Quantifying Cellular Repair, Misrepair and Apoptosis Induced by Boron Ions, Gamma Rays and PRIMA-1 Using the RHR...

Area of Science:

• Radiation Biology
• Molecular Biology
• Cancer Therapy

Background:

• Accurate modeling of radiation-induced cellular damage, including DNA repair and apoptosis, is crucial for understanding cell survival and developing effective cancer treatments.
• Existing models often struggle to fully capture the complex interplay between different DNA repair pathways (NHEJ, HR) and their impact on cell fate, especially in cells with TP53 mutations.

Purpose of the Study:

• To develop and validate a novel interaction cross-section-based formulation for radiation-induced cellular inactivation, encompassing DNA repair, misrepair, and apoptosis.
• To accurately describe cellular responses in both TP53 wild-type and mutant cells, considering the distinct mechanisms of mild and severe DNA damage repair.
• To predict the effectiveness of therapeutic interventions, including boron ions and the compound PRIMA-1, in combination with radiation therapy.

Main Methods:

• Developed a non-homologous repairable-homologous repairable (RHR) damage formulation distinguishing between rapid (NHEJ) and high-fidelity (HR) repair processes.
• Incorporated 7 repair and 8 misrepair mechanisms to model apoptosis induction probability across various radiation types (gamma rays, boron ions) and doses.
• Validated the model using experimental data from wild-type and mutant TP53 cell lines, including studies on DNA repair gene knockouts and the effects of PRIMA-1.

Main Results:

• The new formulation accurately describes cell survival, misrepair, and apoptosis, particularly highlighting the role of apoptosis in early cell kill at low-to-medium LET.
• Apoptosis induction saturates at approximately 10% cell survival across studied LETs, with low-dose hyper-sensitivity (LDHS) explained by delayed DNA repair activation.
• The model successfully predicted apoptotic responses and RBE/RAE values for boron ions, and demonstrated enhanced apoptosis with PRIMA-1 in TP53 mutant cells.

Conclusions:

• The developed DNA repair-based cell survival model provides a significantly improved framework for understanding and predicting cellular responses to radiation.
• The findings support the clinical utility of lower LET light ions for maximizing tumor apoptosis and suggest a combined therapeutic strategy using PRIMA-1 and optimized radiation for TP53 mutant tumors.
• The study underscores the importance of accurately accounting for DNA repair pathway interactions and misrepair processes in radiation oncology.