O⁶-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

Watson, A. J.; Middleton, M. R.; Haydon, A.; Kefford, R.; Lorigan, P.; Mortimer, P.; Sabharwal, A.; Hayward, O.; Margison, G. P.; McGown, G.; Thorncroft, M.; Ranson, M.; Hersey, P.; McArthur, G.; Davis, I. D.; Thomson, D.; Beith, J.

Title: O⁶-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib
Creator: Watson, A. J.; Middleton, M. R.; Haydon, A.; Kefford, R.; Lorigan, P.; Mortimer, P.; Sabharwal, A.; Hayward, O.; Margison, G. P.; McGown, G.; Thorncroft, M.; Ranson, M.; Hersey, P.; McArthur, G.; Davis, I. D.; Thomson, D.; Beith, J.
Relation: British Journal of Cancer Vol. 100, Issue 8, p. 1250-1256
Publisher Link: http://dx.doi.org/10.1038/sj.bjc.6605015
Publisher: Nature Publishing Group
Resource Type: journal article
Date: 2009
Description: 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.
Subject: O⁶ methylguanine DNA methyltransferase; lomeguatrib; temozolomide; melanoma
Identifier: http://hdl.handle.net/1959.13/807485
Identifier: uon:7421
Identifier: ISSN:0007-0920
Language: eng
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