Induction of severe tumor hypoxia by modifiers of the oxygen affinity of hemoglobin.

Methods have been compared for inducing severe hypoxia in experimental tumors. Hypoxic fractions in the tumors were obtained from measurements of the displacement of cellular survival plots in vitro following tumor irradiation in vivo. Two compounds that displace to the left, oxygen-hemoglobin association curves greatly increase the hypoxic fractions in the tumors. The compound BW12C increases the hypoxic fractions in the KHT and Lewis-Lung tumors from about 10% to between 50-100%. The longer acting analogue BW589C increases hypoxic fraction in the KHT tumor to the same level achievable by treatment with the vaso-active drug hydralazine. The effect is also observed in the RIF-1 tumor even though the hypoxic fraction in this tumor is normally only about 1-3%. The kinetics for hypoxia induction by BW589C and its subsequent return to normal levels are comparable to those for the left-shifting of the oxy-hemoglobin association curve observable up to about 2 days post treatment.