The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports

Llanos, Lucía; Moreu, Rocío; Ortin, Teresa Sy; Peiró, Ana M.; Pascual, Sonia; Bellot, Pablo; Barquero, Claudia; Francés, Rubén; Such, José; Pérez‐Mateo, Miguel; Horga, J.F.; Zapater, Pedro

doi:10.1111/j.1365-2036.2010.04298.x

Cited by 17 publications

(13 citation statements)

References 17 publications

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“…Despite the limitations on the predictive value of ALT elevations in individual subjects, it has been found repeatedly that the increased occurrence of such elevations in groups that are being studied is highly predictive of what is later likely to be found in other groups. This is an important point, the significance of which is often misunderstood 47 , 48 , 49 …”

Section: What Does All This Add Up To?mentioning

confidence: 99%

Alanine Aminotransferase: A Clinical and Regulatory Tool for Detecting Liver Injury–Past, Present, and Future

Senior

2012

Clin Pharmacol Ther

205

129

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Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury. But what does an elevated value mean? Not what it is too often mistakenly believed to indicate. It is not a test of liver function. It does not necessarily predict worse effects to come (in a given person). It is not a valid measure of severity of liver injury or dysfunction. It is too unspecific to be reliable in screening for relatively rare effects on the liver. Although these are substantial limitations, ALT is a very useful biomarker if understood and used properly. It is important to consider how and why these erroneous concepts came to have such wide acceptance, and how elevations of ALT activity for evaluating patients and subjects under study might be interpreted better.

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Section: What Does All This Add Up To?mentioning

confidence: 99%

Alanine Aminotransferase: A Clinical and Regulatory Tool for Detecting Liver Injury–Past, Present, and Future

Senior

2012

Clin Pharmacol Ther

205

129

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“…Consistent with body weight data, title compound-treated groups exhibited obvious decrease in tumor weight ( Figure 7c ). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are commonly used as biomarkers for the evaluation of hepatotoxicity, 29 after treatment of the title compound, the levels of AST and ALT were analyzed using an activity assays, the results showed that title compound had nearly no effect on the AST and ALT compared with those of the control group ( Figure 7d ). H&E staining of the organs such as the liver, lung, and kidney demonstrates no serious damage ( Figure 7e ).…”

Section: Resultsmentioning

confidence: 99%

Discovery of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone through upregulating hTERT induces cell apoptosis and ERS

et al. 2017

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Dominant-negative mutants of telomerase hTERT were demonstrated to have selective effects in tumor cells. However, no any effective and highly selective hTERT inhibitor has been developed so far. We focused on developing new hTERT modulators and synthesized a small molecular compound, named (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone. Our in vitro studies found that title compound showed high inhibitory activity against telomerase, had high antiproliferative capacity on SMMC-7721 cells with IC50 value 88 nm, and had no obvious toxic effect on human normal hepatocyte cells with IC50 value 10 μM. Our in vivo studies showed that this compound significantly inhibited tumor growth in xenograft tumor models. The further molecular mechanisms of title compound inhibition SMMC-7721 cell proliferation by modulating hTERT were explored; the results showed that endoplasmic reticulum stress (ERS) through ER over response (EOR) activates the expression of hTERT, and then induces ERS, which is believed to be intricately associated with oxidative stress and mitochondrial dysfunction, resulting in apoptotic cell death, thereby modulating the expression of downstream signaling molecules including CHOP (CAAT/enhancer-binding protein homologous protein)) and mitochondrion pathway of apoptosis, leading to inhibition of cell proliferation.

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“…7d ). Aspartate aminotransferase (AST) and alanine-aminotransferase (ALT) are commonly used as biomarkers for the evaluation of hepatotoxicity [ 31 ], after the treatment of 17-DR or DHQ3, the levels of AST and ALT were analyzed using an activity assays, showing that 17-DR and DHQ3 had nearly no effect on the AST and ALT compared with those of the control group, but obviously lower than those of the DDP-treated group (Fig. 7e ).…”

Section: Resultsmentioning

confidence: 99%

Non-benzoquinone geldanamycin analogs trigger various forms of death in human breast cancer cells

Zhang

Zhou

et al. 2016

J Exp Clin Cancer Res

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BackgroundHsp90 proteins are important therapeutic targets for many anti-cancer drugs in clinical trials. Geldanamycin (GA) was identified as the first natural inhibitor of Hsp90, increasing evidence suggests that GA was not a good choice for clinical trials. In this study, we investigated two new non-benzoquinone geldanamycin analogs of Hsp90 inhibitors, DHQ3 and 17-demethoxy-reblastatin (17-DR), to explore the molecular mechanisms of their anti-cancer activity in vivo and vitro.MethodsMTT and colony formation assays were used to measure cell viability. Flow cytometry, DAPI staining, ATP assay, electron microscopy, western blots, siRNAs transfection and immunofluorescence were used to determine the molecular mechanism of DHQ3- or 17-DR-induced different forms of death in human breast cancer MDA-MB-231 cells. Malachite green reagent was used to measure ATPase activity of the analogs.ResultsDHQ3 and 17-DR presented efficiently inhibitory effect in MDA-MB-231 cell lines, and DHQ3 induced necroptosis by activation of the RIP1-RIP3-MLKL necroptosis cascade. And DHQ3-induced cell death was inhibited by a necroptosis inhibitor, necrostatin-1 (Nec-1), but not by a caspase inhibitor z-VAD-fmk. On the other hand, 17-DR induced apoptosis in MDA-MB-231 cells, indicating a caspase-dependent killing mechanism. We further demonstrated that down-regulation of RIP1 and RIP3 by siRNA protected against DHQ3 but not 17-DR induced cell death. These results were confirmed by electron microscopy. DHQ3 and 17-DR induced the degradation of Hsp90 client proteins, and they showed strong antitumor effects in MDA-MB-231 cell-xenografted nude mice.ConclusionsThese findings supported that DHQ3 and 17-DR induce different forms of death in some cancer cell line via activation of different pathways. All of the results provided evidence for its anti-tumorigentic action with low hepatotoxicity in vivo, making them promising anti-breast cancer agents.

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The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports

Abstract: A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.

Cited by 17 publications

References 17 publications

Alanine Aminotransferase: A Clinical and Regulatory Tool for Detecting Liver Injury–Past, Present, and Future

Alanine Aminotransferase: A Clinical and Regulatory Tool for Detecting Liver Injury–Past, Present, and Future

Discovery of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone through upregulating hTERT induces cell apoptosis and ERS

Non-benzoquinone geldanamycin analogs trigger various forms of death in human breast cancer cells

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