PEG-hemoglobin: Effects on tumor oxygenation and radiosensitization

Derivatization with polyethylene glycol (PEG) is a biocompatible method to improve the therapeutic benefit of administered proteins by increasing their biological half-life. The ability of a PEG-bovine hemoglobin preparation (2-8 ml/kg) to increase the oxygen content of hypoxic tumor regions was determined in rats bearing the 13762 mammary carcinoma using an Eppendorf pO₂ histograph. Administration of PEG-hemoglobin decreased the percent of pO₂ readings ≤ 5 mmHg in animals breathing air or breathing carbogen, respectively. In rats, PEG-hemoglobin has a circulating half-life of 20 hr. A single administration of PEG-hemoglobin was able to provide increased tumor oxygenation on the following at least 3 days if atmospheres of 28% oxygen or carbogen were breathed. PEG-hemoglobin administration along with fractionated radiation therapy (2, 3 or 4 Gy x 5) resulted in radiation dose modifying factors of 1.2 ± 0.2, 1.4 ± 0.2 and 1.5 ± 0.2 when the animals breathed air, 28% oxygen or carbogen prior to and during radiation delivery, respectively. Using the EMT-6 murine mammary carcinoma tumor cell survival assay, administration of PEG-hemoglobin (6 ml/kg) prior to single dose radiation therapy resulted in dose modifying factors of 1.4 ± 0.2 1.8 ± 0.2 and 1.9 ± 0.2 when the animals breathed air, 28% oxygen or carbogen prior to and during radiation delivery, respectively. In EMT-6 tumor growth delay, administration of PEG-hemoglobin (6 ml/kg) along with fractionated radiation therapy (2, 3 or 4 Gy x 5) resulted in dose modifying factors of 1.2 ± 0.2, 1.5 ± 0.2 and 1.7 ± 0.2 when the animals breathed air, 28% oxygen or carbogen prior to and during radiation delivery. Administration of PEG-hemoglobin only on the first treatment day of a 5-day fractionated radiation therapy regimen resulted in dose modifying factors of 1.3 ± 0.2 and 1.4 ± 0.2 if the animals breathed 28% oxygen or carbogen prior to and during each radiation fraction delivery. Further investigation of this potentially clinically important oxygen delivery agent is warranted.