Garcia Darwin A, Rathi Sneha, Connors Margaret A, Grams Michael, Vaubel Rachael A, Bakken Katrina K, Ott Lauren L, Carlson Brett L, Hu Zeng, Decker Paul A, Eckel-Passow Jeanette E, Burgenske Danielle M, Zhong Wei, Trzasko Joshua D, Herman Michael G, Elmquist William F, Remmes Nicholas B, Sarkaria Jann N
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
Mol Cancer Ther. 2025 Feb 4;24(2):299-309. doi: 10.1158/1535-7163.MCT-24-0664.
Ataxia Telangiectasia-mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.
共济失调毛细血管扩张症突变（ATM）抑制剂正作为放射增敏剂进行研发，以提高放射治疗的抗肿瘤效果，但抑制ATM也会使正常组织产生放射增敏作用。因此，了解正常组织毒性风险升高对于放射增敏剂的研发至关重要。本研究着重建立急性黏膜毒性、辐射剂量、分割方案和放射增敏剂暴露之间的关系模型。将ATM抑制剂WSD0628与单次或分次剂量的辐射相结合，照射Friend白血病病毒B（FVB）小鼠的口腔或食管。WSD0628的增敏作用通过增敏剂增强率（SER）进行量化，该指标描述了与仅接受辐射方案相比，联合WSD0628的辐射对辐射耐受性的变化。WSD0628显著增强了辐射诱导的急性口腔和食管毒性。对于口腔黏膜毒性，WSD0628与3次分割辐射联合使用时，SER范围为1.3（0.25 mg/kg）至3.1（7.5 mg/kg）。对于7.5 mg/kg的联合用药，口腔毒性方面，SER随着分割次数从1次（SER为2.2）增加到7次（SER为4.3）而升高，食管毒性方面，SER从1次分割（SER为2.2）增加到3次分割（SER为3.6），这反映了分次辐射对正常组织的保护作用丧失。这些研究结果被用于建立一个改良的生物学有效剂量模型，以确定在有或没有WSD0628的情况下能产生相似毒性水平的替代辐射方案。要成功将放射增敏剂剂量递增至最大有效治疗剂量，需要仔细考虑肿瘤部位，并降低危及器官的辐射剂量体积限制。
