In situ tumour radiosensitization induced by clofibrate administration: single dose and fractionated studies.
It is generally accepted that hypoxia is a common occurrence in many experimental and human tumours and that it is a major cause of local failure after radiotherapy. Many attempts have been made over the last years to eliminate this problem. One of the manoeuvres to improve tumour oxygenation is to manipulate the binding affinity of oxygen (O2) and haemoglobin (Hb). Previous studies have shown that some antilipidaemic drugs (clofibrate and its analogues) can reduce the Hb/O2 binding affinity and sensitize various animal tumours to radiation. The present study evaluated the ability of clofibrate to sensitize in situ a mouse carcinoma (CaNT) to radiation. Clofibrate at 1.5 mmol/kg increased the tumour radiosensitivity, when it was administered per os 2-6 h before a single radiation dose or 2 to 4 h before each of 10 fractions in 5 days. In both the single dose and fractionated regimens, the radiosensitizing effect was drug dose-dependent, but was only statistically significant at doses from 1.0 to 2.0 mmol/kg. These results suggest that clofibrate may be an effective radiosensitizer at radiation doses that are clinically relevant. Further experiments need to be carried out to evaluate clofibrate analogues for their radiosensitizing properties. Clofibrate tolerable doses in man have to be determined first in order to know if clofibrate and analogues could play a role in the clinical management of tumours where hypoxia may limit the outcome of radiotherapy.
Calais
G
G
CRC Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex, U.K.
Hirst
D G
DG
D000818:Animals; D002994:Clofibrate / Q000008:administration & dosage / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D000860:Hypoxia / Q000139:chemically induced; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000532:radiotherapy*; D051379:Mice; D008808:Mice, Inbred CBA; D010101:Oxygen Consumption; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D011879:Radiotherapy Dosage
D011838:Radiation-Sensitizing Agents; D002994:Clofibrate