Translation of novel anti-cancer cytotoxicity biomarkers detected with high content analysis from an in vitro predictive model to an in vivo cell model

Lieggi, Nora T.; Edvardsson, A.; O’Brien, Peter J.

doi:10.1016/j.tiv.2010.07.014

Cited by 16 publications

(19 citation statements)

References 15 publications

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“…Firstly, the studies confirm our previous study [5] that HCA can be conducted on non-adherent cell lines such as neoplastic human lymphocytes. Furthermore, this conclusion is extended to include canine peripheral blood lymphocytes isolated from healthy dogs, as well as a second type of transformed human lymphocytes (HuT-78 human T-lymphoma cells versus Jurkat leukaemic T-lymphocytes).…”

Section: Discussionsupporting

confidence: 85%

“…Thus, concentration-response relationships for drug-induced cytotoxicity can be determined on cell lines and peripheral blood cells. The cytotoxic responses are similar to what has been found for hepatocytes with respect to there being similar parameters affected with similar concentration-response curves that are frequently biphasic [1,5]. The pattern of changes frequently differs across anticancer drug classes.…”

Section: Discussionsupporting

confidence: 79%

“…We previously determined that HCA could be effectively applied to human, Jurkat leukaemic Tlymphocytes and give similar results as for human HepG2 carcinomatous hepatocytes [5]. We first confirmed our previous finding [5] that HCA could be applied to non-adherent cells, lymphocytes, using another cell line (HuT-78 human T-lymphoma cells) and canine peripheral blood lymphocytes to demonstrate concentration-dependent cytotoxicity. We then tested the hypothesis that in vivo cytotoxicity could be detected and assessed on lymphocytes isolated from blood of dogs with drug-induced toxicity occurring during anticancer drug therapy using HCA.…”

supporting

confidence: 74%

“…There were several cytotoxic findings for lymphocytes that were not previously observed by us for hepatocytes [1,5]. Nuclear fragmentation was conspicuous in the lymphocytes but not reported as such with hepatocellular toxicity, although in both cell types nuclear shrinkage occurred with progressive toxicity, which is associated with apoptosis [1,5]. Whereas 75% of drugs took more than one day of incubation with hepatocytes to produce their cytotoxic effect, this effect was clearly seen within one day for the four anticancer drugs studied herein.…”

Section: Discussionsupporting

confidence: 46%

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Application of High‐Content Analysis in Clinical Cytology for Translational Safety Biomarkers of Drug‐Induced Toxicity for Lymphoma Chemotherapy

Domingos

Davies

O’Brien

2014

Basic Clin Pharma Tox

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Drug cytotoxicity detected by high-content analysis (HCA) of live, cultured, human hepatocytes concurs with human toxic potential. We assessed HCA effectiveness in vivo using human, lymphoma line (HuT-78) and blood cells from healthy dogs and lymphomatous dogs treated with anticancer drugs: cytarabine, arsenic trioxide (AT), doxorubicin and mitoxantrone. DNA was stained with Hoechst-33342, calcium with fluo-4, mitochondria with TMRM and cell permeability with toto-3. HuT-78 and canine blood lymphocytes were treated 24 hr with 10 times increasing drug concentrations to determine concentrationresponse relationships to test agents. These showed hormesis (biphasic response) for TMRM and nuclear area. Fluorescence intensity was decreased with AT and mitoantrone but increased with cytarabine for TMRM, decreased from cell injury or anthracycline interaction for Hoechst-33342 and decreased with AT and interfered with by doxorubicin for fluo-4. Nuclear area increased with anthracyclines and AT. Mitochondria, calcium and nuclear area were affected in peripheral blood lymphocytes of lymphomatous dogs receiving chemotherapy: mitochondria were inhibited by acute treatment, but increased 2 weeks after treatment, as were ionized calcium, nuclear area and DNA. We conclude (i) concentration-response relationships are determinable in vitro for human and canine lymphocytes by HCA, (ii) cytotoxicity is detectable in vivo during and after anticancer drug treatment using canine blood lymphocytes: mitochondria are most affected, with smaller changes in calcium and nuclei and (iii) blood cell viability may be a biomarker for anticancer drug toxicity.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 79%

supporting

confidence: 74%

Section: Discussionsupporting

confidence: 46%

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Application of High‐Content Analysis in Clinical Cytology for Translational Safety Biomarkers of Drug‐Induced Toxicity for Lymphoma Chemotherapy

Domingos

Davies

O’Brien

2014

Basic Clin Pharma Tox

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“…For example, above 2 lM, doxorubicin fluorescence interferes with the fluo 4 signal [15]. Also, fluo-4 may not load into cells if they have already experienced cytotoxicity to an extent that inhibits the esterase activity needed for activating the dye or if the membranes have become leaky to the dye and can no longer trap it in the cell.…”

Section: Spurious Hormesismentioning

confidence: 99%

High‐Content Analysis in Toxicology: Screening Substances for Human Toxicity Potential, Elucidating Subcellular Mechanisms and In Vivo Use as Translational Safety Biomarkers

O’Brien

2014

Basic Clin Pharma Tox

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High-content analysis (HCA) of in vitro biochemical and morphological effects of classic (small molecule) drugs and chemicals is concordant with potential for human toxicity. For hepatotoxicity, concordance is greater for cytotoxic effects assessed by HCA than for conventional cytotoxicity tests and for regulatory animal toxicity studies. Additionally, HCA identifies chronic toxicity potential, and drugs producing idiosyncratic adverse reactions and/or toxic metabolites are also identified by HCA. Mechanistic information on the subcellular basis for the toxicity is frequently identified, including various mitochondrial effects, oxidative stress, calcium dyshomeostasis, phospholipidosis, apoptosis and antiproliferative effects, and a fingerprinting of the sequence and pattern of subcellular events. As these effects are frequently non-specific and affect many cell types, some toxicities may be detected and monitored by HCA of peripheral blood cells, such as for anticancer and anti-infective drugs. Critical methodological and interpretive features are identified that are critical to the effectiveness of the HCA cytotoxicity assessment, including the need for multiple days of exposure of cells to drug, use of a human hepatocyte cell line with metabolic competence, assessment of multiple pre-lethal effects in individual live cells, consideration of hormesis, the need for interpretation of relevance of cytotoxicity concentration compared to efficacy concentration and quality management. Limitations of the HCA include assessment of drugs that act on receptors, transporters or processes not found in hepatocytes. HCA may be used in a) screening lead candidates for potential human toxicity in drug discovery alongside of in vitro assessment of efficacy and pharmacokinetics, b) elucidating mechanisms of toxicity and c) monitoring in vivo toxicity of drugs with known toxicity of known mechanism.Classic (small molecule) drug toxicity is one of the major challenges for the pharmaceutical industry, not only because of the associated loss of human life or health, but because of enormous financial loss of past investment and of future revenue potential. Attrition of drugs is progressively more costly the later it occurs. It costs almost two billion dollars to bring the average drug through discovery and development to registration [1]. Furthermore, typically 10-12 years of investment of time by hundreds of pharmaceutical staff will have been mis-spent.Drug safety has been an important cause of this attrition. Analysis of safety attrition of approved drugs over a 25-year period ending in 1999 indicated an annual average of 0.7 approved drugs was withdrawn and two drugs received black box warnings [2]. From 1994 to 2006, the average safety attrition was even higher with 2.1 drugs per year, with 38 drugs withdrawn from the market by the US Food and Drug Agency More than 80% of market withdrawals due to drug toxicity were due to cardiotoxicity and hepatotoxicity. In 2003, druginduced liver injury was found to be the most fr...

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High‐Throughput Toxicity Testing in Drug Development: Aims, Strategies, and Novel Trends

Schoonen

Westerink²,

Water

et al. 2013

High‐Throughput Screening Methods in Toxicity Testing

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Translation of novel anti-cancer cytotoxicity biomarkers detected with high content analysis from an in vitro predictive model to an in vivo cell model

Cited by 16 publications

References 15 publications

Application of High‐Content Analysis in Clinical Cytology for Translational Safety Biomarkers of Drug‐Induced Toxicity for Lymphoma Chemotherapy

Application of High‐Content Analysis in Clinical Cytology for Translational Safety Biomarkers of Drug‐Induced Toxicity for Lymphoma Chemotherapy

High‐Content Analysis in Toxicology: Screening Substances for Human Toxicity Potential, Elucidating Subcellular Mechanisms and In Vivo Use as Translational Safety Biomarkers

High‐Throughput Toxicity Testing in Drug Development: Aims, Strategies, and Novel Trends

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