Ian James Stratford

Structure-activity Relationships in the Development of Hypoxic Cell Radiosensitizers: II. Cytotoxicity and Therapeutic Ratio

This paper describes measurements of the aerobic cytotoxicity of 42 nitroaromatic and nitroheterocyclic compounds towards Chinese Hamster cells in vitro. The results of acute and chronic exposure were quantified, and the concentration C required to achieve a standard response estimated. Fitting the data to an equation of the form - log C = b0 + b1E, where E is the one-electron reduction potential, explained 47 and 71 per cent of the variance in the acute and chronic aerobic cytotoxicity respectively. The addition of further terms to the equation, quantifying partition properties, was not statistically significant. The coefficient b1 was similar for both acute and chronic exposure; the dependence of both cytotoxicity and radiosensitization efficiency on reduction potential was also similar. A therapeutic ratio derived from these in vitro measurements showed no dependence on redox or partition properties. The insensitivity of cytotoxicity and radiosensitization properties to variations in molecular structure, other than those which influence redox behaviour, offers exceptional flexibility in developing compounds of improved therapeutic ratio.

Mammalian cell toxicity of nitro compounds: Dependence upon reduction potentiakl

Summary The toxicity of several classes of nitro-aromatic and -heterocyclic compounds towards W79 mammalian cells in vitro has been determined. Cells with varying concentrations of drugs were incubated in air at 37°C for up to 14 days in order to form colonies. It was found that the concentration of nitro compound required to reduce cell colony-forming ability by 50% was a function of the one-electron reduction potential of the compound, more cytotoxic compounds having more positive potentials.

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

An homologous series of 1-(omega-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.