Nicotinamide (NA) and pentoxifylline (PTX) sensitize experimental murine tumors to radiation without sensitizing normal tissues. They are presumed to exert this effect by reducing hypoxia in tumors. The present study evaluated the individual and combined effects of NA and PTX on oxygen levels in subcutaneous normal tissue and subcutaneous FSa fibrosarcoma tumors in the hind foot dorsum of C3H mice. Oxygen measurements were made using a polarographic needle electrode inserted into the tissue immediately before and/or 15-60 min after intraperitoneal administration of 500 mg/kg of NA, 50 mg/kg of PTX, or saline. The median tumor pO2 increased from a mean +/- S.E.M. of 4.1 +/- 1.1 mm Hg in saline-treated control mice to 6.8 +/- 1.9 mm Hg 15 min after NA, 7.6 +/- 1.4 mm Hg 60 min after PTX, and 6.7 +/- 1.1 mm Hg after NA and PTX in combination. PTX raised the median tumor pO2 level from 21% to 39% of the median subcutaneous normal tissue pO2 (p < 0.01). PTX also significantly reduced the proportion of tumor pO2 values < or = 2 mm Hg from 41 +/- 10% to 8 +/- 7% (p = 0.02). Although NA did increase the proportion of tumor that was well oxygenated, it did not significantly reduce the proportion of tumor pO2 values < or = 2 mm Hg (p = 0.34). The combination of NA and PTX did not add to the tumor oxygenation enhancement achieved by PTX alone. NA increased the median subcutaneous normal tissue pO2 by an average of 5.1 +/- 2.2 mm Hg from a baseline of 17.1 +/- 2.2 mm Hg (p = 0.04). PTX had no effect on the median normal tissue pO2 (p = 0.93). PTX showed greater therapeutic potential in this model system than did NA.