Metabolism of lomustine in dogs and comparative cytotoxicity of lomustine and its major metabolites and O6-methylguanine-DNA methyltransferase expression in canine cells
type: CreativeWork
description: The nitrosourea drug lomustine is used clinically for treating a wide variety of malignancies, most commonly brain tumors and lymphoma. Lomustine undergoes hydrolysis in vivo to form isomeric metabolites, primarily trans-4-hydroxylomustine (trans-4) and cis-4- hydroxylomustine (cis-4) in various animal species including humans. Despite its widespread usage to treat canine lymphoma, the metabolism of lomustine has not been studied in dogs. It is reported that 4’-hydroxylation products of lomustine (trans-4 and cis-4) have enhanced alkylating activity and reduced toxic effects relative to lomustine, resulting in a better therapeutic index of each of the metabolites relative to the parent compound. Our results show that the metabolic profile of lomustine in dogs is similar to that in humans with trans-4 being the major metabolite and cis-4 as the minor metabolite. Comparative cytotoxicity studies of lomustine and its trans-4 and cis-4 metabolites in canine lymphoma cell lines 17-71 and GL-1 show that there is no difference in the cytotoxicity of the three compounds. In addition, a concentration and time-dependent cell killing was seen in both of these cell lines. Also primary canine cells like peripheral blood mononuclear cells (PBMC) from lymphoma dogs and canine hepatocytes for normal dogs did not show any sensitivity towards lomustine and its metabolites. Alkylation is thought to be the reason for the efficacy of lomustine while carbamylation has been implicated as the cause for the side effects seen with lomustine treatment such as hepatotoxicity. In the alkylation study we show that lomustine and its metabolites form similar levels of the DNA adducts N7 hydroxyethylguanine and O6 hydroxyethyldeoxyguanosine. These adducts may be used as molecular dosimeters of therapeutic response thus correlating to the similar cytotoxicity of these compounds. In terms of carbamylation, lomustine showed greater extent of carbamylation in the canine hepatocytes and lymphoma cell li…
abstract: The nitrosourea drug lomustine is used clinically for treating a wide variety of malignancies, most commonly brain tumors and lymphoma. Lomustine undergoes hydrolysis in vivo to form isomeric metabolites, primarily trans-4-hydroxylomustine (trans-4) and cis-4- hydroxylomustine (cis-4) in various animal species including humans. Despite its widespread usage to treat canine lymphoma, the metabolism of lomustine has not been studied in dogs. It is reported that 4’-hydroxylation products of lomustine (trans-4 and cis-4) have enhanced alkylating activity and reduced toxic effects relative to lomustine, resulting in a better therapeutic index of each of the metabolites relative to the parent compound. Our results show that the metabolic profile of lomustine in dogs is similar to that in humans with trans-4 being the major metabolite and cis-4 as the minor metabolite. Comparative cytotoxicity studies of lomustine and its trans-4 and cis-4 metabolites in canine lymphoma cell lines 17-71 and GL-1 show that there is no difference in the cytotoxicity of the three compounds. In addition, a concentration and time-dependent cell killing was seen in both of these cell lines. Also primary canine cells like peripheral blood mononuclear cells (PBMC) from lymphoma dogs and canine hepatocytes for normal dogs did not show any sensitivity towards lomustine and its metabolites. Alkylation is thought to be the reason for the efficacy of lomustine while carbamylation has been implicated as the cause for the side effects seen with lomustine treatment such as hepatotoxicity. In the alkylation study we show that lomustine and its metabolites form similar levels of the DNA adducts N7 hydroxyethylguanine and O6 hydroxyethyldeoxyguanosine. These adducts may be used as molecular dosimeters of therapeutic response thus correlating to the similar cytotoxicity of these compounds. In terms of carbamylation, lomustine showed greater extent of carbamylation in the canine hepatocytes and lymphoma cell li…
author: Chakkath, Thushara
language: en
keywords: Lomustine, metabolites, cytotoxicity, alkylation, carbamylation, O6-methylguanine-DNA methyltransferase (MGMT)
date published: 2014-05-30T17:17:07Z
date modified: 2026-07-22T22:25:40Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/49776