Increased efficacy of chemo- and radio-therapy by a hemoglobin solution in the 9L gliosarcoma.
Tissue oxygen tensions were measured in the rat 9L gliosarcoma under conditions of normal air breathing or carbogen breathing and after intravenous administration of a hemoglobin solution with air breathing or carbogen breathing. Administration of the hemoglobin decreased the level of hypoxia in the tumors. Treatment of the animals with the antiangiogenic combination of TNP-470 and minocycline also increased tumor oxygenation compared with untreated controls. Treatment with the antiangiogenic agents along with administration of the hemoglobin solution/carbogen breathing decreased the hypoxic fraction (% pO2 readings < or = 5 mmHg) from 71 % to 30%. Treatment of the tumor-bearing animals with BCNU or adriamycin modestly reduced hypoxia in the tumors, while treatment with fractionated radiation markedly increased hypoxia in the tumors. Tumor growth delay was used to assess the response of the subcutaneous tumor to the various treatment combinations. There was a strong correlation between increased therapeutic response and decreased tumor hypoxia. Tumor growth delay from BCNU increased from 5.3 days to 16.4 days with TNP-470/-minocycline/hemoglobin solution/carbogen. Similarly, the tumor growth delay from adriamycin increased from 3.9 days to 17.0 days with TNP-470/minocycline/hemoglobin solution/carbogen. Finally, the tumor growth delay from fractionated radiation increased from 4.8 days to 13.3 days with TNP-470/minocycline/hemoglobin solution/carbogen. When etanidazole was added to the complete radiation regimen, the tumor growth delay increased further to 20.5 days. These data show that the addition of non-toxic agents that increase tumor oxygenation to cytotoxic therapies can markedly increase therapeutic response.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Dupuis
N P
NP
Emi
Y
Y
Ikebe
M
M
Kakeji
Y
Y
Menon
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D002245:Carbon Dioxide; D002330:Carmustine / Q000494:pharmacology; D002417:Cattle; D003131:Combined Modality Therapy; D003510:Cyclohexanes; D005260:Female; D018316:Gliosarcoma / Q000188:drug therapy* / Q000532:radiotherapy*; D006454:Hemoglobins / Q000627:therapeutic use*; D006801:Humans; D008911:Minocycline / Q000494:pharmacology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010100:Oxygen / Q000378:metabolism; D011838:Radiation-Sensitizing Agents; D051381:Rats; D011916:Rats, Inbred F344; D012717:Sesquiterpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D006454:Hemoglobins; D011838:Radiation-Sensitizing Agents; D012717:Sesquiterpenes; D002245:Carbon Dioxide; C011700:carbogen; D008911:Minocycline; D010100:Oxygen; D002330:Carmustine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol