The radiation response of KHT sarcomas following nicotinamide treatment and carbogen breathing

Preclinical investigations have demonstrated that both diffusion- and perfusion-limited hypoxic cells may exist in tumors. One approach to target such hypoxic cell subpopulations is through the combined application of nicotinamide (NIC) administration and carbogen (5% CO2:95% O2) breathing. Because carbogen pre-irradiation breathing time (PIBT) can markedly influence the radiosensitizing effectiveness of this gas mixture, in the present experiments the effect of localized radiation on the transplantable KHT sarcoma was investigated in mice receiving NIC while breathing carbogen for various periods of time. When mice were given carbogen prior to radiation therapy, there was a minimum in tumor cell survival for PIBTs of 2-30 min. Longer PIBTs led to a loss of the radiosensitizing effect. NIC, administered as a 1000-mg/kg dose, effectively enhanced radiation cell killing in this tumor if given 45 min to 2 h prior to radiotherapy. In experiments in which either agent was combined on its own under optimum conditions (carbogen, 10 min PIBT; or NIC, 1000 mg/kg 2 h prior to irradiation), with a range of single doses of radiation, the results showed an enhancement ratio of approximately 1.9 as determined from the ratio of the slopes of the cell survival curves obtained in the absence or presence of the radiation sensitizer. This sensitizing effect could not be increased further when NIC and carbogen breathing were combined under optimum conditions.