O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib.
We evaluated the pharmacodynamic effects of the O(6)-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 O(6)-methylguanine (O(6)-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 O(6)-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 O(6)-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 O(6)-meG in PBMC DNA during treatment.
Watson
A J
AJ
Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK.
Middleton
M R
MR
McGown
G
G
Thorncroft
M
M
Ranson
M
M
Hersey
P
P
McArthur
G
G
Davis
I D
ID
Thomson
D
D
Beith
J
J
Haydon
A
A
Kefford
R
R
Lorigan
P
P
Mortimer
P
P
Sabharwal
A
A
Hayward
O
O
Margison
G P
GP
D000970:Antineoplastic Agents / Q000633:toxicity; D001706:Biopsy; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity; D018450:Disease Progression; D006801:Humans; D007700:Kinetics; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D011687:Purines / Q000633:toxicity*; D000077204:Temozolomide
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011687:Purines; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C521206:lomeguatrib; D000077204:Temozolomide