The farnesyltransferase inhibitor L744,832 reduces hypoxia in tumors expressing activated H-ras

Many tumors contain extensive regions of hypoxia. Because hypoxic cells are markedly more resistant to killing by radiation, repeated attempts have been made to improve the oxygenation of tumors to enhance radiotherapy. We have studied the oxygenation of tumor xenografts in nude mice after treatment...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2001-03, Vol.61 (5), p.2289-2293
Main Authors: COHEN-JONATHAN, Elizabeth, EVANS, Sydney M, KOCH, Cameron J, MUSCHEL, Ruth J, MCKENNA, W. Gillies, JUNMIN WU, BERNHARD, Eric J
Format: Article
Language:English
Subjects:
Alkyl and Aryl Transferases - antagonists & inhibitors
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Hypoxia - drug effects
Chemotherapy
Enzyme Inhibitors - pharmacology
farnesyltransferase
Farnesyltranstransferase
Gene Expression
Genes, ras - genetics
H-ras gene
HT29 Cells - drug effects
HT29 Cells - enzymology
HT29 Cells - metabolism
Humans
Medical sciences
Methionine - analogs & derivatives
Methionine - pharmacology
Mice
Mice, Nude
Mutation
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - metabolism
Oxygen - metabolism
Pharmacology. Drug treatments
ras Proteins - biosynthesis
ras Proteins - genetics
Xenograft Model Antitumor Assays
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Summary:Many tumors contain extensive regions of hypoxia. Because hypoxic cells are markedly more resistant to killing by radiation, repeated attempts have been made to improve the oxygenation of tumors to enhance radiotherapy. We have studied the oxygenation of tumor xenografts in nude mice after treatment with the farnesyltransferase inhibitor L744,832. Hypoxia was assessed by measuring the binding of the hypoxic cell marker pentafluorinated 2-nitroimidazole. We show that xenografts from two tumor cell lines with mutations in H-ras had markedly improved oxygenation after farnesyltransferase treatment. In contrast, xenografts from two tumors without ras mutations had equivalent hypoxia regardless of treatment. The effect on tumor oxygenation could be detected at 3 days and remained after 7 days of treatment. These results indicate that treatment with farnesyltransferase inhibitors can alter the oxygenation of certain tumors and suggest that such treatment might be useful in the radiosensitization of these tumors.
ISSN:0008-5472
1538-7445