results:
  • In all four cell lines, cells infected with 25 MOI of the marker virus showed more than 95% stained (infected) cells, with similar efficiency across lines.
  • In HM cells, p53 protein levels rose with increasing doses of the p53 virus. Expression of Waf1/cip21, a gene controlled by p53, followed the rise in p53.
  • The p53 virus inhibited growth of all four cell lines in a dose-dependent way, reaching more than 80% inhibition at 25 MOI. The empty control virus did not interfere with growth even at the highest dose.
  • Microscopic signs of apoptosis were seen only in HM cells infected with the p53 virus, not in uninfected or marker-virus cells.
  • In mice injected under the skin with HM cells pre-infected with the p53 virus, tumours were not measurable for more than 40 days. Mice given uninfected or marker-virus cells developed visible tumours within days.
  • In mice with HM cells injected into the peritoneal cavity and treated 3 days later, tumour growth was significantly reduced only in p53-virus-treated mice. Survival was prolonged up to 120 days compared with controls. No numerical survival figures or statistics are given in the text.
• The authors' conclusion: The authors concluded that gene therapy with wild-type p53 may be considered a promising new approach for treating malignant mesothelioma. In the abstract, they state it should be pursued in clinical trials.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, SV40, Apoptosis, Clinical Trial.

Related studies

• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)
• High levels of MDM2 are not correlated with the presence of wild-type p53 in human malignant mesothelioma cell lines — S. Ungar, A. Van de Meeren, et al. (1996)
• Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy — X.B. Deng, L. Xiao, et al. (2015)
• Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy — W.R. Smythe, H.C. Hwang, et al. (1995)
• Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed — Q. Li, K. Kawamura, et al. (2012)
• Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus — S. Kubo, Y. Kawasaki, et al. (2010)

Browse more research in International Journal of Molecular Medicine, or return to medical research.