Data from Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial
Huw D. ThomasChristopher CalabreseMichael A. BateyStacie CananZdeněk HostomskýSuzanne KyleKaren A. MaegleyDavid R. NewellDonald J. SkalitzkyLan-Zhen WangStephen E. WebberNicola J. Curtin
0
Citation
0
Reference
10
Related Paper
Abstract:
<div>Abstract<p>Poly(ADP-ribose) polymerase (PARP)-1 (EC 2.4.2.30) is a nuclear enzyme that promotes the base excision repair of DNA breaks. Inhibition of PARP-1 enhances the efficacy of DNA alkylating agents, topoisomerase I poisons, and ionizing radiation. Our aim was to identify a PARP inhibitor for clinical trial from a panel of 42 potent PARP inhibitors (<i>K</i><sub>i</sub>, 1.4–15.1 nmol/L) based on the quinazolinone, benzimidazole, tricyclic benzimidazole, tricyclic indole, and tricyclic indole-1-one core structures. We evaluated chemosensitization of temozolomide and topotecan using LoVo and SW620 human colorectal cells; <i>in vitro</i> radiosensitization was measured using LoVo cells, and the enhancement of antitumor activity of temozolomide was evaluated in mice bearing SW620 xenografts. Excellent chemopotentiation and radiopotentiation were observed <i>in vitro</i>, with 17 of the compounds causing a greater temozolomide and topotecan sensitization than the benchmark inhibitor AG14361 and 10 compounds were more potent radiosensitizers than AG14361. In tumor-bearing mice, none of the compounds were toxic when given alone, and the antitumor activity of the PARP inhibitor-temozolomide combinations was unrelated to toxicity. Compounds that were more potent chemosensitizers <i>in vivo</i> than AG14361 were also more potent <i>in vitro</i>, validating <i>in vitro</i> assays as a prescreen. These studies have identified a compound, AG14447, as a PARP inhibitor with outstanding <i>in vivo</i> chemosensitization potency at tolerable doses, which is at least 10 times more potent than the initial lead, AG14361. The phosphate salt of AG14447 (AG014699), which has improved aqueous solubility, has been selected for clinical trial. [Mol Cancer Ther 2007;6(3):945–56]</p></div>Keywords:
Temozolomide
PARP inhibitor
Topotecan
Background/Aim: Poly (ADP-ribose) polymerase (PARP) inhibition could enhance the efficacy of temozolomide and prolong survival in patients with glioblastoma. The aim of this study was to evaluate the combination of the PARP inhibitor olaparib with temozolomide in the treatment of glioblastoma. Materials and Methods: The in vitro and in vivo antitumor effects of the PARP inhibitor olaparib together with temozolomide were evaluated. The in vitro experimental glioblastoma model involved O6-methylguanine methyltransferase (MGMT) promoter-methylated (U87MG, U251MG) and MGMT promoter-unmethylated (T98G) glioblastoma cell lines using In this model cell viability and apoptosis were assessed. For the in vivo studies, nude mice bearing orthotopically xenografted glioblastoma cell lines (U87MG) were randomized to four experimental groups: i) the untreated, ii) temozolomide alone, iii) olaparib alone and iv) olaparib and temozolomide combination groups. Mice were treated daily for 4 weeks and monitored for tumor growth and survival. Results: In vitro we found that the combination of olaparib with temozolomide enhanced temozolomide-induced cytotoxicity in all glioblastoma cell lines regardless of the status of MGMT promoter methylation. In vivo, mice treated with temozolomide alone or in combination with olaparib showed greater survival than those untreated or with the olaparib monotherapy, as well as significantly decreased tumor volume. There was no significant difference in survival and tumor volume between temozolomide alone and the combination treatment. Conclusion: The combination of the PARP inhibitor olaparib with temozolomide could be promising candidates for combination therapy of glioblastoma regardless of the MGMT promoter methylation status.
Temozolomide
Olaparib
PARP inhibitor
Cite
Citations (13)
Abstract Among the clinical inhibitors of poly(ADP-ribose) polymerases (PARPs) and the commonly used PARP research tool compounds, veliparib and niraparib were recently identified as the most selective inhibitors of PARP1 and PARP2. We characterized the potency of A-966492, a PARP inhibitor with a chemical structure similar to veliparib and niraparib, in in vitro inhibition experiments of six PARP family enzymes. We find that the selectivity of A-966492 for PARP1 and PARP2 is intermediate between veliparib and niraparib.
Veliparib
PARP inhibitor
PARP1
Olaparib
Cite
Citations (3)
PARP inhibitor
Olaparib
Cite
Citations (0)
Olaparib
PARP inhibitor
Ex vivo
Cite
Citations (4)
PARP inhibitor
PARP1
Synthetic Lethality
Olaparib
Cite
Citations (410)
Olaparib
PARP inhibitor
Biotransformation
Cite
Citations (4)
TPS2618 Background: PARPs are a highly conserved family of enzymes whose predominant function is to preserve genomic integrity following DNA damage. Preclinical studies demonstrated that PARP inhibitors enhance the cytotoxicity of DNA damaging agents. Specifically, PARP inhibition sensitizes tumor cells to topotecan in vitro and in vivo by trapping PARP1 on damaged DNA and preventing repair of topo I-induced DNA damage (Patel et al., J. Biol. Chem. 287:4198, 2012). Veliparib has been combined with daily topotecan but found to be quite myelosuppressive, requiring reduction in doses of both agents (Kummar et al., Cancer Res. 71:5626, 2011). Based on these data, we sought to determine the maximum tolerated dose (MTD) of veliparib in combination with the less myelosuppressive weekly administration of topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells as well as the pharmacokinetics of both agents. Methods: Eligible patients include any histologically confirmed solid tumor malignancy that is metastatic or unresectable with measurable disease (longest diameter > 2 cm with conventional CT) in patients 18 or older who have received < 2 chemotherapy regimens, ECOG PS < 2 and adequate bone marrow, renal and hepatic function. Using a standard 3+3 design, patients have been treated with veliparib PO twice daily on days 1-3, 8-10 and 15-17 and topotecan IV on days 2, 9 and 16 every 28 days. The trial is currently enrolling at veliparib 300 mg PO twice daily and topotecan 3 mg/m2/dose. Once MTD is established, a phase II clinical trial in platinum resistant ovarian, peritoneal and fallopian tube malignancies is planned. Supported in part by UM1 CA186686 and P50 CA136393. Clinical trial information: NCT01012817 Clinical trial information: NCT01012817.
Veliparib
Topotecan
PARP inhibitor
Olaparib
Cite
Citations (1)
Olaparib
PARP inhibitor
Synthetic Lethality
Cite
Citations (195)
We have tested PJ34, a potent inhibitor of poly(ADP-ribose) polymerase (PARP), against various lung cancer cell lines (Calu-6, A549, and H460) and normal human bronchial epithelial cells (HBECs). While using WST1 dye assay, lung cancer cells exhibited LD(50) values of approximately 30 μM PJ34 (72-hr assay). Molecular data showed that the effect of PJ34-induced apoptosis on lung cancer cells occurs via a caspase-dependent pathway. The present study has clearly shown that (a) PARP inhibitor can independently kill tumor cells, (b) caspase-3 has modest influence on PARP-inhibitor-mediated cancer-specific toxicity, and (c) a pan-caspase inhibitor decreases the apoptotic effect of PJ34.
PARP inhibitor
Ribose
Cite
Citations (17)
Abstract Poly (ADP-ribose) polymerase (PARP) inhibition could enhance the efficacy of temozolomide and prolong survival in patients with glioblastoma. The aim of this study was to evaluate the combination of the PARP inhibitor olaparib with temozolomide in the treatment of glioblastoma by evaluating in vitro and in vivo antitumor effects in an experimental glioblastoma model. The authors investigated antitumor effects of olaparib on temozolomide-induced cytotoxicity on O6-methylguanine methyltransferase (MGMT) promotor methylated (U87MG, U251MG) and MGMT promotor unmethylated (T98G) glioblastoma cell lines using in vitro cell viability and apoptosis assay. We found that the combination of olaparib with temozolomide enhanced temozolomide-induced cytotoxicity in all glioblastoma cell lines regardless of the status of MGMT promotor methylation. For in vivo studies, nude mice bearing orthotopically xenografted glioblastoma cell lines (U87MG) were randomized to four experimental groups: (i) untreated, (ii) temozolomide alone, (iii) olaprib alone and, (iv) olaparib+temozolomide. Mice were treated daily for 4 weeks and monitored for tumor growth, and survival. However, the addition of olaparib had no impact on the efficacy of temozolomide. The combination of PARP inhibitor olaparib with temozolomide could be an effective therapeutic approach for treatment of glioblastoma regardless of MGMT promotor methylation status, although the efficacy still should be evaluated by in vivo and clinical studies.
Temozolomide
Olaparib
PARP inhibitor
O-6-methylguanine-DNA methyltransferase
Cite
Citations (0)