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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 -
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 -
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 -
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