Acetylcholinesterase Blockade Does Not Account for the Adverse Cardiovascular Effects of the Antitumor Drug Irinotecan: A Preclinical Study

Blandizzi, Corrado; Paolis, Barbara De; Colucci, Rocchina; Paolo, Antonello Di; Danesi, Romano; Tacca, M. Del

doi:10.1006/taap.2001.9293

Cited by 8 publications

(9 citation statements)

References 30 publications

(47 reference statements)

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“…Indeed, Tobin et al did not report on the occurrence of cholinergic symptoms in their patients, whereas we observed cholinergic adverse effects in 56% of irinotecan‐treated patients, without concomitant changes in the erythrocyte acetylcholinesterase activity 1 Whereas data from Tobin et al suggest an inhibitory action of irinotecan on human acetylcholinesterase, Gandia et al , 3 in full agreement with our results, 1 did not observe alterations of acetylcholinesterase activity in erythrocytes from patients undergoing irinotecan infusion. Despite in vitro findings, previous studies on preclinical models failed to confirm antiacetylcholinesterase properties of irinotecan, because it was not able to mimic effects elicited by reference acetylcholinesterase inhibitors 4 , 5 . In addition, acetylcholinesterase blockade is expected to promote not only muscarinic receptor activation but also a recruitment of nicotinic receptors expressed in the nervous system and skeletal muscle.…”

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confidence: 89%

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Blandizzi¹,

Danesi²,

Paolis³

et al. 2004

Clinical Pharmacology & Therapeutics

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supporting

confidence: 89%

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Blandizzi¹,

Danesi²,

Paolis³

et al. 2004

Clinical Pharmacology & Therapeutics

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“…FABP4 is a lipid binding protein playing a role in intracellular lipid transport and metabolism, as well as in signal transduction and its expression is regulated by PPAR-dependent transcriptional mechanism [44]. Both gene products are associated with metabolic syndrome, type 2 diabetes mellitus, cancer and atherosclerosis [44–46]. Although in the acute experiment any significant changes could be found in the expression profiles of the treated animals, further studies on the expression alteration of fabp4 , pparg or other gene markers could possibly highlight the effects of chronic hormone replacement therapy applied at different doses and could define the risk population.…”

Section: Resultsmentioning

confidence: 99%

High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

Fábián¹,

Faragó

Feher³

et al. 2011

IJMS

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Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified, namely fabp4 and pparg, which were down-regulated by estradiol treatment.

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“…Other biological activities of CPT are also receiving increased interest, it has been reported that CPT‐11 ( 4 ) inhibited acetylcholinesterase activity . Inhibition of acetylcholinesterase could obviously constitute a dose‐limiting factor for utilization of the drug.…”

Section: Biological Activity Of Cpt and Related Derivativesmentioning

confidence: 99%

“…Compound 146 with dibutyl phosphate group showed greater tumor-inhibitory activity than CPT-11 (4) in an A549 xenograft model, potent activity in a DNA cleavage assay at a concentration of 100 μM, and good stability at both pH 7.4 and 3.0. 76 Seven new 7-trifluoromethylated hCPT derivatives were prepared by Zhu et al 77 Three derivatives (150)(151)(152) (Fig. 20) possessed higher in vitro antitumor activity than 3.…”

Section: A B and E Ring Modified Cpt Analogsmentioning

confidence: 99%

Perspectives on Biologically Active Camptothecin Derivatives

et al. 2015

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.

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Acetylcholinesterase Blockade Does Not Account for the Adverse Cardiovascular Effects of the Antitumor Drug Irinotecan: A Preclinical Study

Cited by 8 publications

References 30 publications

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High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

Perspectives on Biologically Active Camptothecin Derivatives

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