INO-1001 is a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. The present study tested INO-1001 for its in vivo effect on the chemoresponse of two p53 deficient tumors, human breast cancer MDA-MB-231 and murine mammary carcinoma MCa-K. Doxorubicin was used as the DNA damaging agent and tumor growth delay assay was used as the endpoint. Results showed that INO-1001 was highly effective in enhancing the anti-tumor effects of Doxorubicin for both MDA-MB-231 (EF=1.88) and MCa-K (EF=1.64).
|Source||Exp Gerontol (2007). Figure 2. INO-1001|
|Cell Lines||male Lewis rats|
|Incubation Time||2 h|
|Results||Single dose treatment with the potent PARP-inhibitor INO-1001 notably decreased PAR formation both in the myocardium and the aortic wall.|
|Cell lines||cultured podocytes|
|Preparation method||Apoptosis detection. Apoptotic nuclei of cultured podocytes were detected on paraformaldehyde-fixed cells using DAPI (4′,6-diamidino-2-phenylindole) staining (1 μg/ml) for 10 min. Cells were analyzed under a fluorescence microscope and assessed for chromatin condensation and segregation. Caspase-3 activity was measured in podocyte extracts using EnzCheck Caspase-3 Assay kit (Molecular Probes) following the manufacturer’s protocol. Nuclear extracts were prepared using Transfactor DB Nuclear extraction kit (Clontech BD Bioscience) following the manufacturer’s protocol. Western blotting was performed using NFκB p50 (Santa Cruz Biotechnology) antibody. NFκB p50 nuclear binding assay was performed using TransFactor Colorimetric kit (Clontech BD) according to the manufacturer’s protocol.|
|Incubation time||45 min|
|Animal models||diabetic nephropathy of Leprdb/db mice model|
|Dosages||60 mg/kg initiated at 5 weeks of age to around 8 weeks of age|
|Administration||oral in drinking water|
|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.
Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size.
Roesner JP, et al. Shock. 2010 May;33(5):507-12. PMID: 20395771.
A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma.
Bedikian AY, et al. Cancer Invest. 2009 Aug;27(7):756-63. PMID: 19440934.
A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial.
Morrow DA, et al. J Thromb Thrombolysis. 2009 May;27(4):359-64. PMID: 18535785.
INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin.
Mason KA, et al. Invest New Drugs. 2008 Feb;26(1):1-5. PMID: 17628743.
Single dose treatment with PARP-inhibitor INO-1001 improves aging-associated cardiac and vascular dysfunction.
Radovits T, et al. Exp Gerontol. 2007 Jul;42(7):676-85. PMID: 17383839.
|Related PARP Products|
Benzamide is an inhibitor of poly(ADP-ribose) polymerase with an IC50 of 3.3 μM.
Picolinamide is a strong inhibitor of poly (ADP-ribose) synthetase of nuclei from rat pancreatic islet cells.
|Niraparib (MK-4827) tosylate
Niraparib (MK-4827) tosylate is an excellent PARP1 and PARP2 inhibitor with IC50 of 3.8 and 2.1 nM, respectively.
Daidzein is an inactive analogue of genistein, a tyrosine kinase inhibitor and an estrogen receptor activator.
NMS-P118 is a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles, showing 150-fold selectivity for PARP-1 over PARP-2 (Kd 0.009 μM vs 1.39 μM, respectively).
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