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Enhanced apoptotic activity of a p53 variant in tumors resistant to wild-type p53 treatment

I A Atencio1, J B Avanzini, D Johnson

  • 1Canji, Inc., 3525 John Hopkins Court, La Jolla, CA 92121, USA. isabella.atencio@canji.com

Molecular Therapy : the Journal of the American Society of Gene Therapy
|July 27, 2001
PubMed

Insights

A novel p53 variant (rAd-p53 (d 13-19)) enhances apoptosis in wild-type TP53 tumors resistant to standard gene therapy. This p53 variant shows promise for expanding TP53 gene therapy applications in cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • TP53 is a crucial tumor suppressor gene frequently altered in cancer.
  • Elevated MDM2 protein levels in tumors lead to p53 degradation, causing resistance to wild-type p53 gene therapy.
  • A subset of tumors with wild-type TP53 sequence exhibit resistance to conventional p53-based treatments.

Purpose of the Study:

  • To develop and evaluate a novel p53 variant (rAd-p53 (d 13-19)) designed to resist MDM2-mediated degradation.
  • To compare the apoptotic activity and antitumor efficacy of the p53 variant against wild-type p53 in various cancer cell lines and tumor models.
  • To assess the potential of the p53 variant to overcome resistance mechanisms in tumors refractory to standard p53 gene therapy.

Main Methods:

  • Generation of a recombinant adenovirus expressing a p53 variant (rAd-p53 (d 13-19)) with a deletion in the MDM2 binding domain (amino acids 13-19).
  • Comparative analysis of apoptotic activity using annexin V-FITC staining in cancer cell lines with differing endogenous p53 statuses.
  • Evaluation of the p53 variant's antitumor activity in established tumors and its synergy with chemotherapeutic agents in ovarian and breast cancer cell lines.

Main Results:

  • rAd-p53 (d 13-19) induced significantly higher apoptosis in p53 wild-type tumor cells compared to wild-type p53.
  • The p53 variant demonstrated comparable apoptotic activity to wild-type p53 in p53-altered tumor lines.
  • No increased cytopathicity was observed in normal cells treated with rAd-p53 (d 13-19) compared to wild-type p53.
  • The p53 variant exhibited enhanced antitumor activity in vivo and synergistic effects with chemotherapy in preclinical models.

Conclusions:

  • The p53 variant rAd-p53 (d 13-19) effectively overcomes MDM2-mediated degradation, leading to enhanced apoptosis in wild-type TP53 tumors.
  • This p53 variant represents a promising therapeutic strategy to broaden the application of TP53 gene therapy to currently resistant cancers.
  • The findings support the potential of targeting the p53-MDM2 interaction to improve cancer treatment outcomes.

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