AG-014699 (PF-01367338, Rucaparib) is a PARP inhibitor with a Ki of 1.4 nM. AG-014699 is the phosphate salt of AG 014447 (CAS 283173-50-2) and has improved aqueous solubility. Poly (ADP-ribose) polymerases (PARPs) are activated by DNA single- and double-strand breaks and promote repair of DNA damage through the relaxation of chromatin and recruitment of other repair proteins. AG-014699 inactivates PARP activity in cells with homologous recombination DNA repair pathway mutations at LC50 values ranging from 1.3-5.5 μM. Radio-sensitization by AG-014699 is due to downstream inhibition of NF-κB activation, and independent of SSB repair inhibition. Although AG014699 can enhance response to some chemotherapeutic drugs via improved delivery, this does not apply to doxorubicin. PARP inhibitors may still be of use to counter doxorubicin toxicity.
|Cell lines||LoVo and SW620 cells|
|Preparation method||We estimated cell growth inhibition in exponentially growing LoVo and SW620 cells in 96-well plates exposed to increasing concentrations of single-agent PARP inhibitor, temozolomide or topotecan, or combinations of temozolomide or topotecan with PARP inhibitor for 5 days before staining with sulforhodamine B as described previously (18). Cell growth, determined after subtraction of time 0 values, was expressed as a percentage of the relevant DMSO, cytotoxic drug, or PARP inhibitor alone control, as appropriate. GI50 (concentration of drug that inhibited growth by 50%) values were calculated from the computer-generated curves (GraphPad Software, Inc. San Diego CA).|
|Incubation time||5 days|
|Animal models||SW620 tumor xenografts|
|Dosages||0.1, 1, 10mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥80 mg/mL
Water ≥60 mg/mL
Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells.
Chuang et al. Breast Cancer Res Treat. 2012 Jul;134(2):649-59. PMID: 22678161.
The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.
Ali et al. Mol Cancer Ther. 2011 Dec;10(12):2320-9. PMID: 21926192.
NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699.
Hunter et al. Oncogene. 2012 Jan 12;31(2):251-64. PMID: 21706052.
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