Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of inhibitors of DNA repair have been evaluated or are undergoing development as potential cancer treatments. Inhibitors of poly(ADP-ribose) polymerase (PARP) are of particular interest in treating hereditary breast cancers occurring in patients who are carriers of BRCA1 or BRCA2 mutations. In vitro PARP inhibitors are highly cytotoxic to cell lines carrying BRCA mutations while only minimally toxic to cell lines without these mutations. This is thought to be due to a phenomenon known as synthetic lethality where the accumulation of single-strand breaks consequent on PARP inhibition are converted to double-strand breaks on cell division. Cancer cells in BRCA carriers are uniquely unable to repair the consequent double-strand breaks that result during cell division. PARP inhibitors were initially developed as possible chemo-potentiating agents but have now been evaluated clinically in BRCA-related tumors, showing remarkable single-agent activity. The potential future development and use is reviewed.
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PMID:The clinical development of inhibitors of poly(ADP-ribose) polymerase. 2128 53

Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively in HR-deficient cells. Notably, inhibiting DNA-dependent protein kinase activity reverses the genomic instability previously reported in these cells after PARP inhibition. Moreover, disabling NHEJ by using genetic or pharmacologic approaches rescues the lethality of PARP inhibition or down-regulation in cell lines lacking BRCA2, BRCA1, or ATM. Collectively, our results not only implicate PARP1 catalytic activity in the regulation of NHEJ in HR-deficient cells, but also indicate that deregulated NHEJ plays a major role in generating the genomic instability and cytotoxicity in HR-deficient cells treated with PARP inhibitors.
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PMID:Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. 2130 Aug 83

Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common malignancy of females in the developed world. Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 account for 4-6% of all breast cancer cases, and mutation carriers have a lifetime risk of 80% for developing breast cancer and 40% for developing ovarian cancer. Current treatment options are limited and often do not lead to cure. In the 17 years since the discovery of BRCA1, the generation of mouse models for BRCA1 deficiency has greatly aided our understanding of it's role in tumorigenesis. In contrast to human BRCA1 mutation carriers, mice carrying heterozygous mutations in Brca1 did not develop spontaneous tumors. This led to the generation of conditional mouse models in which tissue-specific Brca1 deletion induces formation of mammary tumors that closely resemble human BRCA1-mutated breast tumors. These models have proven useful for studying BRCA1-related tumor development, drug response and resistance. BRCA1-deficient cancer cells are defective in DNA repair mediated by homologous recombination (HR) and therefore highly sensitive to DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. However, BRCA1-mutated tumors can develop resistance to these drugs; hence improved treatment strategies are critical. Existing mouse models have already proven useful for preclinical testing of (combinations of) therapeutic agents that may be beneficial for the treatment of patients with BRCA1-mutated tumors. In this review, we discuss the progress made towards modeling BRCA1-deficient breast cancer in mice and what we have learned from preclinical studies using these models.
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PMID:Studying therapy response and resistance in mouse models for BRCA1-deficient breast cancer. 2133 59

Individuals who inherit a deleterious mutation in BRCA1 or BRCA2 are at very high risk for breast cancer but there are several strategies available for successfully managing this risk. Breast cancers that develop in the context of germline BRCA gene mutation present challenges for management but also opportunities. DNA damaging agents, like cisplatin, and the new class of drugs called PARP inhibitors exploit the underlying defect in DNA damage repair to great effect.
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PMID:New insights into the prevention and treatment of familial breast cancer. 2133 61

Over the past 15 years there has been substantial improvement in the understanding of hereditary breast cancer. Germline genetic testing for mutations in BRCA1, BRCA2, PTEN and TP53 allows for the identification of individuals at increased risk for breast, ovarian and other cancers. Advances in screening, prevention and treatment have led to improved clinical management which is best defined for BRCA1 and BRCA2 mutation carriers. The addition of screening techniques such as breast magnetic resonance imaging has been shown to lead to earlier detection. Risk-reducing salpingo-oophorectomy leads to a reduction in the risk of both ovarian cancer and breast cancer and also is associated with an improvement in overall survival. BRCA1/2 mutation status may be applicable to systemic therapy decisions. Preclinical and early clinical research suggests that specific classes of chemotherapy may be more effective in mutation carriers. Finally, PARP inhibitors represent a novel therapeutic strategy that exploits the weaknesses of BRCA1/2-associated malignancies.
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PMID:Clinical management of hereditary breast cancer syndromes. 2136 2

Poly(ADP-ribose)polymerases(PARPs)can transfer their first ADP-ribose moiety from nicotinamide adenine dinucleotide( NAD+)to an acceptor protein. PARPs play a major role in a wide range of biologic processes through poly(ADP-ribosyl) ation, including the maintenance of genomic stability, transcriptional regulation, energy metabolism, and cell death. Recent findings have thrust(PARPs)into the limelight as potential chemotherapeutic targets, and PARP inhibitors(poly(ADP-ribose) polymerase inhibitors)are currently undergoing clinical evaluation for use as new anti-cancer drugs. PARPs promote the repair of single-strand breaks(SSB)by base excision repair(BER), and the inhibition of PARPs leads to the conversion from single-strand breaks(SSB)to double-strand breaks(DSB). Because BRCA1- or BRCA2-deficient cells are unable to complete homologous recombination efficiently, PARP inhibition in these cells causes a high degree of genomic instability and eventual cell death termed synthetic lethality. This synthetic lethal approach has been validated in studies that show a striking single-agent activity of PARP inhibitors in preclinical models of BRCA1 and BRCA2 inactivation. Consistent with these results, the PARP inhibitor olaparib(previously known as AZD2281)has shown promising single-agent activity against it in early clinical testing. In additional studies, the PARP inhibitor has shown remarkable activity in BRCA1- or BRCA2-mutant tumors when used in combination with gemcitabine and carboplatin. Phase I and Phase II trials of several PARP inhibitors in combination with DNA-damaging agents are ongoing.
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PMID:[PARP inhibitors for cancer therapy]. 2136 55

Despite ongoing trials of PARP inhibitors in the treatment of breast cancer (BC), the extent of poly(ADP-ribose)polymerase-1 (PARP-1) protein expression in BCs, which may influence treatment results, is not known. The purpose of this report is to assess expression of PARP-1 in BC including BRCA1-associated, triple negative (TN), and basal-like tumors. Immunohistochemistry with a PARP-1 antibody on tissue microarrays from 130 BRCA1-associated and 594 BRCA1-non-related BCs was used. The vast majority of breast carcinomas expressed high level of nuclear PARP-1 protein and a small percentage of tumors exhibited both nuclear and cytoplasmic PARP-1 expression. There was a significant difference between the mean nuclear PARP-1 quickscore in BRCA1-associated versus BRCA1-non-associated carcinomas in all tumors (P < 0.0001), in the basal-like group (P = 0.0086), TN (P = 0.0015), and non-basal-like groups (P = 0.016) but not in the non-TN group. Among BRCA1-associated BCs, low PARP-1 expression was found in 18.5% of all cases, 18.9% of basal-like and 21% of TN cancers. Among BRCA1-non-related tumors, low PARP-1 expression was found in 8.8% of all cases, 3.1% of basal-like, and 2.7% of TN cancers. PARP-1 expression is significantly associated with BRCA1 status in basal-like and TN BCs. The assessment of PARP-1 expression in tumor samples may improve the selection of BC patients for PARP inhibitor therapy.
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PMID:PARP-1 expression in breast cancer including BRCA1-associated, triple negative and basal-like tumors: possible implications for PARP-1 inhibitor therapy. 2140 92

The hereditary forms of breast cancer identified by BRCA1 and BRCA2 genes have a defect in homologous DNA repair and demonstrate a dependence on alternate DNA repair processes by base excision repair, which requires poly(ADP-ribose) polymerase 1 (PARP-1). siRNA and deletion mutations demonstrate that interference with PARP-1 function results in enhanced cell death when the malignancy has a defect in homologous recombination. These findings resulted in a plethora of agents in clinical trials that interfere with DNA repair, and these agents offer the potential of being more selective in their effects than classic chemotherapeutic drugs. An electronic search of the National Library of Medicine for published articles written in English used the terms "PARP inhibitors" and "breast cancer" to find prospective, retrospective and review articles. Additional searches were done for articles dealing with mechanism of action. A total of 152 articles dealing with breast cancer and PARP inhibition were identified. PARP inhibition not only affects nonhomologous repair, but also has several other nongenomic functions. Mutational resistance to these agents was seen in preclinical studies. To date, PARP-1 inhibitors were shown to enhance cytotoxic effects of some chemotherapy agents. This new class of agents may offer more therapeutic specificity by exploiting a DNA repair defect seen in some human tumors with initial clinical trials demonstrating antitumor activity. Although PARP inhibitors may offer a therapeutic option for selected malignancies, the long-term effects of these agents have not yet been defined.
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PMID:Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality. 2142 7

Damage to DNA has emerged as a major culprit in cancer. Mammalian cells are continuously exposed to DNA damage, caused by exogenous toxins as well as endogenous activities such as DNA replication and cellular free radical generation. It is therefore essential that cells have DNA repair mechanisms in place to preserve its genomic integrity. Interestingly, cancer cells frequently harbour defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis, but also provides a weakness in the tumour that can be exploited therapeutically. In this context, it has been shown that homologous recombination (HR)-deficient tumour cells--including those with defects in BRCA1/2--are highly sensitive to blockade of the base excision repair (BER) pathway via inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a novel 'synthetic lethal' approach to cancer therapy. Recent clinical trials have shown an enhancement of the cytotoxic effect of chemotherapy by adding a PARP inhibitor to the standard treatment. Still, clinical outcome may be even further improved if these drugs would be used as first-line therapy. In conclusion, it can be stated that an exciting new class of drugs has entered the arena of cancer therapy. However, additional clinical studies are needed before PARP inhibitors can definitely enter daily clinical practice.
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PMID:PARP inhibitors in oncology: a new synthetic lethal approach to cancer therapy. 2148 57

Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.
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PMID:Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. 2148 48


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