Electron-affinic compounds with strong
DNA intercalating properties have demonstrated less than the expected radiosensitization due to restriction of their mobility along the
DNA backbone and their lower extravascular diffusion in
tumors. A
2-nitroimidazole linked 1,2,3,4-tetrahydroacridine derivative (THNLA-1) has been synthesized as a
hypoxia-selective
cytotoxin and radiosensitizer with presumably lower
DNA-binding affinity due to the perturbation of the planarity in the
acridine ring.
THNLA-1 is a good
hypoxia-selective
cytotoxin with a differential toxicity of approximately equal to 11 in V79 cells, but it is approximately equal to 2 times less potent on a concentration basis than
NLA-1 (the 2-
nitroimidazole linked
acridine analog). However,
THNLA-1 is a very efficient radiosensitizer, showing a sensitization enhancement ratio (SER) of 3.04 +/- 0.05 at 100 microM at 25 degrees C, and the concentration giving an SER of 1.6(C1.6) is 19.0 +/- 0.5 microM. The therapeutic index, defined as the ratio of the clonogenic IC50 under aerobic conditions for 1-h exposure (IC50A,1h) to the C1.6 value, is 20 for
THNLA-1 vs. 11 for
NLA-1. THNLA-1's partition coefficient in octanol/water is 0.14 +/- 0.02.
Topoisomerase 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 (> or = 1000 microM), while
topoisomerase II-mediated decatenation of
kinetoplast DNA remained unaffected even in concentrations toxic in vitro under aerobic conditions. Uptake studies under aerobic conditions showed high intracellular
drug concentrations, compatible with the required ones for
topoisomerase I inhibition.