Effects of the interaction between carbogen and nicotinamide on R3230 Ac tumor blood flow in fischer 344 rats

The purpose of this study was to determine whether there are interactions between carbogen breathing and various doses of nicotinamide at the level of the tumor arteriole that might contribute to the improvement in tumor blood flow and pO₂ that is often seen with this combination treatment. R3230 adenocarcinomas were implanted and grown to 4-5 mm in dorsal skin flap window chambers in F344 rats. Saline or 65, 200 or 500 mg/kg nicotinamide was injected i.p. while the rat breathed air through a face mask. After 20 min, either the breathing gas was switched to carbogen for 60 min or the animal remained on air. Measured end points included diameter of tumor arterioles, tumor perfusion, mean arterial blood pressure, and heart rate. None of the measured parameters were affected by injection of saline or nicotinamide, except at the highest nicotinamide dose (500 mg/kg). Mean arterial blood pressure showed a median decrease of 25% when 500 mg/kg nicotinamide was given. Diameter of tumor arterioles decreased significantly from 5-15 min after 500 mg/kg nicotinamide was given but was back to baseline by 20 min. Blood flow decreased significantly 5-20 min after administration of 500 mg/kg nicotinamide compared to the baseline prior to injection. Carbogen breathing resulted in a small increase in mean arterial blood pressure in all groups. There was a transient decrease in the diameter of tumor arterioles and blood flow during the first 5 min of carbogen breathing that was statistically significant in several groups. In the group injected with 500 mg/kg nicotinamide, the diameter of tumor arterioles increased by about 10% during the first 25 min of carbogen breathing, and blood flow increased by a median of 75% over the level prior to carbogen breathing up to 40 min after carbogen breathing. The increase in flow in this group was most likely caused by the concomitant arteriolar vasodilation. Thus there was direct evidence for an interaction between carbogen breathing and nicotinamide, but only at the dose of 500 mg/kg nicotinamide. Since this dose yields plasma levels of nicotinamide that are higher than can be tolerated clinically, it is uncertain whether these changes in arteriolar diameter and blood flow would occur in human tumors.