Nitroimidazole radiopharmaceuticals in hypoxia: part II cytotoxicity and radiosensitization applications.
Feasibility paper explores the cytotoxicity of nitroimidazole on tumor cells and liver cells to establish the 2'-nitroimidazole as radiosensitizer in cancer therapy and hypoxia monitoring. Hypothesis is that the presence of substituted nitro group on 2' position of imidazole ring is more enzyme sensitive and determinant of biochemical cytotoxicity as hypoxia reporter in isolated tumor cells or tumor tissues. Radiolabeling of nitroimidazole imparts tracer properties to locate the distribution (radiosensitizer) of nitroimidazole in the body. A 'theradiagnostic criteria of hypoxia' using nitroimidazole radiosensitizer is proposed based on tumor killing by enhanced tumor oxygen tension (therapeutics) and altered metabolizing enzymes (diagnostics) due to cytotoxicity of radiosensitizer. Both properties of nitroimidazole cytotoxicity and oxygen sensitivity place the nitroimidazole compounds in the class of tumor therapy and hypoxia detection. Initially nitroimidazole cytotoxicity was reported as antiparasitic drug. Now radiolabeled 2'-nitroimidazole is potential radiosensitizer in hypoxia treatment and monitoring in last two decades. Hydrophilic double radiolabel groups on imidazole ring offer multimodal imaging and active nitro- or imidazole ring in nitroimidazoles interact with intracellular metabolism in liver by biotransformation and biooxidation to cause cytotoxicity as biomarker of hypoxia. Nitroimidazole metabolizing and xenobiotic enzymes showed regulatory role to excrete out nitroimidazole from the body and reduced stay time in tissue. Nitroimidazoles showed physicochemical properties with poor tissue diffusion, less antioxidant redox potential and long retention time in tissue making them poor choice of hypoxia markers. Key of success is achieving 2'-Nitroimidazole based multimodal radiopharmaceuticals as less cytotoxic, more tumor oxygen specific multifunctional reporters of apoptosis, proliferation, and hypoxia in theradiagnostics and radiation oncology.
Center of Nanomagnetics and Biotechnology, Florida State University, Tallahassee, FL 32304, USA. rksz2004@gmail.com
Rakesh
R
Sharma
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D003131:Combined Modality Therapy; D004247:DNA / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000627:therapeutic use*; D010587:Phagocytosis / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D004247:DNA