Doxorubicin-induced suppression of poly(ADP-ribose) polymerase-1 (PARP-1) activity and expression and its implication for PARP inhibitors in clinical trials.
OBJECTIVE
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.


METHODS
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.


RESULTS
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 << 0.05) and 24 h (53% control, P << 0.05) but that PARP activity was restored 1 week after DOX treatment (86% control, P = 0.24).


CONCLUSIONS
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.
Zaremba
Tomasz
T
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Thomas
Huw
H
Cole
Michael
M
Plummer
Elizabeth R
ER
Curtin
Nicola J
NJ
D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019042:Muscle Neoplasms / Q000188:drug therapy / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000473:pathology; D014430:Twins, Monozygotic
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004317:Doxorubicin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases