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Radiat Res. 1987 Oct;112(1):164-72.
The modification of hemoglobin affinity for oxygen and tumor radiosensitivity by antilipidemic drugs.

Hirst DG, Wood PJ, Schwartz HC.

Department of Therapeutic Radiology, Stanford School of Medicine, Stanford University, California 94305.

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.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3477829&dopt=Abstract




Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1995 Jun;111(2):317-23.
Hypolipidemic agents alter hepatic mitochondrial respiration in vitro.

Chance DS, McIntosh MK.

Department of Food, Nutrition, and Food Service Management, University of North Carolina at Greensboro 27412, USA.

The direct effects of three different classes of structurally diverse hypolipidemic agents on respiration were studied in mitochondria isolated from donor Sprague-Dawley rats. Two classes of peroxisome proliferators (i.e. plasticizers and hypolipidemic hormones and drugs) and one class of peroxisome inhibitors (i.e. anti-psychotic drugs) were studied. The phthalate ester plasticizers dibutylphthalate, ethylhexanoic acid and di(2-ethylhexyl) adipate, the hypolipidemic hormones or drugs dehydro-epiandrosterone (DHEA), thyroxine (T4), triiodothyronine (T3), gemfibrozil, clofibrate and naphthoflavone, and the anti-psychotic drugs chlorpromazine, thioridazine and fluphenazine were studied. As the dose of the plasticizer dibutylphthalate increased from 8 to 200 mumol/l, there was a decrease (P < 0.05) in state 3 (+ADP) respiration and in the respiratory control ratio for both substrates tested. The anti-psychotic drug chlorpromazine decreased state 3 malate + pyruvate-supported respiration and increased state 3 succinate-supported respiration. As the concentration of all three anti-psychotic drugs increased, there was a linear increase in state 4 respiration (-ADP) and a decrease in the respiratory control ratio for both substrates tested. As the dose of the hypolipidemic agents DHEA, gemfibrozil and T4 increased, there was a linear reduction in state 3 malate + pyruvate-supported respiration. However, when succinate was used as the substrate to support respiration, only the thyroid hormones significantly decreased state 3 respiration. Gemfibrozil, T4 and T3 increased state 4 respiration, regardless of the substrate used. As the dose of clofibrate, gemfibrozil, and the thyroid hormones increased, there was a linear reduction in the respiratory control ratio for both substrates tested.(ABSTRACT TRUNCATED AT 250 WORDS)

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8521251&dopt=Abstract




Atherosclerosis. 1987 Oct;67(2-3):181-9.
Change in composition of high density lipoprotein during gemfibrozil therapy.

Sorisky A, Ooi TC, Simo IE, Meuffels M, Hindmarsh JT, Nair R.

Division of Endocrinology, Ottawa Civic Hospital, Ont., Canada.

We investigated the high density lipoprotein cholesterol (HDL-C) response in 20 middle-aged males during a 12-week course of gemfibrozil. Three aspects of the increase in HDL-C (25%) were studied and our observations are as follows: (1) subfraction analysis showed that HDL3-C rose earlier and to a larger extent (28%) than HDL2-C (15%), (2) analysis of variance group--time interaction effect and correlation studies of HDL-C and total triglycerides suggest the increase in HDL-C was due to a direct effect of gemfibrozil on HDL metabolism, and (3) HDL-C was the only one of 4 HDL components to increase. Apoprotein A-I (apo A-I) and HDL-phospholipid (HDL-PL) did not change, and HDL-triglyceride (HDL-TG) decreased. This pattern is consistent with a change in composition of HDL, i.e. cholesterol enrichment and triglyceride depletion.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3118893&dopt=Abstract












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