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Ras inhibitors and radiation therapy.
H A Jones1, S M Hahn, E Bernhard
1Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, 19104-4283, USA.
Seminars in Radiation Oncology
|October 26, 2001
Summary
Local tumor recurrence after radiation therapy is a major challenge. Inhibiting protein farnesyltransferase (FTase) with farnesyltransferase inhibitors (FTIs) can overcome radiation resistance mediated by Ras oncogenes.
Area of Science:
- Oncology
- Molecular Biology
- Radiation Oncology
Background:
- Local recurrence after radiation therapy is a significant clinical challenge in treating solid tumors.
- Tumor cell sensitivity to ionizing radiation is crucial for local control.
- Activated oncogenes, particularly Ras, are linked to increased radioresistance in various human cancers.
Purpose of the Study:
- To investigate the role of Ras oncogenes in radioresistance.
- To evaluate the potential of protein farnesyltransferase (FTase) inhibitors (FTIs) in overcoming Ras-mediated radioresistance.
Main Methods:
- Preclinical studies examining the effect of mutant Ras expression on cellular radioresistance.
- Investigating the mechanism of Ras localization to the plasma membrane via farnesylation.
- Assessing the efficacy of FTIs in blocking farnesylation and reversing radioresistance in human cell lines.
Main Results:
- Mutant Ras expression increases cellular radioresistance.
- FTase inhibitors block Ras farnesylation, a key step for Ras function.
- FTIs reversed Ras-mediated radioresistance in human cell lines and were well-tolerated in animal studies.
Conclusions:
- Ras oncogenes contribute to radioresistance.
- FTase inhibitors represent a promising therapeutic strategy to enhance radiation therapy efficacy by overcoming Ras-mediated radioresistance.
- Ongoing clinical trials are evaluating FTIs in combination with radiotherapy.