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The modification of hemoglobin affinity for oxygen and tumor radiosensitivity by antilipidemic drugs
D G Hirst1, P J Wood, H C Schwartz
1Department of Therapeutic Radiology, Stanford School of Medicine, Stanford University, California 94305.
Abstract:
It has been recognized for some time that alterations in the affinity of Hb for oxygen could offer a means of improving oxygen delivery to tumors and achieving radiosensitization. Three antilipidemic drugs, clofibrate, bezafibrate, and gemfibrozil, two of which had previously been shown to reduce Hb/O2 affinity in vitro, were tested in mice for their ability to affect Hb/O2 affinity and to alter the radiosensitivity of the RIF-1 sarcoma. Each of the drugs produced a significant increase in the P50 of the blood, from a mean control value of 45 mm Hg to 55, 74, and 51 mm Hg after a dose of 1 g/kg of clofibrate, bezafibrate, and gemfibrozil, respectively. However, they had very different effects on the radiosensitivity of the RIF-1 tumor. When the mice breathed air at the time of irradiation, clofibrate produced a marked sensitization equivalent at the optimum time to a 20-fold reduction in hypoxic fraction; bezafibrate gave a lower sensitization equivalent to a 4-fold reduction, while gemfibrozil caused dramatic radioresistance equivalent to a 10-fold increase in hypoxic fraction. When the mice were given 95% O2/5% CO2 to breathe at the time of irradiation to ensure complete Hb saturation in the lungs, a large increase in the sensitization by bezafibrate was seen, but there was only a small change with clofibrate. We conclude that drugs which reduce Hb/O2 affinity could have a role in sensitizing tumors to radiation.
Insights
Altering hemoglobin (Hb) oxygen affinity with antilipidemic drugs can improve tumor oxygen delivery and radiosensitization. Clofibrate and bezafibrate showed potential for sensitizing tumors to radiation therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Radiation Oncology
Background:
- Altering hemoglobin (Hb) oxygen affinity is a strategy to enhance tumor oxygen delivery and radiosensitization.
- Antilipidemic drugs are investigated for their potential to modify Hb oxygen affinity.
Purpose of the Study:
- To evaluate the effects of clofibrate, bezafibrate, and gemfibrozil on Hb oxygen affinity and RIF-1 sarcoma radiosensitivity in mice.
- To determine if reducing Hb oxygen affinity can sensitize tumors to radiation therapy.
Main Methods:
- Three antilipidemic drugs (clofibrate, bezafibrate, gemfibrozil) were administered to mice at 1 g/kg.
- Hb oxygen affinity was assessed by measuring blood P50 values.
- RIF-1 sarcoma radiosensitivity was evaluated under normal air breathing and hyperoxic conditions (95% O2/5% CO2) during irradiation.
Main Results:
- All three drugs significantly increased blood P50, indicating reduced Hb oxygen affinity.
- Clofiibrate and bezafibrate demonstrated radiosensitizing effects on the RIF-1 tumor, while gemfibrozil induced radioresistance.
- Bezafibrate's sensitization effect was more pronounced under hyperoxic conditions.
Conclusions:
- Drugs that reduce Hb oxygen affinity hold potential for sensitizing tumors to radiation.
- The efficacy of these drugs in modulating radiosensitivity varies, suggesting differential mechanisms of action.
- Further research into Hb oxygen affinity modifiers could lead to improved cancer treatment strategies.