Restoration of tumor oxygenation after cytotoxic therapy by a perflubron emulsion/carbogen breathing.
OBJECTIVE
Hypoxic cells are presumed to be an obstacle to successful cancer treatment because these cells are protected from the cytotoxic effects of radiotherapy and certain anti-cancer drugs. The current study was conducted to determine the effect of cytotoxic therapy on tumor oxygenation and the effect of administration of a perfluorochemical emulsion/carbogen breathing treatment on tumor oxygenation after cytotoxic therapy.


METHODS
Female Fisher 344 rats bearing 13762 mammary carcinoma cells implanted subcutaneously in a hindlimb were treated with standard therapeutic single doses of anti-tumor treatments of several types, including alkylating agents (cisplatin, melphalan, cyclophosphamide); natural products (doxorubicin, paclitaxel, etoposide); antimetabolites (fluorouracil); hypoxic cell-selective agents (mitomycin, SR-4233); and fractionated irradiation (3 Gy/day for 5 days). The oxygen levels in the tumors were measured with an Eppendorf PO2 histograph before the treatment and 24 hours after treatment under air breathing and carbogen breathing conditions, and after administration of a perflubron emulsion under air breathing and carrbogen breathing conditions. Fifty to 60 points were measured per tumor, and 8 to 10 tumors made up each group.


RESULTS
The tumors were more hypoxic after treatment with every anticancer treatment. The percentage of PO2 readings < or = 5 mmHg in the untreated tumors was 49% and ranged from 85% (radiotherapy) to 59% (etoposide) in the treated tumors. Administration of the perflubron emulsion (8 mL/kg) and carbogen breathing (95% O2/5% CO2) increased the oxygenation of the tumors such that the percentage of PO2 readings < or = 5 mmHg was 32% in the untreated control tumors and ranged from 27% (radiotherapy) to 56% (doxorubicin) in the treated tumors. There was a direct correlation between the level of tumor cell killing and the increased oxygenation observed in the tumor.


CONCLUSIONS
Tumors may be more hypoxic after an effective dose of a cytotoxic therapy, and administration of a perflubron emulsion/carbogen mixture can increase the tumor oxygen content when hypoxia is the result of cytotoxic therapy. Hypoxia produced by therapy may be regarded as a mechanism of resistance that leads to diminished tumor cell killing with subsequent doses of drugs or radiation. The restoration of tumor oxygenation by the perflubron emulsion/carbogen breathing may provide a clinically relevant means of overcoming at least in part hypoxia-related resistance.
Teicher
B A
BA
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, Massachusetts 02115, USA.
Holden
S A
SA
Ara
G
G
Dupuis
N P
NP
Goff
D
D
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002245:Carbon Dioxide / Q000627:therapeutic use* / Q000633:toxicity; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004655:Emulsions; D005260:Female; D005466:Fluorocarbons / Q000627:therapeutic use* / Q000633:toxicity; D006842:Hydrocarbons, Brominated; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D010100:Oxygen / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D004655:Emulsions; D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D002245:Carbon Dioxide; C011700:carbogen; C003072:perflubron; D010100:Oxygen