Abstract A005: Enhanced DNA damage and disruption of repair by iodinated thymidine analogues with Tipiracil for clinical radiation sensitization

Abstract

Abstract IUdR incorporation into cellular DNA enhances radiation induced DNA damage and impairs repair pathways. IUdR has been explored as a clinical radiation sensitizer in Phase I and II clinical trials of sarcomas and gliomas, showing clinical activity. A major barrier to acceptance of this therapy has been the poor pharmacokinetic (PK) profile of IUdR which has a blood plasma half-life of less than 10 minutes. Continuous IV infusion of IUdR has been used to achieve clinically relevant DNA incorporation into tumor cells, but technical limitations of delivery and acute toxicities in rapidly proliferating normal tissues presented barriers to advancing this approach. To improve the PK profile of IUdR, a prodrug strategy has been employed leading to the development of ropidoxuridine (IPdR), which improved the PK profile, demonstrated oral bioavailability of the active metabolite IUdR, showed less normal tissue toxicity, and provided tumor radiation sensitization. IPdR plus XRT has been tested in Phase 0 and Phase 1 clinical trials and a phase II trial is proposed for glioblastoma treatment. We report here a second approach to improve the PK profile of orally administered IUdR by combining these iodinated thymidine analogs with the metabolism inhibitor, Tipiracil (TPI) which inhibits thymidine phosphorylase, the primary enzyme responsible for irreversible IUdR degradation, and is currently used in the FDA approved combination drug Lonsurf. Oral co-administration of IUdR and TPI in rats dramatically improved the PK profile of IUdR, increasing the half-life of the compound to 1.5 hours and boosting the maximum plasma concentration by approximately 8-fold. We studied the effects of Tipiracil on the metabolism of IUdR by varying the molecular ratio of IUdR/TPI from 2:1 up to a ratio of 10:1 and discovered that the plasma concentration of IUdR plateaued between a ratio of 5:1 and 10:1. This new combination therapy of IUdR/TPI yields a PK profile of IUdR that is relevant to clinical treatment in combination with RT and offers to expand potential clinical radiation sensitizer applications. Citation Format: Scott Grindrod, Alfredo Velana, Tyvin Rich, Mira Jung, Dalong Pang, Anatoly Dritschilo. Enhanced DNA damage and disruption of repair by iodinated thymidine analogues with Tipiracil for clinical radiation sensitization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A005.