¹⁸Oxygen Substituted Nucleosides Combined with Proton Beam Therapy: Therapeutic Transmutation In Vitro

Proton therapy precisely delivers radiation to cancers to cause damaging strand breaks to cellular DNA, kill malignant cells, and stop tumor growth. Therapeutic protons also generate short-lived activated nuclei of carbon, oxygen, and nitrogen atoms in patients as a result of atomic transmutations that are imaged by positron emission tomography (PET). We hypothesized that the transition of ¹⁸O to ¹⁸F in an ¹⁸O-substituted nucleoside irradiated with therapeutic protons may result in the potential for combined diagnosis and treatment for cancer with proton therapy.

Reported here is a feasibility study with a therapeutic proton beam used to irradiate H₂ ¹⁸O to a dose of 10 Gy produced by an 85 MeV pristine Bragg peak. PET imaging initiated >45 minutes later showed an ¹⁸F decay signal with T_1/2 of ∼111 minutes.

The ¹⁸O to ¹⁸F transmutation effect on cell survival was tested by exposing SQ20B squamous carcinoma cells to physiologic ¹⁸O-thymidine concentrations of 5 μM for 48 hours followed by 1- to 9-Gy graded doses of proton radiation given 24 hours later. Survival analyses show radiation sensitization with a dose modification factor (DMF) of 1.2.

These data support the idea of therapeutic transmutation in vitro as a biochemical consequence of proton activation of ¹⁸O to ¹⁸F in substituted thymidine enabling proton radiation enhancement in a cancer cell. ¹⁸O-substituted molecules that incorporate into cancer targets may hold promise for improving the therapeutic window of protons and can be evaluated further for postproton therapy PET imaging.