Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice

Ban, M.; Hettich, D.; Huguet, Nelly

doi:10.1016/0378-4274(94)90176-7

Cited by 45 publications

(20 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However CDDP has severe toxic effects on normal cells of the gut, bone marrow, 4) nerves and the renal tubular epithelium. [20][21][22] To overcome those problems, several platinum-polymer preparations have been investigated, including polylactic acid microcapsules, 23) and microspheres consisting of Llactic acid, 24) dextran, 25) and HPMA copolymer. 26) Most preparations have failed to demonstrate meaningful benefit in vivo.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin‐incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

Mizumura

Matsumura

Hamaguchi

et al. 2001

Japanese Journal of Cancer Research

View full text Add to dashboard Cite

cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)-poly(aspartic acid) (PEG-P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP-incorporated polymeric micelles (CDDP/m) were evaluated in comparison with those of CDDP. In vitro, CDDP/m exhibited 10-17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP/m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP/m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP/m treatment caused much less renal damage than CDDP. These results indicate that CDDP/m treatment can reduce CDDP-induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.Key words: Polymeric micelles -Cisplatin -Nephrotoxicity -EPR effect -DDS cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), the most commonly used anticancer agent, consists of a central platinum atom surrounded by four ligands, two ammonias and two chlorides.1) A high antitumor activity results when the two chloride ligands in CDDP are bi-aquated in aqueous physiological environments; CDDP can then interact directly with DNA and display cytotoxic activity.2, 3) The clinical utility of CDDP is limited by significant general organ toxicity including myelosuppression, 4) ototoxicity, 5) gastrointestinal disturbance, 5, 6) and especially acute nephrotoxicity.7) CDDP, a low-molecularweight compound, is distributed readily into almost all tissues and intracellular compartments. CDDP traverses plasma membranes rapidly via passive diffusion or active transport, and is also rapidly cleared from blood by glomerular excretion, limiting its therapeutic availability. Injection of the maximum permissible amount of this lowmolecular-weight drug to raise its therapeutic concentration and AUC (area under the curve) results in severe toxicity without significantly greater antitumor efficacy. Therefore, several novel forms of controlled release drug delivery have been designed to improve distribution and to prolong the exposure of the tumor to an effective drug concentration.It is known that solid tumors generally possess the following pathophysiological characteristics: hypervascularity, incomplete vascular architecture, secretion of vascular permeability factors, and also the absence of effective lymphatic drainage, preventing the efficient clearance of accumulated macromolecules. These characteristics, unique to solid tumors, are believed to be the basis of the so-called EPR effect (enhanced permeability and retention ef...

show abstract

Section: Discussionmentioning

confidence: 99%

Cisplatin‐incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

Mizumura

Matsumura

Hamaguchi

et al. 2001

Japanese Journal of Cancer Research

View full text Add to dashboard Cite

show abstract

“…The average number of protein casts per 10ϫ field was computed for each group. effect of acivicin on the renal toxicity of cisplatin in male Swiss OF1 mice (Ban et al, 1994). They quantitated tubule damage in alkaline phosphatase-stained frozen kidney sections from mice sacrificed 72 h after treatment.…”

Section: Tablementioning

confidence: 99%

“…GGT activity was inhibited by acivicin as previously described (Ban et al, 1994). Briefly, acivicin was dissolved in saline at 5 mg/ml.…”

mentioning

confidence: 99%

Inhibition of γ-Glutamyl Transpeptidase or CysteineS-Conjugate β-Lyase Activity Blocks the Nephrotoxicity of Cisplatin in Mice

Townsend¹,

Hanigan²

2002

J Pharmacol Exp Ther

111

View full text Add to dashboard Cite

Cisplatin is nephrotoxic. The mechanism underlying this organspecific toxicity is unknown. We hypothesize that cisplatin is metabolized via a ␥-glutamyl transpeptidase (GGT) and cysteine S-conjugate ␤-lyase-dependent pathway that has been shown to activate several haloalkenes to nephrotoxins. To test this hypothesis, we inhibited GGT and cysteine S-conjugate ␤-lyase in C57BL/6 mice and analyzed the effect of the inhibitors on the nephrotoxicity of cisplatin. GGT was inhibited by pretreating the mice with acivicin. Cysteine S-conjugate ␤-lyase was inhibited by aminooxyacetic acid (AOAA). Male C57BL/6 mice were treated with 15 mg/kg cisplatin (i.p.) and sacrificed on day 5. Half the mice treated with cisplatin alone died before sacrifice. The cisplatin-treated mice sacrificed at 5 days had significantly elevated levels of blood urea nitrogen (BUN). Histologic analysis revealed severe damage to the renal proximal tubules. Pretreatment with acivicin or AOAA protected the mice from the nephrotoxicity of cisplatin. None of the pretreated animals died before sacrifice. BUN levels and quantitative histologic analysis of the kidneys confirmed the protective effect of acivicin and AOAA. Platinum levels in the kidneys were not altered by acivicin or AOAA, indicating that neither affected the uptake of cisplatin into the kidney. Likewise, cisplatin-induced weight loss was not altered by acivicin or AOAA, suggesting that weight loss and nephrotoxicity are via distinct mechanisms. These data support the hypothesis that the nephrotoxicity of cisplatin is due to the metabolism of a platinumglutathione conjugate by GGT and cysteine S-conjugate ␤-lyase to a potent nephrotoxin.Cisplatin is a widely used chemotherapy drug. Nephrotoxicity is one of its dose-limiting side effects (Madias and Harrington, 1978). Our previous studies showed that in rats, inhibition of ␥-glutamyl transpeptidase (GGT) activity blocked cisplatin-induced nephrotoxicity (Hanigan et al., 1994). Inhibition of GGT also inhibits the nephrotoxicity of halogenated alkenes and quinones such as trichloroethene, hexachloro-1,3-butadiene, 2-bromo-2-chloro-1,1-difluoroethene, and 2-bromohydroquinone (Lau and Monks, 1990;Finkelstein et al., 1992;Lash et al., 2001). These compounds form glutathione S-conjugates that are metabolized by GGT in the kidney to nephrotoxins (Anders and Dekant, 1998;Lash et al., 2001). The renal toxicity of both classes of compounds is localized to the proximal tubule cells, the same cells killed by cisplatin (Dekant, 1993;Hanigan et al., 1994). Although the metabolic activation of both the halogenated alkenes and the hydroquinones is initiated by the formation of a glutathione-conjugate and the extracellular cleavage by GGT, the further metabolism of these two classes of compounds diverges downstream of the GGT reaction. The nephrotoxicity of the halogenated alkenes can be inhibited by aminooxyacetic acid (AOAA), which inhibits cysteine S-conjugate ␤-lyase activity (Elfarra et al., 1986;Finkelstein et al., 1992), whereas AOAA has littl...

show abstract

“…Reactive oxygen species, especially the hydroxyl radical, induce lipid peroxidation and cell membrane damage and reduce glomerular filtration rate (GFR) (7)(8)(9). It is reported that CP-induced nephrotoxicity may be ameliorated by scavenging agents such as vitamins E and C, losartan, melatonin, selenium, superoxide dismutase, and erythropoietin (10)(11)(12)(13)(14)(15)(16). Researches indicate that exercise activity changes antioxidant content (17)(18)(19), and as an example, it reduces antioxidant levels of erythrocyte GSH-PX (17).…”

Section: Introductionmentioning

confidence: 99%

Protective Role of Aerobic Exercise Against Cisplatin-Induced Nephrotoxicity in Rats

et al. 2015

View full text Add to dashboard Cite

Background: Cisplatin (CP) is a chemotherapy drug and nephrotoxicity is considered as its major side effect. Aerobic exercise is well known as an approach to reduce the side effects of many drugs. Objectives: This study was designed to determine the protective role of aerobic exercise against CP-induced nephrotoxicity. Materials and Methods: Thirty male Wistar rats were randomly divided into four groups. Group I had aerobic exercise on a treadmill one hour per day and five days per week for eight weeks. Then, the exercise protocol was continued for another week, but during this week, the animals also received CP (2.5 mg/kg/day; ip). Group II underwent the same protocol as group I without exercise in the last week during the CP therapy. Groups III and IV were assigned as positive and negative control groups, and were treated with CP and saline without exercise, respectively. Finally, the animals were sacrificed for the biochemical measurement and tissue histopathology investigation. Results: CP alone without exercise increased serum levels of blood urea nitrogen (BUN), creatinine (Cr), and malondialdehyde (MDA); and kidney nitrite level, while treadmill exercise in group I significantly ameliorated these parameters (P < 0.05). Kidney and serum levels of MDA and nitrite did not alter significantly. Also, the severity of kidney tissue damage decreased significantly in groups I and II (P < 0.05). Conclusions: Aerobic exercise may reduce CP-induced nephrotoxicity with a favorable effect on renal function by increasing activation of antioxidant system.

show abstract

Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice

Cited by 45 publications

References 16 publications

Cisplatin‐incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

Cisplatin‐incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

Inhibition of γ-Glutamyl Transpeptidase or CysteineS-Conjugate β-Lyase Activity Blocks the Nephrotoxicity of Cisplatin in Mice

Protective Role of Aerobic Exercise Against Cisplatin-Induced Nephrotoxicity in Rats

Contact Info

Product

Resources

About