Is sensitization with nicotinamide and carbogen dependent on nicotinamide concentration at the time of irradiation?

To determine whether tumour radiosensitization and the therapeutic benefit of administering carbogen with nicotinamide depend upon irradiating at the time of peak drug concentration.

Local tumour control of CaNT tumours in CBA mice and acute skin reactions in albino WHT mice were assessed after treatment with 10 X-ray fractions in air, carbogen alone or combined with 0.1, 0.2 or 0.5 mg g(-1) nicotinamide, injected 15, 30 or 60 min before irradiation. Plasma and tumour drug pharmacokinetics were performed.

Nicotinamide was rapidly taken up into tumours; a six- and threefold higher concentration was obtained with 0.5 mg g(-1) compared with 0.1 and 0.2 mg g(-1), respectively. Tumour, but not skin, radiosensitization increased as the dose of nicotinamide increased (p = 0.03), but at each dose level there was no significant difference in radiosensitivity when irradiations were done at or after the time of peak concentration. An almost eightfold increase in plasma levels increased tumour enhancement ratios from 1.74 to 1.92 (p < 0.0001). In tumours all schedules gave significant enhancement relative to carbogen alone (p < or = 0.04).

Tumour and skin radiosensitivity was independent of time of nicotinamide administration. Higher drug concentrations were not mirrored by proportionally higher enhancement ratios. Lower plasma levels than previously suggested significantly enhanced tumour radiosensitivity relative to carbogen alone. The clinical implications of these findings are discussed.