Genotoxicity and carcinogenicity studies of antihypertensive agents

Brambilla, Giovanni; Martelli, Antonietta

doi:10.1016/j.mrrev.2005.12.002

Cited by 31 publications

(18 citation statements)

References 107 publications

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“…We identified it as a degree-7 beneficial drug, but there has been no literature suggesting its anti-tumorigenicity. Instead, there are two clinical studies suggesting possible carcinogenic effects in patients [40], [41].…”

Section: Discussionmentioning

confidence: 99%

Functional Module Connectivity Map (FMCM): A Framework for Searching Repurposed Drug Compounds for Systems Treatment of Cancer and an Application to Colorectal Adenocarcinoma

et al. 2014

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Drug repurposing has become an increasingly attractive approach to drug development owing to the ever-growing cost of new drug discovery and frequent withdrawal of successful drugs caused by side effect issues. Here, we devised Functional Module Connectivity Map (FMCM) for the discovery of repurposed drug compounds for systems treatment of complex diseases, and applied it to colorectal adenocarcinoma. FMCM used multiple functional gene modules to query the Connectivity Map (CMap). The functional modules were built around hub genes identified, through a gene selection by trend-of-disease-progression (GSToP) procedure, from condition-specific gene-gene interaction networks constructed from sets of cohort gene expression microarrays. The candidate drug compounds were restricted to drugs exhibiting predicted minimal intracellular harmful side effects. We tested FMCM against the common practice of selecting drugs using a genomic signature represented by a single set of individual genes to query CMap (IGCM), and found FMCM to have higher robustness, accuracy, specificity, and reproducibility in identifying known anti-cancer agents. Among the 46 drug candidates selected by FMCM for colorectal adenocarcinoma treatment, 65% had literature support for association with anti-cancer activities, and 60% of the drugs predicted to have harmful effects on cancer had been reported to be associated with carcinogens/immune suppressors. Compounds were formed from the selected drug candidates where in each compound the component drugs collectively were beneficial to all the functional modules while no single component drug was harmful to any of the modules. In cell viability tests, we identified four candidate drugs: GW-8510, etacrynic acid, ginkgolide A, and 6-azathymine, as having high inhibitory activities against cancer cells. Through microarray experiments we confirmed the novel functional links predicted for three candidate drugs: phenoxybenzamine (broad effects), GW-8510 (cell cycle), and imipenem (immune system). We believe FMCM can be usefully applied to repurposed drug discovery for systems treatment of other types of cancer and other complex diseases.

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Section: Discussionmentioning

confidence: 99%

Functional Module Connectivity Map (FMCM): A Framework for Searching Repurposed Drug Compounds for Systems Treatment of Cancer and an Application to Colorectal Adenocarcinoma

et al. 2014

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“…Reduction of DNA methylation may activate a cascade of genotoxic stress checkpoint proteins, resulting in phosphorylation of Chk1 and 2, gammaH2AX focus formation, and CDC25a degradation [40]. A substantial percentage of the marketed antihypertensive drugs (18%) have been tested positive in at least one genotoxicity assay [41]. Some anti-arthritic compounds also target regulators involved in mitosis and cell cycle [42].…”

Section: Resultsmentioning

confidence: 99%

Effect of training data size and noise level on support vector machines virtual screening of genotoxic compounds from large compound libraries

Kumar

Liu

et al. 2011

J Comput Aided Mol Des

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Various in vitro and in-silico methods have been used for drug genotoxicity tests, which show limited genotoxicity (GT+) and non-genotoxicity (GT-) identification rates. New methods and combinatorial approaches have been explored for enhanced collective identification capability. The rates of in-silco methods may be further improved by significantly diversified training data enriched by the large number of recently reported GT+ and GT- compounds, but a major concern is the increased noise levels arising from high false-positive rates of in vitro data. In this work, we evaluated the effect of training data size and noise level on the performance of support vector machines (SVM) method known to tolerate high noise levels in training data. Two SVMs of different diversity/noise levels were developed and tested. H-SVM trained by higher diversity higher noise data (GT+ in any in vivo or in vitro test) outperforms L-SVM trained by lower noise lower diversity data (GT+ in in vivo or Ames test only). H-SVM trained by 4,763 GT+ compounds reported before 2008 and 8,232 GT- compounds excluding clinical trial drugs correctly identified 81.6% of the 38 GT+ compounds reported since 2008, predicted 83.1% of the 2,008 clinical trial drugs as GT-, and 23.96% of 168 K MDDR and 27.23% of 17.86M PubChem compounds as GT+. These are comparable to the 43.1-51.9% GT+ and 75-93% GT- rates of existing in-silico methods, 58.8% GT+ and 79% GT- rates of Ames method, and the estimated percentages of 23% in vivo and 31-33% in vitro GT+ compounds in the "universe of chemicals". There is a substantial level of agreement between H-SVM and L-SVM predicted GT+ and GT- MDDR compounds and the prediction from TOPKAT. SVM showed good potential in identifying GT+ compounds from large compound libraries based on higher diversity and higher noise training data.

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“…In current study, olmesartan cilexetil did not show positive outcome in bacterial mutation test. Genotoxicity studies for olmesartan and olmesartan medoxomil were performed and observed negative in revertant mutation test and in vitro Syrian hamster embryo cell transformation assay (13). However, both compounds showed a few positive responses in chromosomal aberrations using mammalian cell and in mouse lymphoma assay (13).…”

Section: Discussionmentioning

confidence: 99%

“…Genotoxicity studies for olmesartan and olmesartan medoxomil were performed and observed negative in revertant mutation test and in vitro Syrian hamster embryo cell transformation assay (13). However, both compounds showed a few positive responses in chromosomal aberrations using mammalian cell and in mouse lymphoma assay (13). Olmesartan medoxomil was negative in vivo micronucleus test using MutaMouse at oral doses of up to 2 g/kg and the weight-of-evidence shows that olmesartan medoxomil is not considered as a genotoxic agent at clinically relevant doses.…”

Section: Discussionmentioning

confidence: 99%

“…Olmesartan medoxomil was negative in vivo micronucleus test using MutaMouse at oral doses of up to 2 g/kg and the weight-of-evidence shows that olmesartan medoxomil is not considered as a genotoxic agent at clinically relevant doses. In genotoxicity assays of other AII receptor antagonist drugs, candesartan and eprosartan induced chromosomal aberrations in mammalian cells and showed positive results in the mouse lymphoma assay (13). Therefore, further studies including chromosomal aberration and in vivo micronucleus assay should be performed in order to clarify the genotoxicity of olmesartan cilexetil.…”

Section: Discussionmentioning

confidence: 99%

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Mutagenic Assessment of Olmesartan Cilexetil by Bacterial Mutation Assay

Kim¹,

Ahn

Ryu

et al. 2013

Toxicological Research

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Hypertension is a serious health problem due to high frequency and concomitant other diseases including cardiovascular and renal dysfunction. Olmesartan cilexetil is a new antihypertensive drug associated with angiotensin II receptor antagonist. This study was conducted to evaluate the mutagenicity of olmesartan cilexetil by bacterial reverse mutation test using Salmonella typhimurium (TA100, TA1535, TA98, and TA1537) and Escherichia coli (WP2 uvrA). At the concentrations of 0, 62, 185, 556, 1667, and 5000 μg/ plate, olmesartan cilexetil was negative in both Salmonella typhimurium and Escherichia coli regardless of presence or absence of metabolic activation system (S9 mix). These results demonstrate that olmesartan cilexetil does not induce bacterial reverse mutation.

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Genotoxicity and carcinogenicity studies of antihypertensive agents

Cited by 31 publications

References 107 publications

Functional Module Connectivity Map (FMCM): A Framework for Searching Repurposed Drug Compounds for Systems Treatment of Cancer and an Application to Colorectal Adenocarcinoma

Functional Module Connectivity Map (FMCM): A Framework for Searching Repurposed Drug Compounds for Systems Treatment of Cancer and an Application to Colorectal Adenocarcinoma

Effect of training data size and noise level on support vector machines virtual screening of genotoxic compounds from large compound libraries

Mutagenic Assessment of Olmesartan Cilexetil by Bacterial Mutation Assay

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