Targeting DNA mismatch repair for radiosensitization.

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Postreplicational mismatch repair (MMR) proteins identify DNA replication errors and DNA adducts from chemotherapy agents.
• MMR proteins trigger apoptosis when processing chemotherapy adducts, but repair replication errors to maintain genomic integrity.
• Loss of MMR function leads to cancer development and resistance to chemotherapy drugs.

Purpose of the Study:

• To investigate the potential of radiosensitizing MMR-deficient, chemotherapy-resistant cancer cells.
• To evaluate the efficacy of halogenated thymidine analogs, iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd), in combination with ionizing radiation (IR).

Main Methods:

• Incorporation of IdUrd and BrdUrd into DNA of MMR-proficient and MMR-deficient cells.
• Assessment of DNA strand breaks and cell cycle disruption following ionizing radiation (IR).
• Comparison of toxicity and radiosensitization effects in MMR-proficient versus MMR-deficient cells.

Main Results:

• Halogenated thymidine analogs (IdUrd, BrdUrd) are incorporated into DNA and generate reactive uracil radicals upon IR, increasing DNA strand breaks.
• MMR-deficient cells accumulate higher levels of IdUrd and BrdUrd compared to MMR-proficient cells.
• Significantly enhanced radiosensitization of MMR-deficient cells was observed at analog concentrations with limited toxicity to MMR-proficient cells.

Conclusions:

• Combined IdUrd or BrdUrd therapy with IR effectively radiosensitizes MMR-deficient cells.
• This approach offers a promising strategy for targeting MMR-deficient tumors resistant to conventional chemotherapy.
• Halogenated thymidine analogs show potential for selective killing of MMR-deficient cancer cells.