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Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts

T Watanabe1, B A Sullenger

  • 1Center for Genetic and Cellular Therapies, Departments of Surgery and Genetics, Duke University Medical Center, Durham, NC 27710, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 13, 2000
PubMed

Insights

This study introduces a novel gene therapy using trans-splicing ribozymes to simultaneously reduce mutant p53 and restore wild-type p53 activity in cancer. This approach enhances cancer cell sensitivity to chemotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Gene Therapy

Background:

  • Traditional gene replacement therapy for cancer using wild-type p53 cDNA faces limitations.
  • These limitations include lack of regulated expression and failure to reduce overexpressed mutant p53.
  • Mutant p53 overexpression is a common characteristic of cancerous cells.

Purpose of the Study:

  • To develop an alternative gene therapy strategy for cancer treatment.
  • To simultaneously reduce mutant p53 expression and restore wild-type p53 activity.
  • To enhance cancer cell responsiveness to p53 activity and chemotherapeutic agents.

Main Methods:

  • Utilized trans-splicing ribozymes for p53 mRNA repair.
  • Engineered ribozymes to specifically target and correct defective p53 mRNAs.
  • Assessed the functional restoration of wild-type p53 activity in transfected cancer cells.

Main Results:

  • Ribozymes repaired p53 mRNAs with high fidelity and specificity.
  • Corrected transcripts yielded functional p53, activating p53-responsive promoters.
  • Demonstrated significant induction of p53-responsive promoters (23-fold) and reduction of MDR1 promoter expression (3-fold).

Conclusions:

  • Trans-splicing ribozymes offer a promising strategy for cancer gene therapy.
  • This approach effectively reduces mutant p53 and restores wild-type p53 function.
  • Further development of delivery systems could make cancers more sensitive to p53-based therapies and chemotherapy.

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