PMID- 21811257
OWN - NLM
STAT- MEDLINE
DCOM- 20111025
LR  - 20211020
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 105
IP  - 6
DP  - 2011 Sep 6
TI  - Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib 
      in combination with dacarbazine in patients with advanced melanoma and other 
      solid tumours.
PG  - 773-7
LID - 10.1038/bjc.2011.285 [doi]
AB  - BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) 
      reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion 
      of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the 
      first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, 
      combined with dacarbazine. METHODS: This is a phase I dose-escalation study to 
      determine the maximum tolerated dose and recommended phase II dose (RP2D) of 
      lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. 
      RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma 
      (36/41) and most had no previous chemotherapy (30/41). The most frequent 
      non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The 
      most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia 
      (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 
      patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally 
      twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. 
      Oral administration of lomeguatrib substantially increases the haematological 
      toxicity of dacarbazine consistent with experience with other O6-meG 
      pseudosubstrates.
FAU - Tawbi, H A
AU  - Tawbi HA
AD  - Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, 
      Pittsburgh, PA, USA. tawbih@upmc.edu
FAU - Villaruz, L
AU  - Villaruz L
FAU - Tarhini, A
AU  - Tarhini A
FAU - Moschos, S
AU  - Moschos S
FAU - Sulecki, M
AU  - Sulecki M
FAU - Viverette, F
AU  - Viverette F
FAU - Shipe-Spotloe, J
AU  - Shipe-Spotloe J
FAU - Radkowski, R
AU  - Radkowski R
FAU - Kirkwood, J M
AU  - Kirkwood JM
LA  - eng
GR  - P50 CA090440/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110802
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Purines)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - S79265T71M (lomeguatrib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - Dacarbazine/*administration & dosage
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Melanoma/*drug therapy
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - O(6)-Methylguanine-DNA Methyltransferase/*antagonists & inhibitors
MH  - Purines/*administration & dosage
PMC - PMC3171007
EDAT- 2011/08/04 06:00
MHDA- 2011/10/26 06:00
PMCR- 2012/09/06
CRDT- 2011/08/04 06:00
PHST- 2011/08/04 06:00 [entrez]
PHST- 2011/08/04 06:00 [pubmed]
PHST- 2011/10/26 06:00 [medline]
PHST- 2012/09/06 00:00 [pmc-release]
AID - bjc2011285 [pii]
AID - 10.1038/bjc.2011.285 [doi]
PST - ppublish
SO  - Br J Cancer. 2011 Sep 6;105(6):773-7. doi: 10.1038/bjc.2011.285. Epub 2011 Aug 2.