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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Adenovirus p53 gene therapy
1Department of Thoracic and Cardiovascular Surgery, UT M. D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, USA. jroth@mdanderson.org
Abstract:
To date, dysfunctional tumour suppressor genes are the most common genetic lesions identified in human cancers. Functional copies of tumour suppressor genes can be introduced into cancer cells by gene transfer using adenoviral vectors. This approach has been extensively studied in the clinic with intratumoural injection of a replication-defective adenovirus that expresses p53 (Ad-p53). Overexpression of p53 in cancer cells induces growth arrest and apoptosis. Ad-p53 injections have an excellent safety profile, and have mediated tumour regression and growth arrest as monotherapy, or have overcome resistance or increased the effectiveness of radiation therapy and chemotherapy. Expression of the p53 transgene has occurred at high levels and is associated with the activation of other genes in the p53 pathway. These studies indicate proof-of-principle for tumour suppressor gene therapy and represent a new paradigm in targeted therapy.
Insights
Gene therapy using adenovirus-p53 effectively targets cancer by restoring tumour suppressor gene function. This approach shows promise for cancer treatment, inducing apoptosis and enhancing other therapies.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Dysfunctional tumor suppressor genes are common in human cancers.
- Gene transfer using adenoviral vectors can introduce functional tumor suppressor genes into cancer cells.
- The p53 tumor suppressor gene plays a critical role in cell cycle regulation and apoptosis.
Purpose of the Study:
- To evaluate the efficacy and safety of adenoviral-mediated p53 gene therapy for cancer treatment.
- To assess the potential of Ad-p53 as a monotherapy or in combination with conventional treatments.
- To investigate the molecular mechanisms underlying Ad-p53 therapy, including transgene expression and pathway activation.
Main Methods:
- Intratumoral injection of a replication-defective adenovirus expressing p53 (Ad-p53) in preclinical cancer models.
- Assessment of tumor growth arrest, apoptosis induction, and overall survival.
- Analysis of p53 transgene expression levels and activation of downstream p53 pathway genes.
- Evaluation of safety profile and potential combination effects with radiation and chemotherapy.
Main Results:
- Ad-p53 injections demonstrated an excellent safety profile.
- Monotherapy with Ad-p53 mediated tumor regression and growth arrest.
- Ad-p53 therapy overcame resistance and enhanced the effectiveness of radiation and chemotherapy.
- High-level expression of the p53 transgene was observed, activating other genes in the p53 pathway.
Conclusions:
- Adenovirus-mediated p53 gene therapy represents a proof-of-principle for effective tumor suppressor gene therapy.
- Ad-p53 holds significant potential as a targeted therapy for various human cancers.
- This approach offers a new paradigm in cancer treatment, potentially improving outcomes when used alone or in combination therapies.
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