RT Journal Article
SR Electronic
T1 Temozolomide Pharmacodynamics in Patients with Metastatic Melanoma: DNA Damage and Activity of Repair Enzymes <em>O</em><sup>6</sup>-Alkylguanine Alkyltransferase and Poly(ADP-Ribose) Polymerase-1
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 3402
OP 3409
DO 10.1158/1078-0432.CCR-04-2353
VO 11
IS 9
A1 Plummer, E. Ruth
A1 Middleton, Mark R.
A1 Jones, Christopher
A1 Olsen, Anna
A1 Hickson, Ian
A1 McHugh, Peter
A1 Margison, Geoffrey P.
A1 McGown, Gail
A1 Thorncroft, Mary
A1 Watson, Amanda J.
A1 Boddy, Alan V.
A1 Calvert, A. Hilary
A1 Harris, Adrian L.
A1 Newell, David R.
A1 Curtin, Nicola J.
YR 2005
UL http://clincancerres.aacrjournals.org/content/11/9/3402.abstract
AB Purpose: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)–dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. Experimental Design: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. Results: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 ± 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. Conclusions: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.