NLA-1: a 2-nitroimidazole radiosensitizer targeted to DNA by intercalation.

Abstract

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.

• Authors: W A Denny, P B Roberts, R F Anderson, J M Brown, D Phil, W R Wilson
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 22 Issue 3 Pg. 553-6 ( 1992) ISSN: 0360-3016 [Print] United States
• PMID: 1735695 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoacridines
• DNA, Neoplasm
• Intercalating Agents
• Nitroimidazoles
• Radiation-Sensitizing Agents
• NLA 1
• DNA

Topics

• Aminoacridines (metabolism, pharmacology, therapeutic use)
• Animals
• Cell Hypoxia (drug effects, physiology, radiation effects)
• Cell Line
• Combined Modality Therapy
• DNA (metabolism)
• DNA, Neoplasm (metabolism)
• Intercalating Agents (metabolism, pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Neoplasms, Experimental (drug therapy, radiotherapy)
• Nitroimidazoles (metabolism, pharmacology, therapeutic use)
• Radiation-Sensitizing Agents (metabolism, pharmacology, therapeutic use)