IMIDAZOLYL)PROPYLAMINO]-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE - A NOVEL DNA-AFFINIC HYPOXIC CELL CYTOTOXIN AND RADIOSENSITIZER - COMPARISON WITH NLA-1

Electron-affinic compounds with strong DNA intercalating properties ha ve demonstrated less than the expected radiosensitization due to restr iction of their mobility along the DNA backbone and their lower extrav ascular diffusion in tumors. A 2-nitroimidazole linked 1,2,3,4-tetrahy droacridine derivative (THNLA-1) has been synthesized as a hypoxia-sel ective cytotoxin and radiosensitizer with presumably lower DNA-binding affinity due to the perturbation of the planarity in the acridine rin g. THNLA-1 is a good hypoxia-selective cytotoxin with a differential t oxicity of all in V79 cells, but it is congruent to 2 times less poten t on a concentration basis than NLA-1 (the 2-nitroimidazole linked acr idine analog). However, THNLA-1 is a very efficient radiosensitizer, s howing a sensitization enhancement ratio (SER) of 3.04 +/- 0.05 at 100 mu M at 25 degrees C, and the concentration giving an SER of 1.6 (C-1 .6) is 19.0 +/- 0.5 mu M. The therapeutic index, defined as the ratio of the clonogenic IC50 under aerobic conditions for 1-h exposure (IC50 A,lb) to the C-1.6 value, is 20 for THNLA-1 vs. 11 for NLA-1. THNLA-1' s partition coefficient in octanol/water is 0.14 +/- 0.02. Topoisomera se I and II interaction studies with THNLA-1 showed that topoisomerase I-mediated relaxation of supercoiled DNA was inhibited at relatively high THNLA-1 concentrations (greater than or equal to 1000 mu M), whil e topoisomerase II-mediated decatenation of kinetoplast DNA remained u naffected even in concentrations toxic in vitro under aerobic conditio ns. Uptake studies under aerobic conditions showed high intracellular drug concentrations, compatible with the required ones for topoisomera se I inhibition.