Radiosensitization in Vivo: A Study with an Homologous Series of 2-nitroimidazoles

Summary An homologous series of 1-(ω-morpholino)alkyl-2-nitroimidazoles, previously reported to be more efficient hypoxic cell radiosensitizers than misonidazole (MIS) in vitro, were evaluated in vivo using the murine Lewis Lung carcinoma. When given i.p. the compounds were 3-20 times more acutely toxic (LD50/2d) than MIS and this toxicity increased with both the number of methylene groups (n) in the side chain and the lipophilicity of the compounds. The compounds sensitized the tumour to single doses of X-rays. On the basis of equimolar administered dose, the most effective compounds, n = 2, 4 and 5, were as efficient as MIS. However, on the basis of the measured concentration of drug in the tumour at the optimum time of irradiation the compounds with n = 4 and n = 5 were less efficient than expected from previously published data in vitro. This is attributed to the basicity of the morpholino nitrogen in these compounds such that at physiological pH the compounds are primarily in an ionized form and hence poorly able to penetrate hypoxic cells.