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Lookup NU author(s): Tomasz Zaremba, Huw ThomasORCiD, Mike ColeORCiD, Professor Ruth PlummerORCiD, Professor Nicola CurtinORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Springer, 2010.
For re-use rights please refer to the publisher's terms and conditions.
Monozygotic twins provide an excellent tool to study environmental effects on human health. Poly(ADP-ribose) polymerase-1 (PARP-1) is an important enzyme primarily involved in DNA repair and genomic stability and is under clinical investigation as a target for anticancer therapy. As a part of a PARP pharmacogenetics study, elderly male monozygotic twins, one healthy and the other with a Trojani grade 3 sarcoma treated with doxorubicin (DOX: 142.5 mg/m(2)), were recruited for the study. PARP activity and expression were measured in peripheral blood mononuclear cells (PBMCs) by methods validated to GCLP standard and used as a pharmacodynamic endpoint for clinical trials. The mean PARP activity for the patient before treatment was 160 pmol PAR/10(6) cells and was similar to that of his brother (130 pmol PAR/10(6) cells). There was approximately ninefold decrease (P = 0.001) in PARP activity in a second sample from the patient taken 21 days after the first DOX administration (17 pmol PAR/10(6) cells) and a decrease in PARP-1 expression. Investigations into BALB/C mice revealed that DOX treatment (5 mg/kg) resulted in a significant transient decrease in PARP activity after 1 h (63% control, P a parts per thousand(a) 0.05) and 24 h (53% control, P a parts per thousand(a) 0.05) but that PARP activity was restored 1 week after DOX treatment (86% control, P = 0.24). We showed here that administration of DOX can have a profound effect on the measured level of PARP activity and expression in PBMCs from patients and animals. Results obtained in clinical trials where PARP activity is used as a pharmacodynamic marker of PARP inhibition could reflect the effect of a chemotherapeutic on PBMCs rather than the effectiveness of a tested PARP inhibitor.
Author(s): Zaremba T, Thomas H, Cole M, Plummer ER, Curtin NJ
Publication type: Article
Publication status: Published
Journal: Cancer Chemotherapy and Pharmacology
Year: 2010
Volume: 66
Issue: 4
Pages: 807-812
Print publication date: 01/09/2010
Date deposited: 28/10/2010
ISSN (print): 0344-5704
ISSN (electronic): 1432-0843
Publisher: Springer
URL: http://dx.doi.org/10.1007/s00280-010-1359-0
DOI: 10.1007/s00280-010-1359-0
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