• Title/Summary/Keyword: Cisplatin nephrotoxicity

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A Dunnione Compound MB12662 Improves Cisplatin-Induced Tissue Injury and Emesis

  • Park, Dongsun;Jo, In Geun;Jang, Ja Young;Kwak, Tae Hwan;Yoo, Sang Ku;Jeon, Jeong Hee;Choi, Ehn-Kyoung;Joo, Seong Soo;Kim, Okjin;Kim, Yun-Bae
    • Biomolecules & Therapeutics
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    • v.23 no.5
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    • pp.449-457
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    • 2015
  • The present study was aimed to investigate the effects of MB12662, a synthetic dunnione compound, on cisplatin-induced vomiting reflexes and intestinal, renal, immune system, and hematopoietic toxicities in ferrets and mice, respectively. Male ICR mice were orally administered MB12662 (5, 10, 25 or 50 mg/kg) for 10 days, during which intraperitoneally challenged with cisplatin (3.5 mg/kg) from day 4 to 7, and sacrificed on day 10 for the pathological examination. Male ferrets were orally administered MB12662 (25, 50 or 100 mg/kg) for 7 days, subcutaneously challenged with cisplatin (5 mg/kg), and monitored for vomiting reflexes and survival of the animals. Four-day injection of cisplatin (3.5 mg/kg) to mice caused body weight loss and degeneration and atrophy of intestinal villi, reducing villi/crypt ratio to a half level of control animals. Cisplatin also induced renal and hepatic toxicities, and depletion of splenocytes and bone marrow progenitor cells. The systemic toxicities including decreased villi/crypt ratio, immune system atrophy, splenocyte depletion, and decreased cellularity in bone marrow were improved by MB12662. Cisplatin (5 mg/kg) induced retching and emetic responses of ferrets, which were remarkably attenuated by MB12662 in a dose-dependent manner. All the ferrets pretreated with MB12662 survived the challenge of cisplatin, in comparison with 40% mortality in vehicle-treated animals, and blood parameters of nephrotoxicity and hepatotoxicity were markedly recovered. It is expected that MB12662 could be a candidate for the body protection against burden, including emesis, of chemotherapeutic agents.

Recent Findings on the Mechanism of Cisplatin-Induced Renal Cytotoxicity and Therapeutic Potential of Natural Compounds

  • Lee, Dahae;Choi, Sungyoul;Yamabe, Noriko;Kim, Ki Hyun;Kang, Ki Sung
    • Natural Product Sciences
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    • v.26 no.1
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    • pp.28-49
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    • 2020
  • The efficacy and side effects associated with anticancer drugs have attracted an extensive research focus. Onconephrology is an evolving field of nephrology that deals with the study of kidney diseases in cancer patients. Most renal diseases in cancer patients are unique, and management of renal disease can be challenging especially in the presence of continuing use of the nephrotoxic drugs. Cisplatin is one of the most important chemotherapeutic agents used in the treatment of various malignancies, such as head, neck, ovarian, and cervical cancers. The major limitation in the clinical use of cisplatin is its tendency to induce adverse effects, such as nephrotoxicity. Recently, plant-derived phytochemicals have emerged as novel agents providing protection against cisplatin-induced renal cytotoxicity. Owing to the diversity of phytochemicals, they cover a wide spectrum of therapeutic indications in cancer and inflammation and have been a productive source of lead compounds for the development of novel medications. Of these agents, the effectiveness of triterpenoids, isolated from various medicinal plants, against cisplatin-induced renal cytotoxicity has been reported most frequently compared to other phytochemicals. Triterpenes are one of the most numerous and diverse groups of plant natural products. Triterpenes ameliorate cisplatin-induced renal damage through multiple pathways by inhibiting reactive oxygen species, inflammation, down-regulation of the MAPK, apoptosis, and NF-κB signaling pathways and upregulation of Nrf2-mediated antioxidant defense mechanisms. Here, we reviewed recent findings on the natural compounds with protective potential in cisplatin-induced renal cytotoxicity, provided an overview of the protective effects and mechanisms that have been identified to date, and discussed strategies to reduce renal cytotoxicity induced by anticancer drugs.

Selective Cytotoxicity Platinum (II) Complex Containing Carrier Ligand of cis-1,2-Diaminocyclohexane (Cis-Diaminocyclohexan을 배위자로 하는 배금(II)착체의 선택적 세포독성)

  • 노영수;정세영;정지창
    • Environmental Analysis Health and Toxicology
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    • v.13 no.3_4
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    • pp.87-94
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    • 1998
  • The use of cisplatin is limited by severe side effects such as renal toxicity. Our platinum-base drug discovery is aimed at developing drugs capable of diminishing toxicity and improving antitumor activity. We synthesized new Pt (II) complex analogue [Pt (cis-DACH)(DPPP)]. 2NO$_3$ (PC) containing cis-1,2-diaminocyclohexane as a carrier ligand and 1,3-bis(diphenylphosphino) propane as a leaving group. Furthermore, nitrate was added to improved the solubility. In this study, its structure was determined and its antitumor activity against SKOV-3 and NIH-OVCAR-3 human ovarian adenocarcinoma, and in vitro cytotoxicity was determined against primary cultured rabbit kidney proximal tubular and renal cortical cells of human kidney using colorimetric MTT assay. PC demonstrated acceptable antitumor activity against SKOV-3 and NIH-OVCAR-3 human ovarian adenocarcinoma and significant activity as compared with that of cisplatin. The toxicity of PC was found quite less than that of cisplatin using MTT and $^3$H-thymidine uptake tests in rabbit proximal tubular cells and human kidney cortical cells. PC was used for human cortical tissue in 7 weeks hitoculture by the glucose-consumption tests. We determined that the new platinum drug has lower nephrotoxicity than cisplatin. Based on these results, this novel platinum (II) complex compound (PC) represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low nephrotoxicity.

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Protective Role of Selenium and High Dose Vitamin E against Cisplatin - Induced Nephrotoxicty in Rats

  • Aksoy, Asude;Karaoglu, Aziz;Akpolat, Nusret;Naziroglu, Mustafa;Ozturk, Turkan;Karagoz, Zuhal Karaca
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.16
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    • pp.6877-6882
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    • 2015
  • Background: Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer. We investigated the effect of selenium (Se) with high dose vitamin E (VE) administration to prevent CDDP-induced nephrotoxicity in rats. Materials and Methods: In this study, 40 female Wistar rats were randomly divided into five equal groups. The first group, which served as the control, was administered physiological saline (2.5 cc/day, 5 days) intraperitoneally (IP), while group A was administered cisplatin (6 mg/kg BW/ single dose) plus physiological saline IP. Groups B, C, D received IP five doses of Se (1.5 mg/kg BW), and a high dose of VE (1000 mg/kg BW) (Se-VE) in combination before, simultaneously, and after CDDP, respectively. The rats were sacrificed five days after CDDP administration. Plasma malondialdehide (MDA), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), catalase, urea, creatinine levels, renal histopathological changes were measured. Results: The histopathological injury score, plasma levels of MDA, urea, creatinine were found to increase in group A compared to the control (p<0.05), while plasma levels of GSH-Px, GSH and catalase decreased (p<0.05). In contrast, plasma levels of MDA decreased (p<0.05) in groups B, C, D, which were treated with Se- VE, whereas levels of GSH-Px, GSH were found to increase only for group D (p<0.05). Plasma urea, creatinine levels improved in the treatment groups compared to group A (p<0.001). Histopathological changes caused by CDDP were also significantly improved after Se-VE treatment (p<0.05). Conclusions: Oxidative stress increases with CDDP-induced nephrotoxicity in rats. Se-VE supplementation might thus play a role in the prevention of CDDP-induced nephrotoxicity in patients.

Protective effect of Ganopoly and Ganopoly/C+ on nephrotoxicity induced by cisplatin in rats (Cisplatin의 신장독성에 대한 영지추출물 복합제제의 보호효과)

  • Kim Dae Geun;Kim Kun Jung;Ju Sung Min;Kim Yong Ik;Choi Ho Seung;Keum Kyung Soo;Kim Won Sin;Gao Yiu Ai;Jeon Byung Hun
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.17 no.2
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    • pp.316-325
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    • 2003
  • In this paper, the effect of Ganopoly(extracts of Ganoderma lucidum) and Ganopoly/C+(70% Ganopoly + 30% chitosan) on cisplastin-induced nephrotoxicity was investigated in Sprague-Dawley rats. A single dose of cisplastin(5 ㎎/㎏) kg) was administered intraperitoneally after pretreatment of saline, Ganopoly and Ganopoly/C+ for 7 days. The nephrotoxicity and renal function were manifestated by the changes of body weight, blood pressure, biochemical changes and solute in urine and plasma. After the treatment of CDDP(cis-dichlorodiamineplatinum), a significant elevation of kidney weight, serum urea, cretinine, urine volume for 24 hours, urine magnesium, and a severe or significant decrease in body weight, blood pressure, creatinine clearance, urine osmolarity, serum albumin, etc. The nephrotoxicity was further confirmed by a significant decrease in glutathione S-transferase(GSH) in urine and kidney homogenate, GSH, glutathione peroxidase(GSH-Px) and catalase in kidney tissue. And also the lipid peroxidation was significantly increased in kidney homogenate. These signs of nephrotoxicity was ameliorated by the pretreatment and consecutive administration of Ganopoly and Ganopoly/C+ for 14 days after the Lp. injection of CDDP on 7th day after pretreatment of Ganopoly and Ganopoly/C+. The amelioration of nephrotoxicity was evidenced by significant reduction in serum urea and creatinine concentration, and improvement of other index of renal function. And The activity of antioxidant enzymes were partially recovered in kidney tissue of rats treated by CDDP and the administration of Ganopoly and Ganopoly/C+. These results indicate the cispastin induced nephrotoxicity is due to an impairment of tubular reabsorption systems enhanced by necrosis of proximal tubule, and the Ganopoly and Ganopoly/C+ has a partial protective effect on nephrotoxicity induced by CDDP. The polysacchride of Ganoderma lucidum may improve the therapeutic index of nephrotoxicity induced by CDDP. However, it is needed to elucidate the mechanism for confirming the therapeutic effect.

Selective Cytotoxicity of Novel Platinum(II) Coordination Complexes on Human Bladder Cancer Cell-Lines and Normal Kidney Cells

  • Kim, Jung-Tae;Rho, Young-Soo;Jung, Jee-Chang
    • The Korean Journal of Physiology and Pharmacology
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    • v.7 no.2
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    • pp.111-117
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    • 2003
  • Cisplatin is often effective in cancer treatment, but its clinical use is limited because of its nephrotoxicity. We have synthesized new platinum(II) coordination complexes (PC-1 & PC-2) containing trans-${\iota}$ and cis-1,2-diaminocyclohexane (DACH) as carrier ligands and L-3 -phenyllactic acid (PLA) as a leaving group with the aim of reducing nephrotoxicity but maintaining its anticancer activity. In this study, new platinum(II) complex compounds were evaluated for selective cytotoxicity on cancer cell-lines and normal kidney cells. The new platinum complexes have demonstrated high efficacy in the cytotoxicity against human bladder carcinoma cell-lines (T-24/HT-1376). The cytotoxicity of these compounds against rabbit proximal renal tubular cells and human renal cortical tissues, was determined by MTT assay, the [3H]-thymidine uptake and glucose consumption test, and found to be quite less than those of cisplatin. Based on our results, these novel platinum compounds appear to be valuable lead compounds with high efficacy and low nephrotoxicity.

Coumarins from the Roots of Angelica decursiva-albiflora (개바디 뿌리의 쿠마린성분)

  • Jung, Nam-Il;Yook, Chang-Soo;Lee, Hyeong-Kyu
    • Korean Journal of Pharmacognosy
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    • v.25 no.4 s.99
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    • pp.311-318
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    • 1994
  • From the root of Angelica decursiva-albiflora Yook, which has been used as a folk medicine for a sedative, analgesic and expectorant, four free coumarins, e.g., decursidin(I), decursin(II), umbelliferone(III) and nodakenetin(IV), and two coumarin glycosides, e.g., nodakenin(V) and decuroside I(VI) were isolate. The cytotoxicity of nodakenin(V) against L-1210 leukemia cells was less effective than cisplatin, but in the nephrotoxicity against rabbit kidney proximal tubular cell nodakenin(V) showed remarkably less nephrotoxicant than cisplatin.

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Effect of Cisplatin on Glomerular Filltration Rate and Effective Renal Plasma Flow (Cisplatin의 투여 후 사구체여과율 및 신혈류량의 변화)

  • Lim, Sang-Moo;Hong, Seong-Woon;Kim, Young-Hyun;Hong, Weon-Seon;Song, Jae-Kwan;Kim, Young-Whan;Lee, Jhin-Oh;Kang, Tae-Woong
    • The Korean Journal of Nuclear Medicine
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    • v.23 no.1
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    • pp.55-61
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    • 1989
  • While cisplatin has been widely used in the treatment of a variety of cancers, nephrotoxicity is one of the major problems which frequently limit clinical usefulness of cisplatin. This study has been conducted to investigate nephrotoxicity of cisplatin in terms of changes in glomerular filtration rate (GFR) and effective renal plasma flow (EFPF) measured by the simultaneous use of $^{99m}Tc-DTPA$ and $^{131}I-OIH$, before and after administration of cisplatin, in 12 patients with lung cancer and four patients with esophageal cancer. Cisplatin was administrated at total doses of $75\sim100mg/m^2$ with two hour hydration and diuresis method. GFR determined by the use of $^{99m}Tc-DTPA$ had a good correlation with 24-hour creatinine clearance rate (r=0.77, p<0.001). GFR and filtration fraction decreased immediately after administration of cisplatin, however, they showed a tendency to be in completely recovered four weeks after administration. ERPF was not changed immediately after and four weeks after administration of cisplatin. GFR before and immediately after administration of cisplatin were analyzed with regard to age, sex, performance status, previous adminstration of cisplatin and method of administration. None of these factors had any influence on the rate of decrease in GFR except method of administration. Administration of cisplatin as a single dose lowered GFR more compared with that as divided doses. In this study, we have also demonstrated that the simultaneous use of $^{99m}Tc-DTPA$ and $^{131}I-OIH$ was a useful tool for the measurement of GFR and ERPF respectively.

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In Vitro Antitumor Activity and Nephrotoxicity of the Novel Platinum(II) Coordination Complex Containing Cis-dach/Diphosphine (새로운 Platinum(II)Complex ([Pt(II)(cis-dach)(DPPP)].$(NO_3)_2$의 항암효과 및 신독성)

  • Jung, Jee-Chang;Yim, Sung-Vin;Park, Seung-Joon;Chung, Joo-Ho;Ko, Kye-Chang;Chang, Sung-Goo;Rho, Young-Soo
    • The Korean Journal of Pharmacology
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    • v.32 no.1
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    • pp.93-102
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    • 1996
  • Platinum coordination complexes are currently one of the most compounds used in the treatment of solid tumors. However, its use is limited by severe side effects such as nephrotoxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and broadening the clinical spectrum of activity of cisplatin. We synthesized new Pt(II) complex analogue containing 1,2-diaminocyclohexane (dach) as carrier ligand and 1,3-bis(diphenyl phosphino)propane (DPPP) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of PC-1 [Pt(cis-dach) (DPPP)]. $2NO_3_2$ was synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $^{13}carbon$ nuclear magnetic resonance (NMR)]. PC-1 was demonstrated acceptable antitumor activity aganist SKOV -3, OVCAR-3 human ovarian adenocarcinomacells and significant activity as compared with that of cisplatin. The toxicity of PC-1 was found quite less than that of cisplatin using MTT, $[^3H]thymidine$ uptake and glucose consumption tests in rabbit proximal tubule cells, human kidney cortical cells and human renal cortical tissues. Based on these results, this novel platinum compound represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low toxicity.

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Effect of Nephrotoxicants on $\alpha$-Methylglucose Uptake in LLC-$PK_1$ (LLC-$PK_1$을 이용한 신독성 물질들의 $\alpha$-methyl glucose uptake에 미치는 영향의 평가)

  • Seo, Kyung-Won;Kim, Hyo-Jung;Chung, Se-Young
    • Environmental Analysis Health and Toxicology
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    • v.9 no.1_2
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    • pp.25-35
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    • 1994
  • Many nephrotoxic agents exert their effect primarily on the cells of the proximal tubules. We used the LLC-$PK_1$, kidney epithelial cell line as a model system for studies on nephrotoxicity and investigated whether the uptake of $\alpha$-methylglucose($\alpha$-MG) could serve as a parameter to assess effects of nephrotoxicants on the functional integrity of the cells at an early time of toxicity. The enzyme leakage test which has been used to be as a conventional cytotoxic parameter in vitro, was conducted to compare with $\alpha$-MG uptake. Treatment with cisplatin for 24 and 48 hours significantly increased activities of lactate dehydrogenase and $\gamma$-glutamyltransferase in culture medium at a concentration of 50$\mu$M. However, above 100$\mu$M of concentration, activities of these enzymes in media were dramatically decreased by cisplatin. These observations indicate that cisplatin has direct inhibitory effect on the activities of these enzymes and make it doutful to use enzyme leakage test to demonstrate damage of kidney cells by chemicals such as cisplatin over the appropriate range of concentration. Cisplatin inhibited $\alpha$-MG uptake at a low concentration which enzymes were not leaked. Also cadmium chloride and mercuric chloride which are acutely nephrotoxic in vivo, significantly inhibited $\alpha$-MG uptake at a low concentration. These results indicate that the uptake of $\alpha$-methylglucose in LLC-$PK_1$cell line is a useful biomarker for the study of nephrotoxicity.

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