Related Experiment Videos
An adenovirus mutant that replicates selectively in p53-deficient human tumor cells
J R Bischoff1, D H Kirn, A Williams
1ONYX Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA.
Abstract:
The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.
Insights
A mutant adenovirus, unable to inactivate the p53 tumor suppressor, effectively targets and eliminates p53-deficient cancer cells. This shows potential for oncolytic adenovirus therapy in specific human tumors.
Area of Science:
- Virology
- Oncology
- Molecular Biology
Background:
- Human adenovirus E1B gene produces a 55-kDa protein that inactivates the p53 tumor suppressor.
- p53 is a critical cellular protein involved in tumor suppression.
Purpose of the Study:
- To investigate the efficacy of a mutant adenovirus lacking the E1B 55-kDa protein against human tumor cells.
- To evaluate the therapeutic potential of this mutant adenovirus in a preclinical cancer model.
Main Methods:
- Utilized a mutant adenovirus lacking the E1B 55-kDa protein.
- Tested viral replication and lysis in p53-deficient versus p53-functional human tumor cells.
- Assessed tumor regression in p53-deficient human cervical carcinomas xenografted in nude mice after mutant virus injection.
Main Results:
- The mutant adenovirus replicated in and lysed p53-deficient tumor cells, but not cells with functional p53.
- Ectopic expression of the E1B 55-kDa protein restored sensitivity to the mutant virus in p53-functional cells.
- Injection of the mutant virus led to significant tumor size reduction and 60% complete regression in p53-deficient cervical carcinomas.
Conclusions:
- The mutant adenovirus demonstrates selective oncolytic activity against p53-deficient tumors.
- This engineered adenovirus holds promise as a potential therapeutic agent for specific human cancers lacking p53 function.