06-methyguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

Watson, A. J., Middleton, M. R., McGowan, G., Thorncroft, M., Ranson, M., Hersey, P., McArthur, G., Davis, I. D., Thomson, Damien B., Beith, J., Haydon, A., Kefford, R., Lorigan, P., Mortimer, P., Sabharwal, A., Hayward, O. and Margison, G. P . (2009) 06-methyguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib. British Journal of Cancer, 100 8: 1250-1256. doi:10.1038/sj.bjc.6605015


Author Watson, A. J.
Middleton, M. R.
McGowan, G.
Thorncroft, M.
Ranson, M.
Hersey, P.
McArthur, G.
Davis, I. D.
Thomson, Damien B.
Beith, J.
Haydon, A.
Kefford, R.
Lorigan, P.
Mortimer, P.
Sabharwal, A.
Hayward, O.
Margison, G. P .
Title 06-methyguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib
Formatted title
06-methyguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2009-04-14
Sub-type Article (original research)
DOI 10.1038/sj.bjc.6605015
Open Access Status DOI
Volume 100
Issue 8
Start page 1250
End page 1256
Total pages 7
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Keyword O6-methylguanine-DNA methyltransferase
Lomeguatrib
Temozolomide
Melanoma
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Wed, 14 Apr 2010, 11:50:54 EST by Denise Wilson on behalf of Medicine - Princess Alexandra Hospital