O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib.

Content Provider	Europe PMC
Author	Watson, A J Middleton, M R McGown, G Thorncroft, M Ranson, M Hersey, P McArthur, G Davis, I D Thomson, D Beith, J Haydon, A Kefford, R Lorigan, P Mortimer, P Sabharwal, A Hayward, O Margison, G P
Copyright Year	2009
Abstract	We evaluated the pharmacodynamic effects of the O6-methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O6-methylguanine (O6-meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O6-meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O6-meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O6-meG in PBMC DNA during treatment.
ISSN	00070920
Journal	British Journal of Cancer
Volume Number	100
PubMed Central reference number	PMC2676560
Issue Number	8
PubMed reference number	19367283
e-ISSN	15321827
DOI	10.1038/sj.bjc.6605015
Language	English
Publisher	Nature Publishing Group
Publisher Date	2009-04-01
Access Restriction	Open
Rights License	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. Copyright © 2009 Cancer Research UK
Subject Keyword	O6-methylguanine-DNA methyltransferase lomeguatrib temozolomide melanoma
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology