Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma.
OBJECTIVE
High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers.


METHODS
We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices.


RESULTS
Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5- to 2.3-fold) and temozolomide (3- to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (Cmax, 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (Cmax, 1-2 micromol/L at 120 min), associated with a sustained suppression of PARP-1 enzyme activity. Doses of AG014699 required for potentiation were not toxic per se.


CONCLUSIONS
These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.
Daniel
Rachel A
RA
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Rozanska
Agata L
AL
Thomas
Huw D
HD
Mulligan
Evan A
EA
Drew
Yvette
Y
Castelbuono
Deborah J
DJ
Hostomsky
Zdenek
Z
Plummer
E Ruth
ER
Boddy
Alan V
AV
Tweddle
Deborah A
DA
Curtin
Nicola J
NJ
Clifford
Steven C
SC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077204:Temozolomide; D019772:Topotecan / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D019772:Topotecan; C531549:rucaparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D000077204:Temozolomide