Targeting DNA Repair for Tumor Radiosensitization

As reviewed previously in this chapter, recent advances in our understanding of DNA repair have shown genetic and epigenetic changes in several common human cancers, which result in alterations in IR damage recognition and damage repair processes. DNA mismatch repair (MMR) is a postrepli-cational process whose genes/proteins are not only capable of recognizing and processing single DNA base-pair mismatches and insertion-deletion loops during DNA replication, but also DNA adducts resulting from several types of chemotherapy drugs including the platinum analogues, alkylating/methyl-ating drugs including procarbazine and temozolomide, and various nucleoside analogues including the fluoropyrim-idines, gemcitabine, and the purine analogues, 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP).80 MMR is also involved in processing IR damage.81 As such, MMR-deficient human tumors resulting from genetic defects [e.g., human nonpoly-posis colorectal cancers (HNPCC)] or from epigenetic silencing (methylation) of hMLH1 and hMSH2 genes (e.g., found in 15%-30% of colon, gastric, endometrial, high-grade glioma, and ovarian and breast cancers) show clinical resistance to these chemotherapeutic agents as well as IR.80-82 One approach to target these MMR-deficient human cancers for radiosensitization involves the use of the halogenated thymi-dine analogues such as iododeoxyuridine (IUdR), which are incorporated into DNA in place of thymidine and enhance DNA damage following IR exposure. MMR-deficient tumor cells fail to effectively remove IUdR DNA, unlike normal (MMR+) cells, allowing for preferential tumor radiosensitiza-tion without enhancing normal tissue toxicity as recently shown in vivo.83 A clinical trial of this approach using an oral prodrug of IUdR (IPdR) and radiation therapy in MMR-deficient ("resistant") human cancers is ongoing.

Another potential area for "targeted" radiosensitization involves the use of inhibitory drugs or proteins directed at double-strand break repair. As stated earlier, RAD51 is over-expressed in several clinically radioresistant tumors such as pancreas cancer. Additionally, ionizing radiation treatment can induce expression of RAD51 RNA and RAD51 proteinmediated homologous recombination of double-strand breaks in both normal and human tumor cells. At present, imatnib mesylate (Gleevac; Novartis) is a potential candidate for clinical testing of inhibiting RAD51 at its tyrosine 315 phos-phorylating site.84

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