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

ABSTRACT

PURPOSE: 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.