Abstract PO-007: 18O-substituted nucleosides combined with proton beam: “Theranostic transformation.”

Abstract

Abstract Therapeutic protons (PRT) cause atomic transmutation of 18O to 18F producing positrons and release neutrons. We hypothesize that targeted production of 18F may be achieved with an 18O containing nucleoside that incorporates into DNA and when exposed to PRT alters local chemical behavior. PRT radiation sensitization (RS) was tested in SQ20-B squamous carcinoma and PC3 prostate cancer cells treated with 18O substituted C2-18O-thymidine (18O-TD), C2-18O-Uridine (18O-UD) and also the thymidine analogs IUdR and substituted 5’-18O-5-iododeoxyuridine (18O-IUdR). Proton RS data are reported for Log phase cells exposed to these substituted nucleosides at physiologic concentrations of 5 -10 µM for 48 hours and re-plated in fresh media. PRT 24 hours later delivered 1 to 9 Gy using an 85 MeV beam at the Bragg peak. Survival fractions were determined by colony assays in triplicate for combined treatment vs. PRT alone. The single hit multi-target model was applied to demonstrate RS with dose modification factors of 1.2 for 18O-TD, 1.3 for IUdR, and 1.5 for 18O-IUdR. RS was not seen with 18O-TD, 18O-UD, or H218O irradiated with gamma rays, nor those treated with 18O-UD or H218O combined with PRT (no changes in D0). PRT of H218O with 10 Gy yielded positron emission tomography images in vitro initiated >45 minutes after PRT with a decay signal with T1/2 of ~111 min. We conclude that 18O-substituted nucleosides activated by therapeutic PRT create in situ 18F that may open up new strategies for RS. A wide PRT therapeutic window could result from the metabolic, physical, and chemical effects of “theranostic transmutation” with 18O labelled nucleosides. Citation Format: Tyvin Rich, Dongfeng Pan, Mahendra Chordia, Cynthia Keppel, Mira Jung, Dalong Pang, David Beylin, Scott Grindrod, Anatoly Dritschilo. 18O-substituted nucleosides combined with proton beam: “Theranostic transformation.” [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-007.