Antiangiogenic agents can increase tumor oxygenation and response to radiation therapy

The Lewis lung carcinoma growing subcutaneously in the hind leg of male C57BL mice is very hypoxic, having 92% of the pO₂ measurements ≤ 5 mmHg as determined with a polarographic oxygen electrode. Administration of a perflubron emulsion (8 ml/kg) along with carbogen breathing increased the tumor oxygen level so that 82% of the pO₂ readings were ≤ 5 mmHg. Treating tumor‐bearing animals with TNP‐470 (30 mg/kg, s.c.) on alternate days and minocycline (10 mg/kg, i.p.) daily beginning on day 4 after tumor cell implantation resulted in decreased hypoxia in the tumors on day 9 when pO₂ measurements were made. The percent of pO₂ readings ≤ 5 mmHg in the tumors of the TNP‐470/ minocycline‐treated animals was 75%, which upon administration of the perflubron emulsion along with carbogen breathing was reduced to 45%. Therapeutically daily fractionated radiation (2, 3, or 4 Gy ≤ 5) was used as an oxygen‐dependent cytotoxic modality. The radiation response of the rumors in TNP‐470/minocycline‐treated animals was greater than that in the untreated tumors. The addition of carbogen breathing for 1 hr prior to and during radiation delivery further increased the radiation response so that overall there was a 2.2‐fold increase in the tumor growth delay produced by the fractionated radiation in the animals treated with TNP‐470/minocycline compared with untreated animals. Administration of the perflubron emulsion along with carbogen breathing prior to and during radiation delivery resulted in a 3.4‐fold increase in tumor growth delay by the fractionated radiation regimens in the TNP‐470/minocycline‐treated animals compared with the tumor growth delay obtained with radiation alone. There was a linear relationship between decrease in the percent of pO₂ readings ≤ 5 mmHg and tumor growth delay at each radiation dose indicating that the diminution in tumor hypoxia produced by these treatments may be directly responsible for the increase in the effectiveness of the radiation therapy. © 1995 Wiley‐Liss, Inc.