Intraperitoneal Administration Of Cisplatin Research Articles

Downregulation of Genes for Skeletal Muscle Extracellular Matrix Components by Cisplatin.

The extracellular matrix (ECM) in skeletal muscle is involved in a variety of physiological functions beyond the mechanical support of muscle tissue, nerves, and blood vessels; however, the role of the ECM in skeletal muscle remains unclear. There is little information regarding changes in the expression of factors comprising the ECM during cisplatin-induced muscle atrophy. In the present study, we examined the changes in gene expressions for skeletal muscle extracellular matrix components in skeletal muscle during cisplatin-induced muscle atrophy. Intraperitoneal administration of cisplatin caused muscle atrophy in mice and during this cisplatin-induced muscle atrophy, the expression of many procollagen genes (Col1a1, Col1a2, Col3a1, Col4a1, Col5a1, and Col5a2), elastin (Eln), fibronectin (Fn1), Laminin (Lama1, Lama2, and Lamb1) decorin (Dcn), heparan sulphate proteoglycans (Hspg2) and integrin (Itgb1) constituting the ECM was suppressed. Additional studies are needed to elucidate the pathological significance and mechanisms of reduced gene expression of ECM components associated with cisplatin-induced muscle atrophy.

The Acute Kidney Injury Induced by Cisplatin in Mice is Exacerbated by the Conditioned Medium Derived from the Cultivation of Mesenchymal Stem Cells under Hypoxic Conditions

Background: Acute Kidney Injury (AKI) is a severe complication of cisplatin-based chemotherapy. Thus, searching for novel therapeutic approaches to reduce system toxicity is vital for improving patient outcomes. The use of stem cells or the paracrine factors released by these cells during cultivation is currently being explored as a potential method for AKI prevention during chemotherapy. However, the conditions of stem cell cultivation considerably affect the composition of paracrine factors released by cells. Objective: In this study, we aimed to investigate the impact of paracrine factors derived from mesenchymal stem cells cultured under hypoxic conditions on the progression of AKI induced by cisplatin. Methods: AKI was induced in mice by intraperitoneal administration of cisplatin with the simultaneous injection of fractions of conditioned medium obtained from the cultivation of mesenchymal stem cells under hypoxic conditions. The survival rate of animals was assessed alongside qRTPCR implementation to assess gene expression of cytokines. Results: The total fraction of conditioned medium and >30 kDa fraction had no impact on cisplatin nephrotoxicity in mice. However, either subcutaneous or intraperitoneal administration of <30 kDa fraction of conditioned medium exacerbated animal mortality and led to severe damage to renal tissues. The effect was in a good correlation with KIM-1 and CDKN1A gene expression. Conclusion: The conditioned medium obtained during mesenchymal stem cells under hypoxic conditions has been found to markedly amplify the toxicity of cisplatin, which should be considered in stem cell therapy of AKI patients.

Carbon Monoxide-Loaded Red Blood Cell Prevents the Onset of Cisplatin-Induced Acute Kidney Injury.

Cisplatin-induced acute kidney injury (AKI) is an important factor that limits the clinical use of this drug for the treatment of malignancies. Oxidative stress and inflammation are considered to be the main causes of not only cisplatin-induced death of cancer cells but also cisplatin-induced AKI. Therefore, developing agents that exert antioxidant and anti-inflammatory effects without weakening the anti-tumor effects of cisplatin is highly desirable. Carbon monoxide (CO) has recently attracted interest due to its antioxidant, anti-inflammatory, and anti-tumor properties. Herein, we report that CO-loaded red blood cell (CO-RBC) exerts renoprotective effects on cisplatin-induced AKI. Cisplatin treatment was found to reduce cell viability in proximal tubular cells via oxidative stress and inflammation. Cisplatin-induced cytotoxicity, however, was suppressed by the CO-RBC treatment. The intraperitoneal administration of cisplatin caused an elevation in the blood urea nitrogen and serum creatinine levels. The administration of CO-RBC significantly suppressed these elevations. Furthermore, the administration of CO-RBC also reduced the deterioration of renal histology and tubular cell injury through its antioxidant and anti-inflammatory effects in cisplatin-induced AKI mice. Thus, our data suggest that CO-RBC has the potential to substantially prevent the onset of cisplatin-induced AKI, which, in turn, may improve the usefulness of cisplatin-based chemotherapy.

Ginsenoside Re Attenuates Cisplatin-Induced Intestinal Toxicity via Suppressing GSK-3β-Dependent Wnt/β-Catenin Signaling Pathway In Vivo and In Vitro.

Previous reports have confirmed that crude saponins (ginsenosides) in Panax ginseng have a preventive effect on chemotherapy-induced intestinal injury. However, the protective effects and possible mechanisms of ginsenoside Re (G-Re, a maker saponin in ginseng) against chemotherapy-induced intestinal damage have not been thoroughly studied. In this work, a series of experiments in vivo and in vitro on the intestinal toxicity caused by cisplatin have been designed to verify the improvement effect of G-Re, focusing on the levels of Wnt3a and [Formula: see text]-catenin. Mice were intragastric with G-Re for 10 days, and intestinal injury was induced by intraperitoneal administration of cisplatin at a dose of 20 mg/kg. Histopathology, gastrointestinal digestive enzyme activities, inflammatory cytokines, and oxidative status were evaluated to investigate the protective effect. Furthermore, in IEC-6 cells, G-Re statistically reverses cisplatin-induced oxidative damage and cytotoxicity. The TUNEL and Hoechst 33258 staining demonstrated that G-Re possesses protective effects in cisplatin-induced apoptosis. Additionally, pretreatment with G-Re significantly alleviated the apoptosis via inhibition of over-expressions of B-associated X (Bax), as well as the caspase family members, such as caspase 3 and 9, respectively, in vivo and in vitro. Notably, western blotting results showed that G-Re treatment decreased Wnt3a, Glycogen synthase kinase [Formula: see text] (GSK-[Formula: see text]), and [Formula: see text]-catenin expression, suggesting that nuclear accumulation of [Formula: see text]-catenin was attenuated, thereby inhibiting the activation of GSK-[Formula: see text]-dependent Wnt/[Formula: see text]-catenin signaling, which was consistent with our expected results. Therefore, the above evidence suggested that G-Re may be a candidate drug for the treatment of intestinal injury.

Suppression of cisplatin-induced ovarian injury in rats by chrysin: an experimental study

The aim of this study was to investigate the potential therapeutic efficacy of chrysin (CHS) against ovotoxicity caused by intraperitoneal administration of cisplatin (CDDP) in rats. In this experimental study, 24 female rats were randomly divided into four groups: control, CHS (2 mg/kg), CDDP (5 mg/kg) and CDDP (5 mg/kg) + CHS (2 mg/kg). The levels of malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), superoxide dismutase (SOD), interleukin-6 (IL-6) and myeloperoxidase (MPO) were determined in the ovarian tissues using spectrophotometric methods. In addition, the ovarian samples were evaluated histopathologically by hematoxylin&eosin staining. The results revealed that the levels of MDA, TOS, IL-6 and MPO significantly increased by CDDP administration compared with control group (p < 0.05). Also, it was found that CDDP significantly decreased TAS and SOD levels (p < 0.05). CHS ameliorated CDDP-induced the increased levels of MDA, TOS, IL-6, MPO and increased the levels of TAS and SOD significantly (p < 0.05). Histological findings also supported the therapeutic effect of CHS against CDDP-induced ovarian damage parameters. In conclusion, our results showed that CHS exhibits a therapeutic effect against CDDP-induced ovotoxicity and therefore the use of CHS after chemotherapy may improve the side effets of CDDP. IMPACT STATEMENT What is already known about this subject? Cisplatin (CDDP) is an effective and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited due to dose-related tissue toxicity. Chrysin (CHS), a natural flavone, exhibits various beneficial activities, including antioxidant, anti-inflammatory and anticancer. There are increasing evidences in the literature that CHS reduces the toxicity of various chemotherapeutic agents, such as CDDP, doxorubicin and cyclophosphamide, in colon, kidney and liver tissues through its antioxidant and anti-inflammatory potential. What do the results of this study add? This study demonstrated that CHS can abolish CDDP-induced in vivo ovarian injury by decreasing MDA, TOS, IL-6 and MPO levels and increasing SOD and TAS levels through its antioxidant and anti-inflammatory potential. What are the implications of these findings for clinical practice and/or further research? This study revealed the therapeutic potential of CHS against CDDP-induced acute ovotoxicity, for the first time. Further pre-clinical studies are necessary to prove the beneficial effect of CHS on the prevention of CDDP-induced ovarian toxicity.

Downregulated expression of organic anion transporting polypeptide (Oatp) 2b1 in the small intestine of rats with acute kidney injury

The expression of transporters on the apical and basal membranes of renal tubular cells is modulated under acute kidney injury (AKI). However, little is known about alterations in non-renal transporters in the tissues other than the kidney under AKI situation. This study aimed to assess the modulation of organic anion transporting polypeptide (Oatp) 1a2 and Oatp2b1 expression/function in the small intestine of rats with drug-induced AKI. AKI was induced by intraperitoneal administration of cisplatin at a dose of 5 mg/kg. On day 3 after cisplatin administration, morphological changes in the small intestine, Oatp1a2 and Oatp2b1 expression, and absorption of pravastatin and theophylline were evaluated. Non-negligible atrophy was observed in the jejunum and ileum of the AKI rats. However, the absorption of theophylline was not affected. While intestinal Oatp2b1 expression was markedly decreased in the AKI rats, no alteration was observed in Oatp1a2 expression. The plasma levels of pravastatin after intraluminal administration declined significantly in the AKI rats. However, no such decline was observed after intravenous administration. This study suggested that the responses of intestinal Oatps to experimentally induced AKI was not unidirectional and that pravastatin absorption was governed more potently by Oatp2b1 than by Oatp1a2 in the rat intestine.

Prostaglandin D2 contributes to cisplatin-induced neuropathic pain in rats via DP2 receptor in the spinal cord.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a major reason for stopping or changing anticancer therapy. Among the proposed pathomechanisms underlying CIPN, proinflammatory processes have attracted increasing attention. Here we assessed the role of prostaglandin D2 (PGD2) signaling in cisplatin-induced neuropathic pain.MethodsCIPN was induced by intraperitoneal administration of cisplatin 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. PGD2 receptor DP1 and/or DP2 antagonists were administered intrathecally and the paw withdrawal thresholds were measured using von Frey filaments. Spinal expression of DP1, DP2, hematopoietic PGD synthase (H-PGDS), and lipocalin PGD synthase (L-PGDS) proteins were analyzed by western blotting.ResultsThe DP1 and DP2 antagonist AMG 853 and the selective DP2 antagonist CAY10471, but not the DP1 antagonist MK0524, significantly increased the paw withdrawal threshold compared to vehicle controls (P = 0.004 and P < 0.001, respectively). Western blotting analyses revealed comparable protein expression levels in DP1 and DP2 in the spinal cord. In the CIPN group the protein expression level of L-PGDS, but not of H-PGDS, was significantly increased compared to the control group (P < 0.001).ConclusionsThe findings presented here indicate that enhanced PGD2 signaling, via upregulation of L-PGDS in the spinal cord, contributes to mechanical allodynia via DP2 receptors in a cisplatin-induced neuropathic pain model in rats, and that a blockade of DP2 receptor activation may present a novel therapeutic target for managing CIPN.

Determination of the anticancer properties of cis- and trans-diadamanthylcarboxylates of dirhenium(III)

The aim of the study. The aim of the work was to investigate in vivo anticancer activity of cis- and trans-diadamanthylcarboxylates of dirhenium(III) alone and together with cisplatin in form of nanobins.Materials and methods. Model of tumor growth, Guerin’s carcinoma; intraperitoneal administration of cisplatin, dirhenium(III) compounds in liposomes and of binary liposomes, containing both cytostatics; volumes and final weights of tumors were measured.Results. In vivo antitumor properties of two dirhenium(III) dicarboxylates with 1-adamantanecarboxylic acid moieties as ligands with cis- (I) and trans- (II) orientation of the carboxylic groups around a cluster fragment alone and together with cisplatin were presented; an attempt to understand differences in a possible mechanism of anticancer activity of the substances were undertaken. Antiradical and DNA-binding properties of I and II were the matter of consideration.Conclusions. Cis- and trans- compounds of dirhenium I and II had close antitumor activity in vivo with a little bit superiority of the cis- analog. Mechanisms of anticancer activity of I and II are different and may also include monofunctional adduct formation and subsequent interstrand cross-linking for the II substance, formation of protein-DNA cross-links, etc.

Ameliorative Effect of Rhoifolin in Cisplatin-Induced Nephrotoxicity via Regulating Nuclear Factor-κB Pathway

Dose-dependent nephrotoxicity limits the therapeutic use of cisplatin in tumor chemotherapy. Natural compounds show a protective effect against cisplatin-induced nephrotoxicity. Rhoifolin is a flavone glycoside that demonstrates antioxidant and antiproliferative effects. The influence and mechanism of rhoifolin on cisplatin-induced nephrotoxicity were investigated in this study. First, a rat model of cisplatin-induced nephrotoxicity was established. Intraperitoneal administration of cisplatin induced renal damage in rats as demonstrated by a decrease in body weight, increase in blood urea, nitrogen and creatinine, and destruction of histological integrity. However, treatment with rhoifolin attenuated cisplatin-induced nephrotoxicity. Second, cisplatin induced oxidative stress and inflammatory response in rats as demonstrated by a decrease in superoxide dismutase, glutathione, glutathione S-transferase and catalase, and an increase in malondialdehyde, tumor necrosis factor-α, and interleukin-6. Also, the administration of rhoifolin led to alleviation of cisplatin-induced oxidative stress and inflammatory response. Finally, cisplatin activated the nuclear factor-kappa B signaling pathway via degradation and phosphorylation of IκBα (inhibitor of kappa B). Administration of rhoifolin inhibited nuclear translocation of NF-κB via down-regulation of phospho-IκBα and phospho-p65, as well as up-regulation of IκBα. In conclusion, the administration of rhoifolin attenuated cisplatin-induced renal damage, oxidative stress and inflammatory response through inhibition of the NF-κB signaling pathway, suggesting a potential adjunct candidate for cisplatin in tumor treatment.

Фармакологическая коррекция нарушений системы гемостаза, вызванных применением цисплатина

A single intraperitoneal administration of cisplatin in the MTD to outbred female mice disturbed hemostasis and formed the procoagulant phenotype of hemostatic potential on days 7-10 culminating in a pronounced hypocoagulation on day 15. Hemostasis was corrected with warfarin and an extract containing furocoumarins composed of isopimpinellin (42.97%), bergapten (35.18%), and xanthotoxin (15.41%). The extract was standardized with gas chromatography-mass spectrometry, thin-layer chromatography, and HPLC. Furocoumarins and reference drug warfarin were administered intragastrically during 4 days starting on day 6 after the administration of cisplatin. Both furocoumarins and warfarin corrected hypercoagulation on days 7-10. On day 10, furocoumarins normalized coagulation, whereas warfarin resulted in hypocoagulation. On days 15-30, no effects of warfarin were observed. furocoumarins corrected hypocoagulation on days 15-20 with prolongation of this effect up to experimental day 30.

Stevia and stevioside protect against cisplatin nephrotoxicity through inhibition of ERK1/2, STAT3, and NF-κB activation

We investigated the effect of natural sweetener Stevia rebaudiana and its constituent stevioside in cisplatin (CP)-induced kidney injury. Male BALB/cN mice were orally administered 10, 20, and 50 mg/kg body weight of Stevia rebaudiana ethanol extract (SE) or stevioside 50 mg/kg, 48 h after intraperitoneal administration of CP (13 mg/kg). Two days later, CP treatment resulted in histopathological changes showing kidney injury. Increased expression of 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT), and heme oxygenase-1 (HO-1) in mice kidneys suggested oxidative stress. CP treatment also increased renal expression of nuclear factor-kappaB (NF-κB) p65 subunit and phosphorylated inhibitor of NF-κB (IκBα), as well as expression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Induction of apoptosis and inhibition of the cell cycle in kidneys was evidenced by increased expression of p53, Bax, caspase-9, and p21, proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), with concomitant suppression of Bcl-2 and cyclin D1 expression. The number of apoptotic cells in kidneys was also assessed. CP administration resulted in activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3). Both SE and stevioside attenuated CP nephrotoxicity by suppressing oxidative stress, inflammation, and apoptosis through mechanism involving ERK1/2, STAT3, and NF-κB suppression.

Nanoscopic tumor tissue distribution of platinum after intraperitoneal administration in a xenograft model of ovarian cancer

There is increasing interest in the treatment of advanced stage ovarian cancer (OC) using intraperitoneal (IP) delivery of platinum (Pt)-based chemotherapy. The antitumor efficacy of IP chemotherapy is determined by efficient tumor tissue penetration. Although it is assumed that Pt penetration is limited to a few millimeters after IP delivery, little is known on the distribution of Pt in different tumor compartments at the ultrastructural level following IP administration.Here, using synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), Pt distribution and penetration in OC peritoneal xenografts were determined at nanometer scale after IP chemoperfusion of cisplatin at 37–38°C or 40–41°C (hyperthermic). Using principal component analysis (PCA) the presence of phosphorus, manganese, calcium, zinc, iron, bromine, and sulfur was correlated with the distribution of Pt, while k-means analysis was used to quantify the amount of Pt in weight% in tumor stroma and in tumor cells.The results showed a heterogeneous distribution of Pt throughout the tumor, with an accumulation in the extracellular matrix. LA-ICP-MS mappings indicated significantly higher concentrations of Pt (P=0.0062) after hyperthermic chemoperfusion of cisplatin, while SR-XRF demonstrated a deeper tissue Pt penetration after hyperthermic treatment. Using PCA, it was showed that Pt co-localizes with bromine and sulfur. No differences were observed in Pt distribution regarding tumor cells and stroma, when comparing normo- vs. hyperthermic treatment.In conclusion, SR-XRF and LA-ICP-MS are suitable and highly sensitive techniques to analyze the penetration depth and distribution of Pt-based drugs after IP administration. To the best of our knowledge, this is the first experiment in which the distribution of Pt is analyzed at the cellular level after IP administration of cisplatin.

Amelioration of cisplatin-induced hepatotoxicity by statins in rats

Aim: This study was aimed to investigate the effect of simvastatin (SIM) and rosuvastatin (ROS) on the extent of tissue damage in cisplatin (CIS) induced hepatotoxicity. Methodology: Hepatotoxicity was induced in rats with single intraperitoneal injection of 7 mg/kg cisplatin. Group 1 received 0.5% sodium carboxy methyl cellulose, group 2 and 3 received SIM and ROS, respectively, and group 4 was injected single dose of CIS (7 mg/kg, i.p.).Group 5 and 6 were treated with SIM (10 mg/kg, p.o.) and ROS (10 mg/kg, p.o.) daily from 5 days before to 5 day after intraperitoneal administration of CIS, respectively. Liver function tests like AST, ALT and Total bilirubin, and markers of oxidative stress such as liver malondialdehyde (MDA) level, superoxide dismutase (SOD), catalase (CAT) activities and reduced glutathione (GSH) were measured. All tissues were investigated for histopathological changes. Results: CIS treated rats showed a significant increase in AST, ALT and total bilirubin. Moreover, cisplatin caused liver damage with a higher MDA level, depletion of SOD, CAT activity and GSH. SIM and ROS ameliorate CIS induced liver damage due to improvement in liver function, oxidative stress, and histological alteration. Conclusions: These finding suggests that simvastatin and rosuvastatin may have a protective effect against cisplatin-induced liver damage via amelioration of lipid peroxidation as well as due to improvement of liver function.

Нормотермическая и гипертермическая интраперитонеальная перфузионная химиотерапия диссеминированного рака яичника в эксперименте

Relevance The search and development of effective regimens of normothermic and hyperthermic intraperitoneal chemoperfusion (IPEC and HIPEC) in experiment will allow implementing the technology into clinical practice to treat patients with advanced ovarian cancer and therefore increase their survival. The purpose of the study The development of preclinical model of normo- and hyperthermic chemoperfusion treatment of advanced ovarian cancer and assessment of efficiency of alkylating cytostatics at their intraperitoneal chemoperfusion administration. Materials and methods The study was carried out in 295 Vistar female rats with ovarian cancer which was inoculated intraperitoneally. IPEC and HIPEC were performed with antitumor drugs cisplatin and dioxadet in maximum tolerated doses (MTD) which were 5−20 times higher than those for the standard intraperitoneal administration of the drugs. Antitumor effects of the treatment were estimated in increase of median survival time (MST). Results and their discussion Hyperthermic intraperitoneal perfusion (HIPEP) with saline solution showed significant antitumor activity comparable to effects of intraperitoneal administration of cisplatin and dioxadet. HIPEC with the drugs resulted in larger number of side effects compared to IPEC. Potentiation of antitumor effect of dioxadet and hyperthermia was achieved for HIPEC with dioxadet, where increase in MST of rats was the greatest among all experimental groups – 444% compared to the control group (p=0.038). Conclusion The developed experimental technology of IPEC and HIPEC is recommended for testing of different cytostatic drugs and new methods of intraperitoneal chemoperfusion treatment of malignancies affecting peritoneum.

Pharmacokinetics of cisplatin in the absence or presence of Zengmian Yiliu granules (a traditional Chinese medicine compound) in rats determined via ICP-MS: An investigation on drug–herb interactions

Context: Cisplatin is a highly effective chemotherapeutic agent against many tumors; however, it has potent adverse effects. Zengmian Yiliu granule (ZMYL), a traditional Chinese medicine (TCM) compound, has been clinically used against platinum (Pt)-induced toxicity and to enhance the efficacy of cisplatin.Objective: The study was conducted to investigate the likelihood of potential pharmacokinetics drug–herbs interaction (DHI) between cisplatin and ZMYL.Materials and methods: An improved ICP-MS method combined with ultrafiltration and microwave-assisted digestion was performed to determine the total and free Pt concentrations in rat plasma after intraperitoneal administration of cisplatin (9 mg/kg) or a combined administration with ZMYL (1 g/kg) by gavage.Results: ZMYL produced a potential DHI on the pharmacokinetic parameters of cisplatin, calculated from the total Pt concentration. The clearance rate decreased from 110.52 to 66.12 mLh−1 kg−1, the mean residence time extended from 63.1 to 164.54 h, the area under the plasma concentration–time curve increased from 86.58 to 152.93 µg h mL−1, the elimination half-life extended from 48.38 to 126.4 h, and the elimination rate constant decreased from 0.017 to 0.006 h, in the ZMYL combination group (p < 0.05). In terms of free Pt concentration, the apparent volume of distribution and clearance rate was statistically different (p < 0.05). The Pt plasma protein binding ratios in the early dose stages were significantly boosted by the co-administration of ZMYL (p < 0.01).Discussion and conclusion: ZMYL is a potential complementary and alternative medicine for cisplatin chemotherapy. The therapeutic benefits of ZMYL–cisplatin chemotherapy derived from pharmacokinetic interaction needs further investigation.

Alleviation of hepatic injury by chrysin in cisplatin administered rats: Probable role of oxidative and inflammatory markers

BackgroundCisplatin is an effective and extensively used chemotherapeutic agent to treat range of malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity and hepatotoxicity. Several published reports advocate that supplementation with antioxidant can influence cisplatin induced hepatic damage. MethodIn the present study the Wistar rats were subjected to concurrent prophylactic oral treatment of chrysin (25 and 50mg/kgb.wt.) against the hepatotoxicity induced by intraperitoneal administration of cisplatin (7.5mg/kgb.wt.). Efficacy of chrysin against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of molecular markers of inflammation. ResultsChrysin ameliorated cisplatin-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, superoxide dismutase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated expression of COX-2, iNOS and levels of NFκB and TNF-α, and hepatic tissue damage which were induced by cisplatin. Histological findings further supported the protective effects of chrysin against cisplatin-induced hepatic damage. ConclusionThe results of the present study demonstrate that oxidative stress and inflammation are closely associated with cisplatin-induced toxicity and chrysin shows the protective efficacy against cisplatin-induced hepatotoxicity possibly via attenuating the oxidative stress and inflammatory response.

In vivo Efficacy of PAMAM-Dendrimer-Cisplatin Complexes in SKOV-3 Xenografted Balb/C Nude Mice

Loco-regional delivery of cisplatin by Intraperitoneal (IP) administration in ovarian cancer is highly advantageous, since it exposes high concentrations of cisplatin to tumors in the peritoneal cavity. PAMAM-dendrimer-cisplatin complexes are expected to enhance the penetration of tumors in the peritoneal cavity, and aid in enhancing antitumor efficacy of cisplatin. In the present study, PAMAM G4 NH2 and Biotin PAMAM G4 NH2 dendrimer cisplatin complexes were administered intraperitoneally to SKOV xenografted athymic nude mice at a dose of 4 mg/kg. The increase in lifespan of tumor bearing mice and biodistribution of cisplatin in various organs was evaluated after IP administration of cisplatin and dendrimer-cisplatin complexes. The lifespan of mice increased by 41.93% and 25.8%, after treatment with PAMAM G4 NH2 and Biotin PAMAM G4 NH2 dendrimer cisplatin complexes, respectively. A 3-fold increase in the levels of platinum in plasma was observed, after administration of both PAMAM G4 NH2 and Biotin PAMAM G4 NH2 dendrimer cisplatin complexes. Biodistribution studies have shown higher accumulation of platinum in liver, spleen and kidneys with PAMAM G4 NH2 dendrimer-cisplatin complexes. The increased plasma concentration and enhanced tissue accumulation after IP administration of dendrimer-cisplatin complexes offer advantage of administering low dose of cisplatin, which would reduce the dose-dependent toxic effects of cisplatin.

Acute neurological disorders following intraperitoneal administration of cisplatin

Posterior reversible encephalopathy syndrome (PRES) is a rare syndrome that can be caused by a variety of clinical conditions (e.g. severe hypertension) or the administration of immunosuppressive drugs or cytotoxic agents [1,2]. Symptoms can include headache, confusion, nausea, hearing loss, seizures, and visual disturbances. The pathophysiology of PRES is poorly understood, but reversible alterations in the cerebrovascular autoregulatory control mechanism and blood–brain integrity are thought to play an important role. In general, PRES has a good prognosis resulting in full recovery after removal of the causative agent, although cases with a fatal outcome have been described [1,2]. A 51-year-old womanwas diagnosed with ovarian cancer, classified as FIGO Stage IIIC. Initial treatment consisted of 3 cycles of carboplatin (600 mg) and taxol. Treatment was uneventful and resulted in a partial response. The patient provided informed consent for inclusion in a randomized multicenter clinical trial comparing optimal surgical cytoreduction versus optimal cytoreduction followed by hyperthermic intraperitoneal chemotherapy (HIPEC) currently being conducted in the Netherlands [3]. The patient was randomized to undergo an adjuvant HIPEC procedure. Heated cisplatin (41 °C, 100 mg/m) was administered into the peritoneal cavity for 90 minutes after complete cytoreduction had been achieved. The patient's body temperature increased to a maximum of 38.7 °C during the procedure, normalizing 2 hours after the procedure. On the first postoperative day the patient complained of severe headache, nausea, and hearing loss in her left ear, and became progressively confused. Neurological examination showed a slightly decreased level of consciousness (eyes 3, motor 6, vocal 4) on the Glasgow Coma Scale, but without focal symptoms. Physical examination and laboratory tests were normal with the exception of a mild increase in serum creatinine levels from 57 to 83 μmol/L on the first postoperative day. CT scan of the brain showed generalized edema and a subsequent MRI of the cerebrum revealed symmetrical bilateral occipital white matter lesions. This radiological image is typical for PRES [1]. Supportive carewas initiated and all symptoms resolved completely over the following 72 hours. The patient was treated with an additional 3 cycles of chemotherapy, during which no recurrence of the neurological symptoms occurred. Intraperitoneal administration of heated cisplatin following cytoreduction was thought to be the causative agent. Indeed, several case reports have previously described PRES following intravenous administration of cisplatin [4]. HIPEC procedures are increasingly being applied to treat a variety of malignancies confined to the peritoneal cavity, including ovarian cancer [3]. In such cases, the development of PRES should be considered when a patient develops neurological symptoms in the early postoperative period.

Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFκB, TNF-α and caspase-3 expression in wistar rats

Cisplatin is an effective chemotherapeutic agent that displays dose-limiting nephrotoxicity. In the present study the wistar rats were subjected to concurrent prophylactic oral treatment of rutin (75 and 150mg/kgb.wt.) against the nephrotoxicity induced by intraperitoneal administration of cisplatin (7mg/kgb.wt.). Efficacy of rutin against the nephrotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of molecular markers of inflammation and apoptosis. Rutin pretreatment prevented deteriorative effects induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress as well as caspase-3, TNF-α and NFκB protein expression levels. We found that the beneficial effect of rutin pretreatment is mediated partially by its inhibitory effect on NFκB and TNF-α pathway mediated inflammation, caspase-3 mediated-tubular cell apoptosis, as well as by restoration of histopathological changes against cisplatin administration.

Role of the Copper Transporter, CTR1, in Platinum-Induced Ototoxicity

The goal of this study was to determine the role of an influx copper transporter, CTR1, in the ototoxicity induced by cisplatin, a potent anticancer platinum analog used in the treatment of a variety of solid tumors. As determined through reverse transcriptase-PCR (RT-PCR), quantitative RT-PCR, Western blot, and immunohistochemistry, mouse CTR1 (Ctr1) was found to be abundantly expressed and highly localized at the primary sites of cisplatin toxicity in the inner ear, mainly outer hair cells (OHCs), inner hair cells, stria vascularis, spiral ganglia, and surrounding nerves in the mouse cochlea. A CTR1 substrate, copper sulfate, decreased the uptake and cytotoxicity of cisplatin in HEI-OC1, a cell line that expresses many molecular markers reminiscent of OHCs. Small interfering RNA-mediated knockdown of Ctr1 in this cell line caused a corresponding decrease in cisplatin uptake. In mice, intratympanic administration of copper sulfate 30 min before intraperitoneal administration of cisplatin was found to prevent hearing loss at click stimulus and 8, 16, and 32 kHz frequencies. To date, the utility of cisplatin remains severely limited because of its ototoxic effects. The studies described in this report suggest that cisplatin-induced ototoxicity and cochlear uptake can be modulated by administration of a CTR1 inhibitor, copper sulfate. The possibility of local administration of CTR1 inhibitors during cisplatin therapy as a means of otoprotection is thereby raised.