Ocular absorption and toxicity of a radiosensitizer and its effect on hypoxic cells

The recurrence of retinoblastoma after radiation treatment may be related to hypoxic cell radioresistance. Radiosensitizing drugs acting on hypoxic cells without affecting the response of oxygenated cells could improve treatment of ocular tumors while minimizing complications of radiotherapy. A desmethyl derivative of misonidazole is as effective a radiosensitizer as misonidazole (as measured in vitro) and is better suited to ocular administration, since it is more soluble than misonidazole. We studied the ocular toxic effects of a desmethyl derivative of misonidazole after subconjunctival administration of 140 and 70 mg. The higher dose produced an intolerable ocular toxic effect, but at the lower dose, the toxic effect was moderate and reversible. We compared ocular pharmacokinetics of the desmethyl derivative of misonidazole after subconjunctival and intravenous (IV) injections. Subconjunctival administration yielded vitreous and anterior chamber concentrations of the radiosensitizer sufficient to produce a notable dose-modifying effect (as high as 1.8 in the anterior chamber and 1.25 in the vitreous at 70-mg doses). In contrast, even at doses of 140 mg, IV injections of the desmethyl derivative of misonidazole did not result in therapeutically useful ocular levels.