1,721,014 research outputs found
Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors
Full text linkInhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors
Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro
No full textmicroRNAs (miRNAs) are small noncoding RNA molecules produced by miR genes which are able to control the expression of a large number of cellular proteins by targeting mRNAs of protein coding genes. It has been suggested that modification of miR gene expression could be an important factor in the development and maintenance of the neoplastic state. It is a] so reasonable to hypothesize that antineoplastic drugs could be able to alter miR gene expression pattern since most of them are able to interfere with nucleic acid metabolism and gene expression. here we show that 5-fluorouracil (5-FU), a classical antimetabolite largely used in the clinic, is able to change significantly the expression of several miR genes. In colon cancer cells, at a clinically relevant concentration, the drug up-regulates or down-regulates in vitro the expression of 19 and 3 miR genes, respectively, by a factor of not less than two-fold. In some instances, 5-FU up-regulates miR genes that are already over-expressed in neoplastic tissues, including, for example, miR-21 that is associated with anti-apoptotic functions characterizing malignant cells. In this case, it is possible that drug-induced miR gene dysregulation could be the expression of cellular response to the toxic effects of the agent. on the contrary, in other instances the drug influences the expression of miR genes in a direction that is opposite to that induced by neoplastic transformation. a typical example is provided by miR-200b, that is up-regulated in various tumors and down-regulated by treatment with the antimetabolite. Noteworthy, it is known that miR-200b suppresses a gene that codes for a protein tyrosine phosphatase (PTPN12) that inactivates products of oncogenes, such as c-Abl, Src or Ras. In conclusion, the present results support the hypothesis that 5-FU can alter profoundly miR gene expression pattern. This effect could be responsible, at least in part, of the multi-target pleiotropic influence manifested by the drug on malignant cells. (c) 2007 Elsevier Ltd. All rights reserved
Telomerase as a potential anticancer target: growth inhibition and genomic instability
No full textStabilization of telomere length in chromosomes by an RNA-dependent DNA polymerase (telomerase) appears to be responsible for the replicative immortality of cancer cells. These findings provide the rational basis for generating experimental models to develop anti-telomerase drugs. However, there is conflicting evidence in the literature about the outcome of telomerase inhibition. While tumor cytostatic and cytotoxic effects associated with telomerase inhibition have been described, absence of telomerase has been associated with genetic instability and tumor development. Therefore, a therapeutic strategy based on telomerase inhibition will likely have to cope with problems related to innate or acquired mechanisms of drug resistance and possibly to therapy-related tumors. Copyright 2000 Harcourt Publishers Ltd
Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications
Full text linkReceptor recognition is a crucial step in viral infection and is a critical factor for cell entry and tissue tropism. In several recent studies, angiotensin-converting enzyme 2 (ACE2) has been demonstrated to be the cellular receptor of SARS-CoV-2 as it was previously well known as the receptor of SARS-CoV. SARS-CoV-2 can bind with high affinity to human ACE2 and engages it as an entry receptor. It seems that the genetic, notably epigenetic variations of ACE2 are less known in different populations, indicating the need for its further investigation. These variations have the potential to affect its contribution to the pathogenicity of COVID-19. The contribution of epigenetics in the interindividual variability of ACE2 merits more attention because epigenetic processes can play important roles in ACE2 alterations in various tissues and different people and populations. Analyzing different DNA methylation patterns and microRNAs, contributing to the ACE2 modulation in the lungs will have a high priority. The epigenetic and genetic variations of ACE2 become even more important when considering that some people have mild clinical symptoms despite having COVID-19. The pathogenicity of SARS-CoV-2 infection is complex; therefore, a better understanding of the underlying pathobiology, especially binding the virus to its receptors, could help improve therapeutic and preventive approaches. This review aims to highlight the importance of evaluating both the epigenetic and genetic variations of ACE2 as a receptor for the deadly SARS-CoV-2
Strategies to improve ellagic acid bioavailability: from natural or semisynthetic derivatives to nanotechnological approaches based on innovative carriers
Full text linkEllagic acid (EA) is a polyphenolic compound whose dietary consumption is mainly associated with the intake of red fruits, including pomegranates, strawberries, blackberries, blackcurrants, raspberries, grapes or dried fruits, like walnuts and almonds. A number of studies indicate that EA exerts health-beneficial effects against several chronic pathologies associated with oxidative damage, including different kinds of cancer, cardiovascular and neurodegenerative diseases. Furthermore, EA possesses wound-healing properties, antibacterial and antiviral effects, and acts as a systemic antioxidant. However, clinical applications of this polyphenol have been hampered and prevented by its poor water solubility (9.7 +/- 3.2 mu g ml(-1)in water) and pharmacokinetic profile (limited absorption rate and plasma half-life <1 h after ingestion of pomegranate juice), properties due to the chemical nature of the organic heterotetracyclic compound. Little has been reported on efficient strategies to enhance EA poor oral bioavailability, including chemical structure modifications, encapsulation within nano-microspheres to be used as carriers, and molecular dispersion in polymer matrices. In this review we summarize the experimental approaches investigated so far in order to improve EA pharmacokinetics, supporting the hypothesis that enhancement in EA solubility is a feasible route for increasing its oral absorption
Clinical applications of telomerase in cancer treatment
No full textTelomerase activity has been found in most cancer cells, but not in the majority of normal differentiated tissues. Therefore, telomerase has been considered a relatively selective and widely expressed tumor marker to be used as a diagnostic tool, and in some cases, as a potential prognostic indicator. Telomerase activity can also be used to evaluate chemosensitivity of neoplastic cells obtained from cancer patients, by measuring residual telomerase activity after drug treatment. Finally, telomerase has been considered to represent a suitable target for designing new anticancer strategies. This review focuses on present and future clinical applications of telomerase studies in cancer management. Copyright 2000 Harcourt Publishers Ltd
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders
No full textAcute myeloid leukaemia (AML) is a highly heterogeneous disease characterized by uncontrolled proliferation, block in myeloid differentiation and recurrent genetic abnormalities. In the search of new effective therapies, identification of synthetic lethal partners of AML genetic alterations might represent a suitable approach to tailor patient treatment. Genetic mutations directly affecting DNA repair genes are not commonly present in AML. Nevertheless, several studies indicate that AML cells show high levels of DNA lesions and genomic instability. Leukaemia-driving oncogenes (e.g., RUNX1-RUNXT1, PML-RARA, TCF3-HLF, IDH1/2, TET2) or treatment with targeted agents directed against aberrant kinases (e.g., JAK1/2 and FLT3 inhibitors) have been associated with reduced DNA repair gene expression/activity that would render leukaemia blasts selectively sensitive to synthetic lethality induced by poly(ADP-ribose) polymerase inhibitors (PARPi). Thus, specific oncogenic chimeric proteins or gene mutations, rare or typically distinctive of certain leukaemia subtypes, may allow tagging cancer cells for destruction by PARPi. In this review, we will discuss the rationale for using PARPi in AML subtypes characterized by a specific genetic background and summarize the preclinical and clinical evidence reported so far on their activity when used as single agents or in combination with classical cytotoxic chemotherapy or with agents targeting AML-associated mutated proteins
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