The interaction between two radiosensitizers: 5-iododeoxyuridine and caffeine

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy

Background:

• 5-Iododeoxyuridine (IUdR) and caffeine are radiosensitizers with distinct mechanisms.
• The role of p53 status in the efficacy of combined radiosensitizer therapy is not fully understood.

Purpose of the Study:

• To investigate the combined effect of IUdR and caffeine with ionizing radiation (IR) on p53-proficient and p53-deficient human colon cancer cells.
• To elucidate the underlying mechanisms of radiosensitization by IUdR and caffeine in different p53 contexts.

Main Methods:

• Clonogenic survival assays were performed on HCT116 and RKO cell lines (and their p53-deficient counterparts) treated with IR, IUdR, caffeine, or combinations thereof.
• DNA repair inhibition and cell cycle regulation were analyzed to understand drug interactions.

Main Results:

• Single agents and IUdR or caffeine combined with IR showed less or equal efficacy in p53-deficient cells compared to p53-proficient cells.
• Combined IUdR and caffeine demonstrated significantly greater radiosensitization in p53-deficient cells.
• Caffeine enhanced IUdR incorporation and radiosensitization by inhibiting IUdR and IR-induced DNA double-strand break repair, particularly in p53-deficient cells.

Conclusions:

• Caffeine enhances IUdR-mediated radiosensitization by inhibiting DNA repair pathways, with a more pronounced effect in p53-deficient cells.
• The combination of IUdR and caffeine offers a potential therapeutic strategy to improve tumor cytotoxicity in p53-deficient human tumors.
• Differential radiosensitization by combining IUdR and caffeine-like drugs in p53-deficient tumors may lead to greater therapeutic gain.