Poly(ADP-ribose) synthesis in human cervical cancer cell — Diagnostic cytological usefulness

Fukushima, Masanori; Kuzuya, Kazuo; K, Ota; Ikai, Kouichi

doi:10.1016/0304-3835(81)90148-8

Cited by 36 publications

(22 citation statements)

References 17 publications

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“…Whereas PARP is ubiquitously expressed in almost all types of eukaryotic cells (9), PARP activity is increased in the nuclei of actively proliferating cells (1). Enhanced PARP-1 expression and/or activity has been shown in several hematologic and solid tumors (7,8,10). This differential expression of PARP in normal versus tumor cells supports the observed selectivity of PARP inhibitors to affect proliferating tumor cells.…”

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confidence: 73%

ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models

Donawho

Luo

et al. 2007

Clinical Cancer Research

692

564

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Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K i s of 5.2 and 2.9 nmol/L, respectively.The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d Â 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.poly(ADP-ribose) polymerase (PARP)-1 is the founding member of a family of poly(ADP-ribosyl)ating proteins. All PARP family members are characterized by the ability to poly(ADP-ribosyl)ate protein substrates and all share a catalytic PARP homology domain (1). PARP-1 and the closely related PARP-2 are nuclear proteins and the only PARPs with DNA binding domains. These DNA binding domains localize PARP-1 and PARP-2 to the site of DNA damage serving as DNA damage sensors and signaling molecules for repair. The knockout of PARP-1 is sufficient to significantly impair DNA repair following damage via radiation (2) or cytotoxic (3) insult. The residual PARP-dependent repair activity (f10%) is due to PARP-2 (4, 5). These data imply that inhibition of only PARP-1 and PARP-2 will impair DNA repair following damage and that inhibition of other PARP family members is not required in the process. The functions of other PARP family members remain to be elucidated, but poly(ADP-ribosyl)ation has been implicated in many cellular processes, including differentiation, gene regulation, protein degradation, spindle maintenance, as well as replication and transcription (6).Higher expression of PARP in cancer compared with normal cells has been linked to...

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confidence: 73%

ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models

Donawho

Luo

et al. 2007

Clinical Cancer Research

692

564

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“…For example, PARP mRNA levels were found to be enhanced in malignant lymphomas but not in normal lymph nodes or reactive proliferative lymph nodes (17). Elevated PARP activity was identified in peripheral lymphocytes from patients with low-grade malignant non -Hodgkin's lymphoma (18), hepatocellular carcinomas (19,20), small-cell lung cancer lines (21), cervical cancer cells from patients (22), and the prostate cancer cell line LnCaP (23). Elevated PARP expression has also been shown to be associated with chemoresistance (21).…”

Section: Introductionmentioning

confidence: 99%

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

Liu¹,

Shi²,

Guan³

et al. 2008

Molecular Cancer Research

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Poly(ADP-ribose) polymerase (PARP) senses DNA breaks and facilitates DNA repair via the polyADP-ribosylation of various DNA binding and repair proteins. We explored the mechanism of potentiation of temozolomide cytotoxicity by the PARP inhibitor ABT-888. We showed that cells treated with temozolomide need to be exposed to ABT-888 for at least 17 to 24 hours to achieve maximal cytotoxicity. The extent of cytotoxicity correlates with the level of double-stranded DNA breaks as indicated by ;H2AX levels. In synchronized cells, damaging DNA with temozolomide in the presence of ABT-888 during the S phase generated high levels of double-stranded breaks, presumably because the single-stranded DNA breaks resulting from the cleavage of the methylated nucleotides were converted into double-stranded breaks through DNA replication. As a result, treatment of temozolomide and ABT-888 during the S phase leads to higher levels of cytotoxicity. ABT-888 inhibits poly(ADP-ribose) formation in vivo and enhances tumor growth inhibition by temozolomide in multiple models. ABT-888 is well tolerated in animal models. ABT-888 is currently in clinical trials in combination with temozolomide. (Mol Cancer Res 2008;6(10):1621 -9)

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“…Evaluation of PARP-1 protein expression in hepatocellular carcinoma (HCC) by western blotting revealed that it was significantly increased in HCC, especially moderately differentiated, compared with the non-tumour samples (Shimizu et al, 2004). Increased poly(ADP-ribosyl)ation has also been reported in cancers compared with adjacent tissues, i.e., HCC (Nomura et al, 2000), colon carcinoma (Hirai et al, 1983), cervical cancer (Fukushima et al, 1981), melanoma and basal cell carcinoma (Ikai et al, 1980). Recent studies link PARP-1 to inflammation and cancer through the activation of the stress-inducible transcription complex, NF-kB.…”

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confidence: 99%

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

et al. 2009

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BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair and other cellular processes. Poly(ADP-ribose) polymerase activity can be higher in cancer than in adjacent normal tissue, but cancer predisposition is reported to be greater in individuals with a single-nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that reduces PARP-1 activity. METHODS: To resolve these divergent observations, we determined PARP-1 polymorphisms, PARP-1 protein expression and activity in a panel of 19 solid and haematological, adult and paediatric human cancer cell lines. RESULTS: There was a wide variation in PARP activity in the cell line panel (coefficient of variation, CV ¼ 103%), with the lowest and the highest activity being 2460 pmol PAR/10 6 (HS-5 cells) and 85 750 pmol PAR/10 6 (NGP cells). Lower variation (CV ¼ 32%) was observed in PARP-1 protein expression with the lowest expression being 2.0 ng mg À1 (HS-5 cells) and the highest being 7.1 ng mg À1 (ML-1 cells). The mean activity in the cancer cells was 45-fold higher than the mean activity in normal human lymphocytes and the PARP-1 protein levels were 23-fold higher. CONCLUSIONS: Surprisingly, there was no significant correlation between PARP activity and PARP-1 protein level or the investigated polymorphisms, T2444C and CA.

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Poly(ADP-ribose) synthesis in human cervical cancer cell — Diagnostic cytological usefulness

Cited by 36 publications

References 17 publications

ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models

ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

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