Potential Cytoprotective Agent Research Articles

Thyroid hormone protects human lung epithelial cells from cold preservation and warm reperfusion-induced injury

BackgroundCellular stress associated with static-cold storage (SCS) and warm reperfusion of donor lungs can contribute to ischemia–reperfusion (IR) injury during transplantation. Adding cytoprotective agents to the preservation solution may be conducive to reducing graft deterioration and improving post-transplant outcomes.MethodsSCS and warm reperfusion were simulated in human lung epithelial cells (BEAS-2B) by exposing cells to low potassium dextran glucose solution at 4 °C for different periods and then switching back to serum-containing culture medium at 37 °C. Transcriptomic analysis was used to explore potential cytoprotective agents. Based on its results, cell viability, caspase activity, cell morphology, mitochondrial function, and inflammatory gene expression were examined under simulated IR conditions with or without thyroid hormones (THs).ResultsAfter 18 h SCS followed by 2 h warm reperfusion, genes related to inflammation and cell death were upregulated, and genes related to protein synthesis and metabolism were downregulated in BEAS-2B cells, which closely mirrored gene profiles found in thyroid glands of mice with congenital hypothyroidism. The addition of THs (T3 or T4) to the preservation solution increases cell viability, inhibits activation of caspase 3, 8 and 9, preserves cell morphology, enhances mitochondrial membrane potential, reduces mitochondrial superoxide production, and suppresses inflammatory gene expression.ConclusionAdding THs to lung preservation solutions may protect lung cells during SCS by promoting mitochondrial function, reducing apoptosis, and inhibiting pro-inflammatory pathways. Further in vivo testing is warranted to determine the potential clinical application of adding THs as therapeutics in lung preservation solutions.

Cytoprotection Alternatives for Cancer Treatment: In-vitro Evaluation of Alpinia Zerumbet as a Radioprotective Agent

Cancer radiotherapy and modern synthetic medicine are critical for the treatment of cancer patients, but on the other hand they may have tremendous harmful side effect from the point of view of a weakened immune system. The focus of current research efforts in the industry and academia is not only to find affordable treatment methodologies but also to discover sources that mitigates or prevents the negative impact of these treatments on the patient’s immune system. This review will provide details of optimal methodology involving Invitro application of techniques such as phytochemical analysis, thin layer chromatography, cytogenetic analysis that were adopted to assess the efficacy of Alpinia Zerumbet extracts as a radioprotector. These methodologies provide a holistic evaluation technique for assessing any potential cytoprotective agent, especially if it’s from the herbal domain. As a case study, analytical and inferential results summary of the research conducted to assess radioprotective property of Alpinia Zerumbet, a herbal and readily available derivative, will be presented. The key findings from the research indicate that the Alpinia Zerumbet extract has potential to be an effective radioprotector, with minimal side effects as compared to synthetic chemical cytoprotective agents.
 Keywords: Radioprotection; cancer; herbal; Alpinia Zerumbet

Buffalo casein derived peptide can alleviates H2O2 induced cellular damage and necrosis in fibroblast cells

Oxidative stress is one of a critical pathogenic factor in the progression of aging and chronic diseases such as cancer, myocardial inflammation and diabetes. In the present scenario, peptides with short half life and more biological specificities are gaining much attention as prodrugs. Thus, the present investigation carried out to screen potential antioxidative peptide, VLPVPQK to cope with the cellular oxidative damage. Our results showed that treatment of rat fibroblast cells with 0.2mM H2O2 for 6h significantly declined different oxidative stress biomarkers such as SOD, CAT, GSH, and promoted LDH activity. In addition, ROS and TNF-α levels were also increased upon H2O2 exposure for 6h and thereby, it induced cell death. Amazingly, pretreatment of the peptide (VLPVPQK) significantly elevated cell survivability, by reversing all H2O2 induced alterations in fibroblast cells. Therefore, our results indicated that, the peptide (VLPVPQK) acted as a potential cytoprotective agent, who restored redox balance and cell homeostasis in cultured fibroblast cells, even after H2O2 exposure, suggesting that the peptide can be valuable as an effective remedy in treatment of oxidative stress related diseases and skin inflammation related disorders.

Cytoprotective Effects of Cell‐Permeable Bifunctional Antioxidant Enzyme, GST‐TAT‐SOD, against Cisplatin‐Induced Cell Damage

GST-TAT-SOD, a cell-permeable bifunctional antioxidant enzyme, is a potential selective radioprotector. This study aimed to investigate the cytoprotective activity of GST-TAT-SOD against cisplatin-induced damage. The current study showed that cisplatin induced the formation of reactive oxygen species in normal L-02 cells. GST-TAT-SOD (2000 U/mL) executed its antioxidant role by directly scavenging excess intracellular free radicals and augmenting cellular antioxidant defense such as reducing MDA level, enhancing the SOD activity, GST activity, and T-AOC. Thus, it suppressed the growth inhibition and apoptosis of cisplatin-treated normal cells. Meanwhile, the growth inhibition of tumor cells (SMMC-7721) caused by cisplatin was unaffected by GST-TAT-SOD pretreatment. GST-SOD, as a comparison, seemed to be powerless for related indicators as it could not enter into cells without cell-permeating peptide. These results suggest that GST-TAT-SOD might be a potential cytoprotective agent for cisplatin-induced side effects.

Evaluation of a Series of Different Surface Charged Fullerenol Nanoparticles as Reactive Oxygen Species Scavengers and Potential Cytoprotective Agents

Evaluation of a Series of Different Surface Charged Fullerenol Nanoparticles as Reactive Oxygen Species Scavengers and Potential Cytoprotective Agents

Novel long chain fatty acid derivatives of quercetin-3-O-glucoside reduce cytotoxicity induced by cigarette smoke toxicants in human fetal lung fibroblasts

Smoking has become a global health concern due to its association with many disease conditions, such as chronic obstructive pulmonary disease (COPD), cardiovascular diseases (CVD) and cancer. Flavonoids are plant polyphenolic compounds, studied extensively for their antioxidant, anti-inflammatory, and anti-carcinogenic properties. Quercetin-3-O-glucoside (Q3G) is a flavonoid which is widely found in plants. Six novel long chain fatty acid [stearic acid, oleic acid, linoleic acid, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] derivatives of Q3G were evaluated for their potential in protecting human lung fibroblasts against cytotoxicity induced by selected cigarette smoke toxicants: 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK), benzo-α-pyrene (BaP), nicotine and chromium (Cr[VI]). Nicotine and Cr[VI] induced toxicity in fibroblasts and reduced the percentage of viable cells, while BaP and NNK did not affect cell viability. The fatty acid derivatives of Q3G provided protection against nicotine- and Cr[VI]-induced cell death and membrane lipid peroxidation. Based on the evaluation of inflammatory markers of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), the fatty acid derivatives of Q3G were found to be effective in lowering the inflammatory response. Overall, these novel fatty acid esters of Q3G warrant further investigation as potential cytoprotective agents.

Cytoprotective effect of palm kernel cake phenolics against aflatoxin B1-induced cell damage and its underlying mechanism of action.

BackgroundPalm kernel cake (PKC), a by-product of the palm oil industry is abundantly available in many tropical and subtropical countries. The product is known to contain high levels of phenolic compounds that may impede the deleterious effects of fungal mycotoxins. This study focused on the evaluation of PKC phenolics as a potential cytoprotective agent towards aflatoxin B1 (AFB1)-induced cell damage.MethodsThe phenolic compounds of PKC were obtained by solvent extraction and the product rich in phenolic compounds was labeled as phenolic-enriched fraction (PEF). This fraction was evaluated for its phenolic compounds composition. The antioxidant activity of PEF was determined by using 1,1-diphenyl-2-picryl-hydrazil scavenging activity, ferric reducing antioxidant power, inhibition of ß-carotene bleaching, and thiobarbituric acid reactive substances assays. The cytotoxicity assay and molecular biomarkers analyses were performed to evaluate the cytoprotective effects of PEF towards aflatoxin B1 (AFB1)-induced cell damage.ResultsThe results showed that PEF contained gallic acid, pyrogallol, vanillic acid, caffeic acid, syringic acid, epicatechin, catechin and ferulic acid. The PEF exhibited free radical scavenging activity, ferric reducing antioxidant power, ß-carotene bleaching inhibition and thiobarbituric acid reactive substances inhibition. The PEF demonstrated cytoprotective effects in AFB1-treated chicken hepatocytes by reducing the cellular lipid peroxidation and enhancing antioxidant enzymes production. The viability of AFB1-treated hepatocytes was improved by PEF through up-regulation of oxidative stress tolerance genes and down-regulation of pro-inflammatory and apoptosis associated genes.ConclusionsThe present findings supported the proposition that the phenolic compounds present in PKC could be a potential cytoprotective agent towards AFB1 cytotoxicity.

Gastroretentive Matrix Tablets of Boswellia Oleogum Resin: Preparation, Optimization, In Vitro Evaluation, and Cytoprotective Effect on Indomethacin-Induced Gastric Ulcer in Rabbits.

Currently available anti-ulcer drugs suffer from serious side effects which limited their uses and prompted the need to search for a safe and efficient new anti-ulcer agent. Boswellia gum resin (BR) emerged as a safe, efficient, natural, and economic potential cytoprotective agent. Thus, it is of medical importance to develop gastroretentive (GR) formulations of BR to enhance its bioavailability and anti-ulcer efficacy. Early attempts involved the use of organic solvents and non-applicability to large-scale production. In this study, different tablet formulations were prepared by simple direct compression combining floating and bioadhesion mechanisms employing hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), pectin (PC), and/or carbopol (CP) as bioadhesive polymers and sodium bicarbonate (SB) as a gas former. The prepared tablets were subjected for assessment of swelling, floating, bioadhesion, and drug release in 0.1 N HCl. The optimized GR formulation was examined for its protective effect on the gastric ulcer induced by indomethacin in albino rabbits compared with lactose tablets. The obtained results disclosed that swelling, floating, bioadhesion, and drug release of the GR tablets of BR depend mainly on the nature of the matrix and the ratio of polymer combinations. Moreover, a combination of SCMC-CP in a ratio of 2:1 (SCP21) exhibited desirable floating, bioadhesion, swelling, and extended drug release. Also, a 6-h pretreatment with SCP21 tablets decreased the severity of inflammation and number of bleeding spots among ulcer-induced rabbits in comparison to those treated with lactose tablets.

Hsp20 Protects against Oxygen-Glucose Deprivation/Reperfusion-Induced Golgi Fragmentation and Apoptosis through Fas/FasL Pathway.

Cerebral ischemia-reperfusion injury plays an important role in the development of tissue injury after acute ischemic stroke. Finding effective neuroprotective agents has become a priority in the treatment of ischemic stroke. The Golgi apparatus (GA) is a pivotal organelle and its protection is an attractive target in the treatment of cerebral ischemia-reperfusion injury. Protective effects of Hsp20, a potential cytoprotective agent due to its chaperone-like activity and involvement in regulation of many vital processes, on GA were assessed in an ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces Golgi fragmentation, apoptosis, and p115 cleavage in N2a cells. However, transfection with Hsp20 significantly attenuates OGDR-induced Golgi fragmentation and apoptosis. Hsp20 interacts with Bax, decreases FasL and Bax expression, and inhibits caspases 3 and p115 cleavage in N2a cells exposed to OGDR. Our data demonstrate that increased Hsp20 expression protects against OGDR-induced Golgi fragmentation and apoptosis, likely through interaction with Bax and subsequent amelioration of the OGDR-induced elevation in p115 cleavage via the Fas/FasL signaling pathway. This neuroprotective potential of Hsp20 against OGDR insult and the underlying mechanism will pave the way for its potential clinical application for cerebral ischemia-reperfusion related disorders.

Mangiferin activates the Nrf2-ARE pathway and reduces etoposide-induced DNA damage in human umbilical cord mononuclear blood cells

Context: Mangiferin (2-C-β-d-gluco-pyranosyl-1,3,6,7-tetrahydroxyxanthone) is a well-known natural antioxidant distributed in various plants of the Anacardiaceae and Gentianaceae families. Mangiferin can inhibit carcinogen-induced lung or colon tumor formation in experimental animals. However, the molecular mechanisms of its chemopreventive activity remain unexplored.Objective: This study aimed to investigate the effects of mangiferin on chemical carcinogen-induced DNA damage and Nrf2-ARE signaling in hematopoietic cells.Materials and methods: Mononuclear cells (MNCs) were isolated from human umbilical cord blood (hUCB). DNA damage was evaluated by comet and micronucleus assays. The expression of Nrf2 and NQO1 was examined by immunofluorescence and western blotting. An electrophoretic mobility shift assay (EMSA) was used to detect the binding activity of Nrf2 with NQO1-ARE sequences.Results: We found that mangiferin treatment significantly reduced DNA damage in etoposide-treated MNCs, which was verified by decreased olive tail moment (OTM) and micronucleus (MN) frequency. Mangiferin treatment significantly promoted Nrf2 translocation into the nucleus and increased nuclear Nrf2 expression. Moreover, NQO1, an Nrf2 signaling target, was significantly upregulated by mangiferin treatment, and the binding activity of Nrf2 with NQO1-ARE sequences was elevated after mangiferin treatment.Discussion and conclusion: Mangiferin activated Nrf2 signaling, upregulated NQO1 expression, and significantly reduced etoposide-induced DNA damage. Thus, mangiferin is a potential cytoprotective agent for hematopoietic cells.

Isolation and identification of cytoprotective agents from nonpolar extracts of buckwheat flour

Buckwheat is a raw material used in formulating many foods, and some evidence exists that it can contribute health benefits beyond simple nutritive value. The objective of this study was to isolate and identify potential cytoprotective agents from buckwheat crude extracts using a bioassay-guided strategy. Crude extracts were obtained by successively extracting with n-hexane and ethyl acetate, followed by solvent partitioning. The active fraction(s) were then screened by a quinone reductase (QR) induction bioassay in vitro, and subjected to sequential fractionation with flash column chromatography and preparative thin-layer chromatography. Consequently, three pure compounds were isolated, identified and evaluated for bioactivity. Ferulic acid ethyl ester (1) was the most potent isolate (reported for the first time in buckwheat), doubling QR specific activity (CD value) at 2.1μM, whereas furaneol (2) was a moderate QR inducer with a CD value of 185μM. Protocatechuic acid (3) was least ineffective at inducing QR with a CD value of 2.0mM. Binary mixtures of the three isolated components acted borderline additively/antagonistically in the QR bioassay.

The impact of anti-inflammatory cytokines on the pancreatic β-cell

Considerable efforts have been invested to understand the mechanisms by which pro-inflammatory cytokines mediate the demise of β-cells in type 1 diabetes but much less attention has been paid to the role of anti-inflammatory cytokines as potential cytoprotective agents in these cells. Despite this, there is increasing evidence that anti-inflammatory molecules such as interleukin (IL)-4, IL-10 and IL-13 can exert a direct influence of β-cell function and viability and that the circulating levels of these cytokines may be reduced in type 1 diabetes. Thus, it seems possible that targeting of anti-inflammatory pathways might offer therapeutic potential in this disease. In the present review, we consider the evidence implicating IL-4, IL-10 and IL-13 as cytoprotective agents in the β-cell and discuss the receptor components and downstream signaling pathways that mediate these effects.

Dependence of cytotoxicity of menadione and cytoprotection by antioxidants in human endothelial cells on oxygen levels: Atmospheric oxygen versus physiological levels

The goal of in vitro screens of potential cytoprotective agents is to identify drugs that will be beneficial in vivo. However, in vitro screens are usually performed on cells cultured in atmospheric oxygen (AtmO2; 20.9%), which is much higher than the levels found in tissues in vivo (3–5%). The aim of this study was to evaluate the cytotoxicity and cytoprotective effects of an oxidant generating injurant (50, 60, and 70μM menadione; MD) and several antioxidants on human umbilical vein endothelial cells (HUVEC). Dose response studies demonstrated that 50μM MD reduced viability by 85% at AtmO2, but only by 20% at 3%O2. Antioxidants (N‐acetyl cysteine, gamma‐glutamyl cysteine, and glutathione) were more effective cytoprotectants at 3%O2 than AtmO2, and lower doses (5 and 50μM) were more effective at 3% O2 than AtmO2. However, all three compounds proved to be cytoprotective to HUVEC against MD‐induced oxidant stress at their highest dose of 500μM. These preliminary results indicate that the relatively high amount of oxygen in room air is a substrate for generating oxidants, and screens for cytoprotective antioxidants might be more predictive of in vivo performance if done at more physiologic levels.

Cellular assessment of the extract of bambangan (Mangifera pajang) as a potential cytoprotective agent for the human hepatocellular HepG2 cell line

This study was conducted to investigate the potential of bambangan (Mangifera pajang) fruit extracts in the protection against oxidative damage caused by tert-butyl hydroperoxide in the human hepatocellular HepG2 cell line. Proteins which might be involved in the cytoprotective mechanism were investigated using western blotting technique. Quercetin was used as a positive control. The results showed that only the kernel extract of M. pajang and quercetin displayed cytoprotective activity in HepG2 cells, with EC50 values of 1.2 and 5.3μg/ml, respectively. Expression of quinone reductase, glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by quercetin, suggesting their involvement in the cytoprotective activity of quercetin. However, expressions of only glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by the kernel extract, again suggesting their involvement in the cytoprotective activity of bambangan kernel extract. Future study is needed to investigate the involvement of other cytoprotective proteins in the cytoprotection mechanism.

Luteolin extracted from Platycodon grandiflorum protects retinal pigment epithelial cells from oxidative stress-induced caspase-3 dependent apoptosis

Luteolin, a flavonoid isolated from the flowers of Platycodon grandiflorum (balloon flower, Campanulaceae), has been examined with regard to the inhibition of apoptosis in human retinal pigment epithelium (RPE) cells under oxidative stress. Luteolin from P. grandiflorum protected human RPE cells from oxidative stress-induced cell death. The toxicity of the effective luteolin (1μM) was very low. Luteolin significantly inhibits reactive oxygen species (ROS) generation in human RPE cells under t-BOOH induced oxidative stress. T-BOOH induced activation of caspase-3 was reduced by 1μM luteolin, from 1.7 fold to 1.1 fold, compared with untreated control (P<0.05). These results suggest that luteolin from P. grandiflorum may be used as a potential cytoprotective agent for oxidative stress-induced apoptosis in RPE cells.

Alcohol, insulin resistance and the liver–brain axis

Chronic alcohol exposure inhibits insulin and insulin-like growth factor signaling in the liver and brain by impairing the signaling cascade at multiple levels. These alterations produced by alcohol cause severe hepatic and central nervous system insulin resistance as the cells fail to adequately transmit signals downstream through Erk/mitogen-activated protein kinase (MAPK), which is needed for DNA synthesis and liver regeneration, and phosphatidylinositol 3-kinase (PI3K), which promotes growth, survival, cell motility, glucose utilization, plasticity, and energy metabolism. The robust inhibition of insulin signaling in liver and brain is augmented by additional factors involving the activation of phosphatases such as phosphatase and tensin homologue (PTEN), which further impairs insulin signaling through PI3K/Akt. Thus, intact insulin signaling is important for neuronal survival. Chronic alcohol consumption produces steatohepatitis, which also promotes hepatic insulin resistance, oxidative stress and injury, with the attendant increased generation of "toxic lipids" such as ceramides that increase insulin resistance. The PI3K/Akt signaling cascade is altered by direct interaction with ceramides as well as through PTEN upregulation as a downstream target gene of enhanced p53 transcriptional activity. Cytotoxic ceramides transferred from the liver to the blood can enter the brain due to their lipid-soluble nature, and thereby exert neurodegenerative effects via a liver-brain axis. We postulate that the neurotoxic and neurodegenerative effects of liver-derived ceramides activate pro-inflammatory cytokines and increase lipid adducts and insulin resistance in the brain to impair cognitive and motor function. These observations are discussed in the context of insulin sensitizers as potential cytoprotective agents against liver and brain injury induced by alcohol.

EPO and Super-EPO: Erythropoietins Direct Neoangiogenesis by Cardiac Progenitor Cells

Erythropoietin, the red blood cell-making cytokine, is also a potential cytoprotective agent in heart disease. In this issue of Cell Stem Cell, Hoch etal. (2011) use two heart failure models, including chemotherapeutic cardiotoxicity, to reveal a mechanistic connection between reduced cardiomyocyte production of erythropoietin and neoangiogenesis by cardiac progenitors.

Pifithrin-α as a Potential Cytoprotective Agent in Radiotherapy: Protection of Normal Tissue without Decreasing Therapeutic Efficacy in Glioma Cells

Activation of p53 has been causally linked to normal tissue damage after irradiation. Pifithrin-α (PFT-α), a specific inhibitor of p53, has been suggested as a combinatory agent in the treatment of p53-deficient tumors in which inhibition of p53 would not compromise therapeutic efficacy but would decrease p53-mediated side effects in normal tissue. We tested this concept for radiotherapy of p53-deficient and -proficient glioma. We observed significant interaction of PFT-α with radiation-induced G(1) checkpoint activation and plating efficiency only in glioma cells expressing at least one wild-type allele of p53. This interaction was correlated with PFT-α-mediated inhibition of radiation-induced expression of the p53 target gene p21(Waf1). Despite inhibition of p53 function we did not observe significant changes in radiosensitivity after treatment with PFT-α in either p53-deficient or p53-proficient tumor cells. We confirmed these results in p53-proficient lung cancer cells. In contrast, PFT-α significantly increased the fraction of normal astrocytes and fibroblasts surviving irradiation; this was accompanied by improved DNA damage repair, speaking against an accumulation of cells with genetic lesions after PFT-α treatment. In conclusion, PFT-α might prove useful in protecting normal tissue from the side effects of radiotherapy without reducing the efficacy of treatment for both p53-proficient and -deficient tumors.

Squalene Selectively Protects Mouse Bone Marrow Progenitors Against Cisplatin and Carboplatin-Induced Cytotoxicity In Vivo Without Protecting Tumor Growth

Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.

Cumulative toxicities from cisplatin therapy and current cytoprotective measures

Cisplatm (cis-diamminedichloroplatinum), an inorganic platinum coordination complex, has been assessed clinically against a variety of tumours (1) because of its solid antineoplastic activity against testicular (2) and ovarian (3) cancers. However, renal and gastrointestinal toxicities originally limited its clinical development (1). Cisplatin became a major chemotherapeutic agent when Hayes and associates demonstrated that patient hydration can significantly reduce cisplatin-induced nephrotoxicity (4) while increasing the therapeutic index of cisplatin threefold. This development was a major factor in the cisplatin approval decision, although the incidence of adverse effects, such as renal dysfunction, neurotoxicity, and nausea and vomiting, remained high. Since the time of its approval, cisplatin has been widely used, either alone or, more often, in combination with other antineoplastics (1). The therapeutic activity of cisplatin appears to be proportional to the intensity of the individual dose and to the cumulative treatment dose (5-7). However, the exploitation of its full therapeutic potential has been limited by dose-dependent nephrological and neurological toxicities (8-11). Since the development of hydration, additional efforts have been made to reduce cisplatin-induced toxicity. Effective antiemetic regimens have been developed, and potential cytoprotective agents have