Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals.

Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals. Research Abstract Details 

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Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals. Abstract Text:

Ryan J Hansen,Susan M Ludeman,Sari J Paikoff,Anthony E Pegg,M Eileen Dolan,Ryan J Hansen,Susan M Ludeman,Sari J Paikoff,Anthony E Pegg,M Eileen Dolan,

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects cells from the biological consequences of alkylating agents by removing alkyl groups from the O(6)-position of guanine. Cyclophosphamide and ifosfamide are oxazaphosphorines used clinically to treat a wide variety of cancers; however, the role of MGMT in recognizing DNA damage induced by these agents is unclear. In vitro evidence suggests that MGMT may protect against the urotoxic oxazaphosphorine metabolite, acrolein. Here, we demonstrate that Chinese hamster ovary cells transfected with MGMT are protected against cytotoxicity following treatment with chloroacetaldehyde (CAA), a neuro- and nephrotoxic metabolite of cyclophosphamide and ifosfamide. The mechanism by which MGMT recognizes damage induced by acrolein and CAA is unknown. CHO cells expressing a mutant form of MGMT (MGMT(R128A)), known to have >1000-fold less repair activity towards alkylated DNA while maintaining full active site transferase activity towards low molecular weight substrates, exhibited equivalent CAA- and acrolein-induced cytotoxicity to that of CHO cells transfected with plasmid control. These results imply that direct reaction of acrolein or CAA with the active site cysteine residue of MGMT, i.e. scavenging, is unlikely a mechanism to explain MGMT protection from CAA and acrolein-induced toxicity. In vivo, no difference was detected between Mgmt-/- and Mgmt+/+ mice in the lethal effects of cyclophosphamide. While MGMT may be important at the cellular level, mice deficient in MGMT are not significantly more susceptible to cyclophosphamide, acrolein or CAA. Thus, our data does not support targeting MGMT to improve oxazaphosphorine therapy.

Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals. Publishing Authors By Initials

RJ Hansen,SM Ludeman,SJ Paikoff,AE Pegg,ME Dolan,RJ Hansen,SM Ludeman,SJ Paikoff,AE Pegg,ME Dolan,

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Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: DNA repair

VOLUME: 6

Page Numbers: 1145-54

Journal Abbreviation: DNA Repair (Amst.)

ISSN: 1568-7864

DAY: 7

MONTH: 05

YEAR: 2007

Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals. Information

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LANGUAGE: eng

NlmUniqueID: 101139138

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Grant and Affiliation Information for Role of MGMT in protecting against cyclophosphamide-induced toxicity in cells and animals.

AFFILIATION: Committee on Cancer Biology, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.

Country: Netherlands

AGENCY: United States NCI

GRANT: R01 CA081485-03

ACRONYM: CA

MEDLINETA: DNA Repair (Amst)

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