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Lung Cancer (Amsterdam, Netherlands) Jun 2011In small-cell lung cancer (SCLC), resistance to cancer drugs presents a major problem, limiting the effectiveness of chemotherapy. A better understanding of the... (Review)
Review
In small-cell lung cancer (SCLC), resistance to cancer drugs presents a major problem, limiting the effectiveness of chemotherapy. A better understanding of the molecular biology is essential to improve currently available cytotoxic therapy. Herein, a systematic review of studies evaluating the predictive value of multidrug resistance-associated proteins (MDR1, MRP1, MRP2 and MVP), topoisomerase II and ERCC1 for chemotherapy outcomes is presented. The role of MDR1, MRP1 and MRP2 as predictive markers in SCLC has not yet been elucidated. The majority of studies reported an association between protein or gene expression and response to chemotherapy; however, the evidence is limited to univariate analyses performed in the frame of small retrospective trials. In addition, the largest trial did not confirm an independent predictive value for response rates or survival. Genetic variability may be overseen as a more promising marker. Available data on the predictive value of topoisomerase II are scarce and in contrast to the general idea that higher protein or gene expression correlate with greater chemo-sensitivity. The data on a possible predictive value of ERCC1 are also quite limited; in two retrospective studies, ERCC1 turned out to be a significant predictive marker for survival, but only for limited disease patients. In conclusion, a continuous research, with standardized and validated methodology of markers' determination, should be aspired at all times; a better understanding of the biology of SCLC is of utmost importance to enable personalized therapy and to improve survival rates in this, so far, poorly controlled disease.
Topics: ATP Binding Cassette Transporter, Subfamily B; Biomarkers, Pharmacological; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Therapy; Endonucleases; Humans; Lung Neoplasms; Predictive Value of Tests; Prognosis; Treatment Outcome
PubMed: 21440950
DOI: 10.1016/j.lungcan.2011.02.014 -
Mutation Research Mar 2004The potential role of genotoxicity in human leukemias associated with benzene (BZ) exposures was investigated by a systematic review of over 1400 genotoxicity test... (Review)
Review
The potential role of genotoxicity in human leukemias associated with benzene (BZ) exposures was investigated by a systematic review of over 1400 genotoxicity test results for BZ and its metabolites. Studies of rodents exposed to radiolabeled BZ found a low level of radiolabel in isolated DNA with no preferential binding in target tissues of neoplasia. Adducts were not identified by 32P-postlabeling (equivalent to a covalent binding index <0.002) under the dosage conditions producing neoplasia in the rodent bioassays, and this method would have detected adducts at 1/10,000th the levels reported in the DNA-binding studies. Adducts were detected by 32P-postlabeling in vitro and following high acute BZ doses in vivo, but levels were about 100-fold less than those found by DNA binding. These findings suggest that DNA-adduct formation may not be a significant mechanism for BZ-induced neoplasia in rodents. The evaluation of other genotoxicity test results revealed that BZ and its metabolites did not produce reverse mutations in Salmonella typhimurium but were clastogenic and aneugenic, producing micronuclei, chromosomal aberrations, sister chromatid exchanges and DNA strand breaks. Rodent and human data were compared, and BZ genotoxicity results in both were similar for the available tests. Also, the biotransformation of BZ was qualitatively similar in rodents, humans and non-human primates, further indicating that rodent and human genotoxicity data were compatible. The genotoxicity test results for BZ and its metabolites were the most similar to those of topoisomerase II inhibitors and provided less support for proposed mechanisms involving DNA reactivity, mitotic spindle poisoning or oxidative DNA damage as genotoxic mechanisms; all of which have been demonstrated experimentally for BZ or its metabolites. Studies of the chromosomal translocations found in BZ-exposed persons and secondary human leukemias produced by topoisomerase II inhibitors provide some additional support for this mechanism being potentially operative in BZ-induced leukemia.
Topics: Animals; Benzene; Biological Assay; DNA Damage; Female; Humans; Male; Mutagenicity Tests; Mutagens; Topoisomerase II Inhibitors
PubMed: 15164977
DOI: 10.1016/s1383-5742(03)00053-x -
The Oncologist Oct 2009Anthracycline regimens have been the mainstay of adjuvant care in breast cancer for >20 years. A growing body of clinical experience has uncovered an unacceptable rate... (Review)
Review
Anthracycline regimens have been the mainstay of adjuvant care in breast cancer for >20 years. A growing body of clinical experience has uncovered an unacceptable rate of significant cardiac and leukomogenic toxicities. A systematic review of the literature was performed highlighting anthracycline- and nonanthracycline-based adjuvant regimens. The published data suggest that nonanthracycline alternatives are less toxic than anthracycline-containing regimens and equally, if not more, efficacious. Molecular predictors, such as human epidermal growth factor receptor 2 and topoisomerase II alpha, are further refining the optimal role of anthracyclines. With these new advances, the current role of anthracycline-based chemotherapy in early-stage breast cancer demands re-examination.
Topics: Anthracyclines; Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; DNA Topoisomerases, Type II; DNA-Binding Proteins; Female; Heart Diseases; Humans; Leukemia; Neoplasm Staging; Receptor, ErbB-2; Treatment Outcome
PubMed: 19561291
DOI: 10.1634/theoncologist.2008-0070 -
PloS One 2024Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results.... (Meta-Analysis)
Meta-Analysis
Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.
Topics: Meningioma; Humans; Biomarkers, Tumor; Prognosis; Meningeal Neoplasms; DNA Topoisomerases, Type II; Ki-67 Antigen; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Immunohistochemistry; Poly-ADP-Ribose Binding Proteins
PubMed: 38758750
DOI: 10.1371/journal.pone.0303337 -
European Journal of Medicinal Chemistry Nov 2018In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer... (Review)
Review
In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer agents. The 1,8-naphthalimides binds to the DNA via intercalation, and exert their antitumor activities through Topoisomerase I/II inhibition, photoinduced DNA damage or related mechanism. Here, our discussion focused on works published over the last ten years (2007-2017) related to therapeutic applications, in the order of cancer treatment followed by other properties of 1,8-naphthalimides. In preparing for this review, we considered that several seminal reviews have appeared over the last fifteen years and focused on closely related subjects, however, none of them is exhaustive.
Topics: Antineoplastic Agents; Cell Proliferation; DNA Damage; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA, Neoplasm; Humans; Intercalating Agents; Naphthalimides; Neoplasms; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors
PubMed: 30312931
DOI: 10.1016/j.ejmech.2018.09.055 -
Medical Oncology (Northwood, London,... 2013The incidence of therapy-related acute promyelocytic leukemia (t-APL) is apparently rising. We systematically reviewed the English literature until March 15, 2013, and... (Review)
Review
The incidence of therapy-related acute promyelocytic leukemia (t-APL) is apparently rising. We systematically reviewed the English literature until March 15, 2013, and collected a total of 326 t-APL cases, with the following results: (1) t-APL affects predominantly middle-aged adults with a median age at diagnosis of 47 years and a female-to-male ratio of 1.7:1; (2) after an incidence peak at 2 years following the completion of treatment for the primary antecedent disease, the risk of developing t-APL quickly diminishes with time; (3) the four most common primary antecedent conditions are breast cancer, hematological malignancies, multiple sclerosis, and genitourinary malignancies; (4) topoisomerase II inhibitors and radiation represent the most common potential risk factors; (5) despite different DNA damage "hot spot" sites, t-APL has no significant clinicopathologic differences from de novo APL (dn-APL); (6) t(15;17) is the sole cytogenetic abnormality in the vast majority of patients; (7) only a small minority of cases have a myelodysplastic or pancytopenic preleukemic phase; (8) more than one-third of patients come to medical attention incidentally (i.e., due to laboratory abnormalities), while the most common symptom is mucocutaneous bleeding, and 79 % have clinical DIC; and (9) the remission rate of t-APL is about 80 %, similar to dn-APL.
Topics: Humans; Leukemia, Promyelocytic, Acute; Neoplasms, Second Primary
PubMed: 23771799
DOI: 10.1007/s12032-013-0625-5 -
PloS One 2015The detection of mutations in the gyrA and gyrB genes in the Mycobacterium tuberculosis genome that have been demonstrated to confer phenotypic resistance to... (Review)
Review
Frequency and geographic distribution of gyrA and gyrB mutations associated with fluoroquinolone resistance in clinical Mycobacterium tuberculosis isolates: a systematic review.
BACKGROUND
The detection of mutations in the gyrA and gyrB genes in the Mycobacterium tuberculosis genome that have been demonstrated to confer phenotypic resistance to fluoroquinolones is the most promising technology for rapid diagnosis of fluoroquinolone resistance.
METHODS
In order to characterize the diversity and frequency of gyrA and gyrB mutations and to describe the global distribution of these mutations, we conducted a systematic review, from May 1996 to April 2013, of all published studies evaluating Mycobacterium tuberculosis mutations associated with resistance to fluoroquinolones. The overall goal of the study was to determine the potential utility and reliability of these mutations as diagnostic markers to detect phenotypic fluoroquinolone resistance in Mycobacterium tuberculosis and to describe their geographic distribution.
RESULTS
Forty-six studies, covering four continents and 18 countries, provided mutation data for 3,846 unique clinical isolates with phenotypic resistance profiles to fluoroquinolones. The gyrA mutations occurring most frequently in fluoroquinolone-resistant isolates, ranged from 21-32% for D94G and 13-20% for A90V, by drug. Eighty seven percent of all strains that were phenotypically resistant to moxifloxacin and 83% of ofloxacin resistant isolates contained mutations in gyrA. Additionally we found that 83% and 80% of moxifloxacin and ofloxacin resistant strains respectively, were observed to have mutations in the gyrA codons interrogated by the existing MTBDRsl line probe assay. In China and Russia, 83% and 84% of fluoroquinolone resistant strains respectively, were observed to have gyrA mutations in the gene regions covered by the MTBDRsl assay.
CONCLUSIONS
Molecular diagnostics, specifically the Genotype MTBDRsl assay, focusing on codons 88-94 should have moderate to high sensitivity in most countries. While we did observe geographic differences in the frequencies of single gyrA mutations across countries, molecular diagnostics based on detection of all gyrA mutations demonstrated to confer resistance should have broad and global utility.
Topics: Anti-Bacterial Agents; DNA Gyrase; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Meta-Analysis as Topic; Mutation; Mycobacterium tuberculosis; Tuberculosis, Pulmonary
PubMed: 25816236
DOI: 10.1371/journal.pone.0120470 -
Clinical Microbiology and Infection :... Nov 2021The fact that Mycobacterium leprae does not grow in vitro remains a challenge in the survey of its antimicrobial resistance (AMR). Mainly molecular methods are used to... (Review)
Review
BACKGROUND
The fact that Mycobacterium leprae does not grow in vitro remains a challenge in the survey of its antimicrobial resistance (AMR). Mainly molecular methods are used to diagnose AMR in M. leprae to provide reliable data concerning mutations and their impact. Fluoroquinolones (FQs) are efficient for the treatment of leprosy and the main second-line drugs in case of multidrug resistance.
OBJECTIVES
This study aimed at performing a systematic review (a) to characterize all DNA gyrase gene mutations described in clinical isolates of M. leprae, (b) to distinguish between those associated with FQ resistance or susceptibility and (c) to delineate a consensus numbering system for M. leprae GyrA and GyrB.
DATA SOURCES
Data source was PubMed.
STUDY ELIGIBILITY CRITERIA
Publications reporting genotypic susceptibility-testing methods and gyrase gene mutations in M. leprae clinical strains.
RESULTS
In 25 studies meeting our inclusion criteria, 2884 M. leprae isolates were analysed (2236 for gyrA only (77%) and 755 for both gyrA and gyrB (26%)): 3.8% of isolates had gyrA mutations (n = 110), mostly at position 91 (n = 75, 68%) and 0.8% gyrB mutations (n = 6). Since we found discrepancies regarding the location of substitutions associated with FQ resistance, we established a consensus numbering system to properly number the mutations. We also designed a 3D model of the M. leprae DNA gyrase to predict the impact of mutations whose role in FQ-susceptibility has not been demonstrated previously.
CONCLUSIONS
Mutations in DNA gyrase are observed in 4% of the M. leprae clinical isolates. To solve discrepancies among publications and to distinguish between mutations associated with FQ resistance or susceptibility, the consensus numbering system we proposed as well as the 3D model of the M. leprae gyrase for the evaluation of the impact of unknown mutations in FQ resistance, will provide help for resistance surveillance.
Topics: DNA Gyrase; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium leprae
PubMed: 34265461
DOI: 10.1016/j.cmi.2021.07.007 -
Journal of Neuroimmunology Jul 2019The review assessed the efficacy and tolerability of mitoxantrone in patients with neuromyelitis optica spectrum disorder (NMOSD). Eight articles were reviewed with a...
The review assessed the efficacy and tolerability of mitoxantrone in patients with neuromyelitis optica spectrum disorder (NMOSD). Eight articles were reviewed with a total of 117 patients. Annualized relapse rate and progression of disability dramatically decreased post-treatment in most studies. Mitoxantrone was generally tolerated. Only one patient developed acute myeloid leukemia, which lead to septicemia and death. No serious cardiotoxicity was reported. Mitoxantrone may be effective in reducing the frequency of relapse and slowing down the progression of disability in patients with NMOSD. The risk of cardiotoxicity and leukemia detains it as a second-line agent for NMOSD.
Topics: Cardiomyopathies; Disease Progression; Epidemiologic Studies; Humans; Immunosuppressive Agents; Infections; Intercalating Agents; Leukemia, Myeloid, Acute; Leukopenia; Mitoxantrone; Neuromyelitis Optica; Randomized Controlled Trials as Topic; Recurrence; Topoisomerase II Inhibitors; Treatment Outcome
PubMed: 31005713
DOI: 10.1016/j.jneuroim.2019.04.007 -
The Journal of Antimicrobial... Aug 2010Multidrug-resistant tuberculosis has emerged as a global health threat. Given poor treatment outcomes of fluoroquinolone-resistant multidrug-resistant tuberculosis,... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Multidrug-resistant tuberculosis has emerged as a global health threat. Given poor treatment outcomes of fluoroquinolone-resistant multidrug-resistant tuberculosis, there is a pressing need for rapid drug susceptibility testing of multidrug-resistant Mycobacterium tuberculosis against fluoroquinolones. This review aims at evaluating these rapid assays.
METHODS
PubMed and OvidSP were used to search MEDLINE and EMBASE for publications in English regarding rapid assays that tested ofloxacin, levofloxacin or moxifloxacin. Studies were included only in the concurrent presence of sensitivity and specificity data. Summary estimates of sensitivity and specificity were generated by the bivariate random effects model when there were at least three sets of data under the same assay category that tested the same fluoroquinolone with reference to a standard test.
RESULTS
Of 108 articles identified, 24 articles were included in a meta-analysis of rapid assays that tested ofloxacin in culture isolates. Overall, rapid genotypic assays targeting gyrA only are significantly less specific (96% versus 99%) and non-significantly less sensitive (88% versus 94%) than rapid phenotypic assays. To test for the presence or absence of ofloxacin resistance to a certainty threshold of 90%, the required pre-test prevalence ranges of ofloxacin resistance for genotypic assays targeting gyrA only are 29%-47% overall, 36%-55% for PCR-DNA sequencing and 23%-44% for others. Corresponding ranges are 7%-65% for phenotypic assays overall and 3%-75% for Mycobacteria Growth Indicator Tube (MGIT).
CONCLUSIONS
Assuming that the mean pre-test prevalence of fluoroquinolone resistance in culture isolates of multidrug-resistant M. tuberculosis is approximately 20%, rapid genotypic assays other than PCR-DNA sequencing, targeting gyrA only, can reliably screen for ofloxacin resistance.
Topics: Antitubercular Agents; Aza Compounds; Bacterial Proteins; DNA Gyrase; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Genotype; Humans; Levofloxacin; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Quinolines; Sensitivity and Specificity; Tuberculosis, Multidrug-Resistant
PubMed: 20542907
DOI: 10.1093/jac/dkq202