1. Antiandrogen Therapy Radiosensitizes Androgen Receptor–Positive Cancers to (18)F-FDG
- Author
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Indulekha Singaravelu, Zhongyun Dong, Mary C. Mahoney, Nalinikanth Kotagiri, and Henry B. Spitz
- Subjects
Radiosensitizer ,Radiation-Sensitizing Agents ,Bicalutamide ,Ultraviolet Rays ,Androgen Receptor Positive ,Triple Negative Breast Neoplasms ,Basic Science Investigation ,Prostate cancer ,Mice ,In vivo ,Fluorodeoxyglucose F18 ,Cell Line, Tumor ,Nitriles ,Medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,business.industry ,Androgen Antagonists ,medicine.disease ,Androgen receptor ,Receptors, Androgen ,Radionuclide therapy ,Toxicity ,Cancer research ,business ,medicine.drug - Abstract
A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited efficacy, with about a 19% clinical benefit rate. We investigated the therapeutic enhancement of antiandrogens as radiosensitizers in combination with (18)F-FDG in TNBC. Methods: We screened 5 candidate drugs to evaluate shared toxicity when combined with either (18)F-FDG, x-rays, or ultraviolet radiation, at doses below their respective half-maximal inhibitory concentrations. Cytotoxic enhancement of antiandrogen in combination with (18)F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, the therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Results: Bicalutamide, an antiandrogen drug, was found to share similar toxicity in combination with either (18)F-FDG or x-rays, indicating its sensitivity as a radiosensitizer to (18)F-FDG. Cell proliferation assays demonstrated selective toxicity of combination bicalutamide-(18)F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation-induced damage to cells, suggesting the role of bicalutamide as a radiosensitizer to (18)F-FDG–mediated radiation damage. Animal studies in MDA-MB-231, 22RV1, and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of bicalutamide and (18)F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathologic examination corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. Conclusion: These data provide evidence that (18)F-FDG in conjunction with antiandrogens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers. more...
- Published
- 2022