Nitrofurans as radiosensitizers of hypoxic mammalian cells.

Abstract

Summary Our studies showed that various nitrofuran derivatives have excellent radiosensitizing properties in hypoxic Chinese hamster cells at concentrations at which there is no effect on plating efficiency. The radiosensitizing effect is primarily a dose-modifying effect, with nitrofurantoin, nitrofurazone, and nifuroxime (each at 500 µm) in complete medium giving enhancement ratios of 1.65, 2.0, and 2.2, respectively. In parallel studies, the radiosensitizing effect of molecular oxygen (air-saturated conditions) was found to be dose modifying, with an enhancement ratio of ∼2.9. Selective radiosensitization in hypoxia has been demonstrated in proliferating populations of cells in every phase of the cell cycle, as well as in nonproliferating populations which were contact inhibited at the time of irradiation. In all cell populations tested, these compounds did not alter radio-sensitivity in air-saturated conditions. The permeability of phospholipid membranes to nitrofurazone in 0.1 m NaCl has been measured, and a permeability constant (K) of 1.5 (± 0.7) × 10 -5 cm/sec obtained. No diffusion time lag was observed. In the presence of 0.1 m NaCl and 0.5 mm MgCl 2 , the permeability constant was increased to 2.5 (± 0.4) × 10 -5 cm/sec, and a diffusion lag time of 12 ± 3 min was obtained. Comparison of this constant with permeability constants for other molecules suggests that the phospholipid membrane presents no great barrier to the penetration of this compound. Hypoxia is shown to enhance the rate of radiation-induced binding of the label from nitrofurazone- 14 C to bovine serum albumin, DNA, polynucleotides, and Chinese hamster cells. Mechanisms of radiosensitization are discussed in relation to the observed binding and the antibacterial mode of action of the nitrofurans. The potential application of this class of compounds in the radiotherapy of tumors in which hypoxia is suspected is discussed in relation to their known pharmacological properties and current clinical usage.