Editorial

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Toxicities of Therapeutic Agents Used in Medicine

by Valentina Alda Carozzi and Guido Cavaletti

Toxics 2016, 4(3), 14; https://doi.org/10.3390/toxics4030014 - 27 Jul 2016

Cited by 3 | Viewed by 3131

This Special Issue on “Toxicities of Therapeutic Agents Used in Medicine” reports on some peculiar cases of toxicities related to widely and commonly employed drugs.[...] Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

Research

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Transcriptional Suppression of Renal Antioxidant Enzyme Systems in Guinea Pigs Exposed to Polymerized Cell-Free Hemoglobin

by Otgonchimeg Rentsendorj, Xiaoyuan Zhang, Matthew C. Williams, Paul W. Buehler and Felice D’Agnillo

Toxics 2016, 4(1), 6; https://doi.org/10.3390/toxics4010006 - 19 Feb 2016

Cited by 19 | Viewed by 5258

Abstract

Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury has raised safety concerns. Using a guinea pig exchange transfusion model, we examined the effects of polymerized bovine hemoglobin (HbG) on the [...] Read more.

Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury has raised safety concerns. Using a guinea pig exchange transfusion model, we examined the effects of polymerized bovine hemoglobin (HbG) on the transcriptional regulation, activity, and expression of the renal antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). HbG infusion downregulated the mRNA levels for genes encoding SOD isoforms 1-3, GPx1, GPx3, GPx4, and CAT. This transcriptional suppression correlated with decreased enzymatic activities for SOD, CAT, and GPx. Immunostaining revealed decreased protein expression of SOD1, CAT, and GPx1 primarily in renal cortical tubules. DNA methylation analyses identified CpG hypermethylation in the gene promoters for SOD1-3, GPx1, GPx3, and GPx4, suggesting an epigenetic-based mechanism underlying the observed gene repression. HbG also induced oxidative stress as evidenced by increased renal lipid peroxidation end-products and 4-HNE immunostaining, which could be the result of the depleted antioxidant defenses and/or serve as a trigger for increased DNA methylation. Together, these findings provide evidence that the renal exposure to HbG suppresses the function of major antioxidant defense systems which may have relevant implications for understanding the safety of hemoglobin-based products. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Neurotoxic Effects of Platinum Compounds: Studies in vivo on Intracellular Calcium Homeostasis in the Immature Central Nervous System

by Graziella Bernocchi, Francesco P. Fanizzi, Sandra A. De Pascali, Valeria M. Piccolini, Caterina Gasperini, Violetta Insolia and Maria Grazia Bottone

Toxics 2015, 3(2), 224-248; https://doi.org/10.3390/toxics3020224 - 19 Jun 2015

Cited by 6 | Viewed by 8851

Abstract

Platinum compounds cause significant clinical neurotoxicity. Several studies highlight neurological complications especially in paediatric oncology patients with Central Nervous System (CNS) and non-CNS malignancies. To understand the toxicity mechanisms of platinum drugs at cellular and molecular levels in the immature brain, which appears [...] Read more.

Platinum compounds cause significant clinical neurotoxicity. Several studies highlight neurological complications especially in paediatric oncology patients with Central Nervous System (CNS) and non-CNS malignancies. To understand the toxicity mechanisms of platinum drugs at cellular and molecular levels in the immature brain, which appears more vulnerable to injury than in the adult one, we compared the effects in vivo of the most used platinum compounds, i.e., cisdichlorodiammineplatinum (cisplatin, cisPt), and the new [Pt(O,O′-acac)(γ-acac)(DMS)] (PtAcacDMS). As models of developing brain areas, we have chosen the cerebellum and hippocampus dentate gyrus. Both areas show the neurogenesis events, from proliferation to differentiation and synaptogenesis, and therefore allow comparing the action of platinum compounds with DNA and non-DNA targets. Here, we focused on the changes in the intracellular calcium homeostasis within CNS architecture, using two immunohistochemical markers, the calcium buffer protein Calbindin and Plasma Membrane Calcium ATPase. From the comparison of the cisPt and PtAcacDMS effects, it emerges how essential the equilibrium and synergy between CB and PMCA1 is or how important the presence of at least one of them is to warrant the morphology and function of nervous tissue and limit neuroarchitecture damages, depending on the peculiar and intrinsic properties of the developing CNS areas. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Review

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Axonal Transport Impairment in Chemotherapy-Induced Peripheral Neuropathy

by Gabriella Nicolini, Marianna Monfrini and Arianna Scuteri

Toxics 2015, 3(3), 322-341; https://doi.org/10.3390/toxics3030322 - 07 Aug 2015

Cited by 20 | Viewed by 5023

Abstract

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a dose-limiting side effect of several antineoplastic drugs which significantly reduces patients’ quality of life. Although different molecular mechanisms have been investigated, CIPN pathobiology has not been clarified yet. It has largely been recognized that Dorsal Root Ganglia [...] Read more.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a dose-limiting side effect of several antineoplastic drugs which significantly reduces patients’ quality of life. Although different molecular mechanisms have been investigated, CIPN pathobiology has not been clarified yet. It has largely been recognized that Dorsal Root Ganglia are the main targets of chemotherapy and that the longest nerves are the most damaged, together with fast axonal transport. Indeed, this bidirectional cargo-specific transport has a pivotal role in neuronal function and its impairment is involved in several neurodegenerative and neurodevelopmental diseases. Literature data demonstrate that, despite different mechanisms of action, all antineoplastic agents impair the axonal trafficking to some extent and the severity of the neuropathy correlates with the degree of damage on this bidirectional transport. In this paper, we will examine the effect of the main old and new chemotherapeutic drug categories on axonal transport, with the aim of clarifying their potential mechanisms of action, and, if possible, of identifying neuroprotective strategies, based on the knowledge of the alterations induced by each drugs. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Current View in Platinum Drug Mechanisms of Peripheral Neurotoxicity

by Alessia Chiorazzi, Sara Semperboni and Paola Marmiroli

Toxics 2015, 3(3), 304-321; https://doi.org/10.3390/toxics3030304 - 07 Aug 2015

Cited by 43 | Viewed by 5913

Abstract

Peripheral neurotoxicity is the dose-limiting factor for clinical use of platinum derivatives, a class of anticancer drugs which includes cisplatin, carboplatin, and oxaliplatin. In particular cisplatin and oxaliplatin induce a severe peripheral neurotoxicity while carboplatin is less neurotoxic. The mechanisms proposed to explain [...] Read more.

Peripheral neurotoxicity is the dose-limiting factor for clinical use of platinum derivatives, a class of anticancer drugs which includes cisplatin, carboplatin, and oxaliplatin. In particular cisplatin and oxaliplatin induce a severe peripheral neurotoxicity while carboplatin is less neurotoxic. The mechanisms proposed to explain these drugs’ neurotoxicity are dorsal root ganglia alteration, oxidative stress involvement, and mitochondrial dysfunction. Oxaliplatin also causes an acute and reversible neuropathy, supposed to be due by transient dysfunction of the voltage-gated sodium channels of sensory neurons. Recent studies suggest that individual genetic variation may play a role in the pathogenesis of platinum drug neurotoxicity. Even though all these mechanisms have been investigated, the pathogenesis is far from clearly defined. In this review we will summarize the current knowledge and the most up-to-date hypotheses on the mechanisms of platinum drug-induced peripheral neurotoxicity. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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An Overview of Bortezomib-Induced Neurotoxicity

by Cristina Meregalli

Toxics 2015, 3(3), 294-303; https://doi.org/10.3390/toxics3030294 - 27 Jul 2015

Cited by 38 | Viewed by 5484

Abstract

The boronic acid dipeptide bortezomib, able to induce tumor cell death by degradation of key proteins, is the first proteasome inhibitor drug to enter clinical practice. It is employed as first-line treatment in relapsed or resistant multiple myeloma (MM) patients. However, bortezomib often [...] Read more.

The boronic acid dipeptide bortezomib, able to induce tumor cell death by degradation of key proteins, is the first proteasome inhibitor drug to enter clinical practice. It is employed as first-line treatment in relapsed or resistant multiple myeloma (MM) patients. However, bortezomib often induces a dose-limiting toxicity in the form of painful sensory neuropathy, which can mainly be reduced by subcutaneous administration or dose modification. In this review we focus on the current understanding of the pathophysiological mechanisms of bortezomib-induced neuropathy to allow further studies in animal models and humans, including analysis of clinical and pharmacogenetic aspects, to optimize the treatment regimens. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Open AccessReview

Cisplatin-Induced Ototoxicity: Effects, Mechanisms and Protection Strategies

by Angela Callejo, Lara Sedó-Cabezón, Ivan Domènech Juan and Jordi Llorens

Toxics 2015, 3(3), 268-293; https://doi.org/10.3390/toxics3030268 - 15 Jul 2015

Cited by 97 | Viewed by 8845

Abstract

Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat solid organ malignancies. However, serious side effects have been associated with its use, such as bilateral, progressive, irreversible, dose-dependent neurosensory hearing loss. Current evidence indicates that cisplatin triggers the production [...] Read more.

Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat solid organ malignancies. However, serious side effects have been associated with its use, such as bilateral, progressive, irreversible, dose-dependent neurosensory hearing loss. Current evidence indicates that cisplatin triggers the production of reactive oxygen species in target tissues in the inner ear. A variety of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models. However, many of them interfere with the therapeutic effect of cisplatin, and therefore are not suitable for systemic administration in clinical practice. Consequently, local administration strategies, namely intratympanic administration, have been developed to achieve otoprotection, without reducing the antitumoral effect of cisplatin. While a considerable amount of pre-clinical information is available, clinical data on treatments to prevent cisplatin ototoxicity are only just beginning to appear. This review summarizes clinical and experimental studies of cisplatin ototoxicity, and focuses on understanding its toxicity mechanisms, clinical repercussions and prevention strategies. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN)

by Annalisa Canta, Eleonora Pozzi and Valentina Alda Carozzi

Toxics 2015, 3(2), 198-223; https://doi.org/10.3390/toxics3020198 - 05 Jun 2015

Cited by 136 | Viewed by 13220

Abstract

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root [...] Read more.

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling. Cisplatin and oxaliplatin form adducts with mitochondrial DNA producing inhibition of replication, disruption of transcription and morphological abnormalities within mitochondria in DRG neurons, leading to a gradual energy failure. Bortezomib is able to modify mitochondrial calcium homeostasis and mitochondrial respiratory chain. Moreover, the expression of a certain number of genes, including those controlling mitochondrial functions, was altered in patients with bortezomib-induced peripheral neuropathy. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Updates on Oxaliplatin-Induced Peripheral Neurotoxicity (OXAIPN)

by Andreas A. Argyriou

Toxics 2015, 3(2), 187-197; https://doi.org/10.3390/toxics3020187 - 29 May 2015

Cited by 26 | Viewed by 7238

Abstract

Oxaliplatin-induced peripheral neuropathy (OXAIPN) is of great clinical interest as it ranks among the most common dose limiting toxicities of oxaliplatin (OXA) administration with an obvious impact on the outcome of cancer patients. In addition, OXAIPN has a detrimental effect on the quality [...] Read more.

Oxaliplatin-induced peripheral neuropathy (OXAIPN) is of great clinical interest as it ranks among the most common dose limiting toxicities of oxaliplatin (OXA) administration with an obvious impact on the outcome of cancer patients. In addition, OXAIPN has a detrimental effect on the quality of life of cancer patients because it can be long lasting or even permanent. It has a unique spectrum of clinical presentation, being manifested with two distinct syndromes: the acute neurotoxicity that appears soon after OXA administration and is usually transient, and the chronic cumulative syndrome that resembles the characteristics of all platinum compounds. Despite advances in research in relation to the elucidation of the true OXAIPN pathogenesis, characteristics and management, there are still several open issues to be addressed. One of the most important open issues is to determine reliable biomarkers to allow prompt identification of patients at high risk to develop OXAIPN and towards this view well designed genome wide analyses are warranted to adequately address this gap in knowledge. Recent updates are provided in this article in relation to the pathogenesis, clinical characteristics, pharmacogenetics and management of OXAIPN. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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Taxane-Induced Peripheral Neurotoxicity

by Roser Velasco and Jordi Bruna

Toxics 2015, 3(2), 152-169; https://doi.org/10.3390/toxics3020152 - 28 Apr 2015

Cited by 76 | Viewed by 8543

Abstract

Taxane-derived agents are chemotherapy drugs widely employed in cancer treatment. Among them, paclitaxel and docetaxel are most commonly administered, but newer formulations are being investigated. Taxane antineoplastic activity is mainly based on the ability of the drugs to promote microtubule assembly, leading to [...] Read more.

Taxane-derived agents are chemotherapy drugs widely employed in cancer treatment. Among them, paclitaxel and docetaxel are most commonly administered, but newer formulations are being investigated. Taxane antineoplastic activity is mainly based on the ability of the drugs to promote microtubule assembly, leading to mitotic arrest and apoptosis in cancer cells. Peripheral neurotoxicity is the major non-hematological adverse effect of taxane, often manifested as painful neuropathy experienced during treatment, and it is sometimes irreversible. Unfortunately, taxane-induced neurotoxicity is an uncertainty prior to the initiation of treatment. The present review aims to dissect current knowledge on real incidence, underlying pathophysiology, clinical features and predisposing factors related with the development of taxane-induced neuropathy. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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L-Dopa and Brain Serotonin System Dysfunction

by Branden J. Stansley and Bryan K. Yamamoto

Toxics 2015, 3(1), 75-88; https://doi.org/10.3390/toxics3010075 - 05 Mar 2015

Cited by 41 | Viewed by 7691

Abstract

L-dopa is used to treat the motor symptoms associated with Parkinson’s disease, a neurodegenerative movement disorder characterized by a loss of dopamine neurons. L-dopa is the precursor to dopamine and crosses the blood-brain barrier to increase dopamine neurotransmission. This review will focus on [...] Read more.

L-dopa is used to treat the motor symptoms associated with Parkinson’s disease, a neurodegenerative movement disorder characterized by a loss of dopamine neurons. L-dopa is the precursor to dopamine and crosses the blood-brain barrier to increase dopamine neurotransmission. This review will focus on the findings that dopamine produced from L-dopa is mediated in part by serotonin neurons. Direct evidence will be provided that increases in dopamine cause oxidative stress and damage serotonin neurons. Similarly, chronic L-dopa produces deficits in serotonin neurotransmission, including decreases in both serotonin cell bodies within the dorsal raphe and serotonin neurotransmitter concentrations in several forebrain regions. Since serotonin is involved in many important physiological processes including mood and cognition, L-dopa induced serotonin deficits may play a role in the side-effect symptoms observed in Parkinson’s disease patients treated with L-dopa. Full article

(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)

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