| Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor. Olaparib has been shown to induce significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Recent studies show that Olaparib increases radiosensitivity of a lung tumor xenograft, making it a potential candidate for use in combination with radiotherapy. PARP1 acts as a critical molecule in the repair of DNA single-strand breaks (SSBs) and plays an important role in maintaining DNA integrity. de Murcia, J., et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc. Natl. Acad. Sci. USA 94: 7303-7307 (1997). PARP inhibitors inhibit PARP1 during S-phase and induce inactivation of SSB repair and thus cause DNA double-strand breaks, which induces BRCA-deficient cancer cell apoptosis. Bryant, H.E., et al. Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose) polymerase. Nature 434: 913-917 (2005). Farmer, H., et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917-921 (2005). The PARP inhibitor olaparib was tested in a genetically engineered mouse model for BRCA1-associated breast cancer. Olaparib inhibited tumor growth and significantly improved survival without signs of toxicity. Rottenberg, S., et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. USA 105: 17079-17084 (2008). Long-term treatment with olaparib caused the development of drug resistance, which was induced by up-regulation of Abcb1a/b genes encoding P-glycoprotein efflux pumps. The resistance to olaparib could be overcome by tariquidar, a P-glycoprotein inhibitor. Rottenberg, S., et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. USA 105: 17079-17084 (2008). Combination treatment using olaparib with cisplatin or carboplatin improved the recurrence-free and overall survival in a murine model, indicating that olaparib enhances the effect of these DNA-damaging agents. Rottenberg, S., et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. USA 105: 17079-17084 (2008). Olaparib inhibited the growth of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Combination treatment of olaparib and cisplatin had a synergistic cytotoxicity against BRCA2-deficient cells but not against BRCA2-proficient control cells. Evers, B., et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14: 3916-3925 (2008). Synonyms: 4-[[3-[[4-(Cyclopropylcarbonyl)-1-piperazinyl]carbonyl]-4-fluorophenyl]methyl]-1(2H)-phthalazinone, AZD-2281, KU 0059436, KU-59436, 1-(Cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine CAS No: 763113-22-0 Molecular Formula: C24H23FN4O3 Molecular Weight: 434.46 Purity: 99% (HPLC, TLC) Appearance: White to off-white, cystalline or powder Melting Point: 208-209C Elemental Analysis: Calculated: %C: 66.35% %H: 5.34% %F: 4.37% %N: 12.90% Solubility: Soluble in DMSO at 33mg/ml, soluble in ethanol at 1.7mg/ml with slight warming, very poorly soluble in water, maximum solubility in plain water is estimated to be about 10-20uM buffers, serum, or other additives may increase or decrease the aqueous solubility. Storage and Stability: Lyophilized and reconstituted products are stable for 6 months after receipt at -20C. Reconstitute with DMSO. Aliquot to avoid repeated freezing and thawing. Store at -20C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer. |
