NLA-1 : A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation
| Autor: | W A, Denny, P B, Roberts, R F, Anderson, J M, Brown, D, Phil, W R, Wilson |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Radiation-Sensitizing Agents
Cancer Research Radiosensitizer Misonidazole Pharmacology Cell Line Toxicology Mice chemistry.chemical_compound Therapeutic index In vivo Animals Pimonidazole Medicine Potency Radiology Nuclear Medicine and imaging Cytotoxicity Mice Inbred BALB C Mice Inbred C3H Radiation Aminoacridines business.industry DNA DNA Neoplasm Neoplasms Experimental Combined Modality Therapy Cell Hypoxia Intercalating Agents In vitro Oncology chemistry Nitroimidazoles business |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 22:553-556 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/0360-3016(92)90874-h |
| Popis: | Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is approximately 1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (approximately 11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C1.6) of 9 microM. The mean intracellular concentration at the C1.6 is 400 microM, on which basis its potency is about twice that of MISO. The in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C1.6) of NLA-1 is approximately 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors in vivo at the maximum tolerated dose (MTD) of 100 mumol.kg-1. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|