Comparative nephrotoxicity of some antitumour-active platinum and ruthenium complexes in rats

Kersten, L; Bräunlich, H; Keppler, Bernhard K.; Gliesing, Christiane; Wendelin, Matthias; Westphal, J.

doi:10.1002/(sici)1099-1263(199803/04)18:2<93::aid-jat472>3.0.co;2-w

Cited by 38 publications

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“…In the case of its toxic imidazole analogue (KP418), non‐coordinate protein interactions are also observed, however, they form at a much slower rate 14b. 20 The reduced rate of hsA binding by KP418 has been suggested to leave more of the complex free in vivo, and is possibly responsible for its observed toxicity 39. In light of these reports, we have studied the ability of complexes 1 a – 5 a and 1 b – 5 b to bind to hsA, both through hydrophobic interactions and through direct coordination.…”

Section: Resultsmentioning

confidence: 99%

Increasing the Bioavailability of Ru^IIIAnticancer Complexes through Hydrophobic Albumin Interactions

Webb

Jang

et al. 2013

Chemistry A European J

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A series of pyridine-based derivatives of the clinically successful Ru(III)-based complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (KP1339) have been synthesized to probe the effect of hydrophobic interactions with human serum albumin (hsA) on anticancer activity. The solution behavior and protein interactions of the new compounds were characterized by using electron paramagnetic resonance (EPR) and UV/Vis spectroscopy. These studies have revealed that incorporation of hydrophobic substituents at the 4'-position of the axial pyridine ligand stabilizes non-coordinate interactions with hsA. As a consequence, direct coordination to the protein is inhibited, which is expected to increase the bioavailability of the complexes, thus potentially leading to improved anticancer activity. By using this approach, the lifetimes of hydrophobic protein interactions were extended from 2 h for the unsubstituted pyridine complex, to more than 24 h for several derivatives. Free complexes were tested for their anticancer activity against the SW480 human colon carcinoma cell line, exhibiting low cytotoxicity. Pre-treatment with hsA improved the solubility of every compound and led to some changes in activity. Particularly notable was the difference in activity between the methyl- and dibenzyl-functionalized complexes. The former shows reduced activity after incubation with hsA, indicating reduced bioavailability due to protein coordination. The latter exhibits little activity on its own but, following treatment with hsA, exhibited significant cytotoxicity, which is consistent with its ability to form non-coordinate interactions with the protein. Overall, our studies demonstrate that non-coordinate interactions with hsA are a viable target for enhancing the activity of Ru(III)-based complexes in vivo.

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Section: Resultsmentioning

confidence: 99%

Increasing the Bioavailability of Ru^IIIAnticancer Complexes through Hydrophobic Albumin Interactions

Webb

Jang

et al. 2013

Chemistry A European J

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“…The changes induced by cisplatin in the kidney functions were characterized by signs of injury, such as changes in urine volume, in glutathione status, increase of products of lipid peroxidation, and changes in creatinine clearance, 1 . Cisplatin also induces a reduction in antioxidant status, leading to a failure of the antioxidant defense against freeradical damage generated by antitumor drugs, 2, 3 .…”

Section: Introduction:-mentioning

confidence: 99%

Biological Impact of Moringa Oleifera Extract on Parotid Gland of Cisplatin- Induced Renal Failure in Albino Rats.

Moawad¹,

Mohammed²,

Ibrahim³

et al. 2016

IJAR

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Background:-Cisplatin is a major antineoplasticdrug for the treatment of solid tumors, but it has dose-dependent renal toxicity. Aim:-in the present study we reported the effect of moringa oleifera extract on the parotid gland of cisplatin-induced renal failure of albino rats. Material and methods:-Adult male albino rats were divided into three treated groups and control group of 12 rats each,1. Control rats I, (6 mg/ kg body wt. of saline by i.p. injection and repeated after 2 weeks). 2. Study groups (II, III and IV) induction of renal failure done by single i.p. injection of 6 mg/ kg body wt. of cisplatin in group III, while in group II and IV this dose was repeated after 2 weeks, 4 days later after the first injection of cisplatin blood samples were collected for creatinine level analysis. In group III after the blood analysis animals received 5 mg /kg body wt. /day of moringa oleifera extract for 2 weeks. In group IV after the second injection of cisplatin, animals received the same dose of moringa oleifera extract for 2 weeks. Animals were sacrificed at 2 intervals, in group I: after 18& 32 days from the start of experiment. In group II: after collection of blood samples&1 week later.in group III and IV at the end of moringa treatment& 1 week later. Results:-Cisplatin administration induced renal failure which was accompanied by increase in serum creatinine level and manifested histologically in parotid gland as cracks like vacuolations, widening of connective tissue septa, loss of acinar outlines and hydropic degeneration. The administration of moringa minimized the cytotoxic effect of cisplatin in group III & IV which was detected by decrease in serum creatinine level, and evidenced histologically as densely packed serous acini with regular basally located nuclei having symmetrical shape and size restoring its normal pattern. Conclusion:-These results suggest that moringa oleifera extract protect against the effect of renal failure on parotid gland.

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“…High doses of CDDP produce the impairment of kidney function, which is recognized as the main side-effect and the most important dose-limiting factor [ 2 ]. The alterations induced by CDDP in the kidney functions were characterized by signs of injury, such as changes in urine volume, body weight, in glutathione status, increase of products of lipid peroxidation, and changes in creatinine clearance [ 3 ]. Histologically, the acute toxic tubular necrosis observed after CDDP administration is similar to that produced in intoxication by mercury or cadmium [ 4 ] suggesting that CDDP nephropathy may be attributable ultimately to the toxicity of the platinum molecules which induce damage in the proximal tubular cells.…”

Section: Introductionmentioning

confidence: 99%

Lipid Peroxides and Antioxidant Enzymes in Cisplatin‐Induced Chronic Nephrotoxicity in Rats

González

Romay

Borrego

et al. 2005

Mediators of Inflammation

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Cisplatin (CDDP), an anticancer drug, induces remarkable toxicity in the kidneys of animals and humans and it has been well documented that reactive oxygen species and the renal antioxidant system are strongly involved in acute renal damage induced by CDDP. The aim of the present study was to investigate whether or not the renal antioxidant system plays also an important role in chronic renal damage induced by repeated doses of CDDP (1 mg/kg intraperitoneally twice weekly during 10 weeks in rats). In order to elucidate it, serum creatinine and urea levels, renal glutathione and thiobarbituric acid-reactive substances (TBARS) content, as well as renal superoxide dismutase and glutathione peroxidase activities were measured in the kidney homogenates of chronically CDDP-treated rats and additionally histological studies were performed in the rat kidneys. The chronic treatment with CDDP induced a significant increase in creatinine and urea levels in serum, but the other parameters mentioned above were not significantly modified as compared to the values in nontreated rats. Taking into account these results, we conclude that chronic CDDP administration induces also severe nephrotoxicity, in contrast to CDDP acute application, without any significant modification in the activity of relevant antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, renal glutathione and lipid peroxides, by which the role of the antioxidant system in chronic nephrotoxicity induced by CDDP in rats is uncertain.

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Comparative nephrotoxicity of some antitumour-active platinum and ruthenium complexes in rats

Cited by 38 publications

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Increasing the Bioavailability of Ru^IIIAnticancer Complexes through Hydrophobic Albumin Interactions

Increasing the Bioavailability of Ru^IIIAnticancer Complexes through Hydrophobic Albumin Interactions

Biological Impact of Moringa Oleifera Extract on Parotid Gland of Cisplatin- Induced Renal Failure in Albino Rats.

Lipid Peroxides and Antioxidant Enzymes in Cisplatin‐Induced Chronic Nephrotoxicity in Rats

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Comparative nephrotoxicity of some antitumour-active platinum and ruthenium complexes in rats

Cited by 38 publications

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Increasing the Bioavailability of RuIIIAnticancer Complexes through Hydrophobic Albumin Interactions

Increasing the Bioavailability of RuIIIAnticancer Complexes through Hydrophobic Albumin Interactions

Biological Impact of Moringa Oleifera Extract on Parotid Gland of Cisplatin- Induced Renal Failure in Albino Rats.

Lipid Peroxides and Antioxidant Enzymes in Cisplatin‐Induced Chronic Nephrotoxicity in Rats

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Increasing the Bioavailability of Ru^IIIAnticancer Complexes through Hydrophobic Albumin Interactions

Increasing the Bioavailability of Ru^IIIAnticancer Complexes through Hydrophobic Albumin Interactions