• Biomedical Science Letters
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• v.8 no.4
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• pp.251-256
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• 2002

This study was undertaken to determine the underlying mechanisms of reactive oxygen species-induced cell injury in renal epithelial cells and whether there is a difference in the role of lipid peroxidation between freshly isolated renal cells and cultured renal cells. Rabbit renal cortical slices were used as a model of freshly isolated cells and opossum kidney (OK) cells as a model of cultured cells. Cell injury was estimated by measuring lactate dehydrogenase (LDH) release in renal cortical slices and frypan blue exclusion in OK cells. $H_2O$$_2$ was used as a drug model of reactive oxygen species. $H_2O$$_2$ induced cell injury in a dose-dependent manner in both cell types. However, renal cortical slices were resistant to $H_2O$$_2$ approximately 50-fold than OK cells. $H_2O$$_2$-induced cell injury was prevented by thiols (glutathione and dithiothreitol) and iron chelators (deferoxamine and phenanthroline) in both cell types. $H_2O$$_2$-induced cell injury in renal cortical slices was completely prevented by antioxidants N,N-diphenyl-p -phenylenediamine and Trolox, but the cell injury was not affected by these antioxidants in OK cells. $H_2O$$_2$ increased lipid peroxidation in both cell types, which was completely inhibited by the antioxidants. These results suggest that $H_2O$$_2$ induces cell injury through a lipid peroxidation-dependent mechanism in freshly isolated renal cells, but via a mechanism independent of lipid peronidation in cultured cells.

• YAKHAK HOEJI
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• v.42 no.5
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• pp.494-499
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• 1998

As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of 1,2-bis(diphenylphosphino)ethane(1,2-diaminopro pane)platinum(II)dinitrate (KHPC-070) has been evaluated in vitro against various tumor cell lines and normal kidney cells. The structure of this new compound was determined by elemental analysis, infrared spectroscopy (IR) and $^{13}carbon$ nuclear magnetic resonance (NMR). With the use of nine tumor cell lines, KHPC-070 exhibited a comparable cytotoxic to cisplatin. The cytotoxicity of KHPC-070 in normal cells was quite less than that of cisplatin using 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and [$^3H$]-thymidine uptake tests in rabbit renal proximal tubular cells and human renal cortical cells. Based on these results, KHPC-070 is considered to have more selective cytotoxicity toward cancer cells than normal human/rabbit kidney cells.

• The Korean Journal of Physiology and Pharmacology
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• v.4 no.2
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• pp.159-167
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• 2000

We have synthesized a novel platinum(II) coordination complex containing cis-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,2-dichloroethane (DCE) as a leaving group. In addition, nitrate was added to improve the water-solubility. A new series of [Pt(cis-DACH)(DCE)] $2NO_3(PC)$ was evaluated for its cytotoxic activity on T-24 and J-82 human bladder carcinoma cells and normal primary cultured kidney cells. PC has demonstrated high levels of cytotoxicity against T-24 and J-82 cells. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined using the MTT assaying technique, the $[^3H]-thymidine$ uptake and glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new clinically available anticancer chemotherapeutic agents.

• YAKHAK HOEJI
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• v.44 no.5
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• pp.399-405
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• 2000

We have synthesized a novel platinum (II) coordination complex containing trans-ι-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,2-bis (diphenylphosphino)ethane (DPPE) as a leaving group. In addition, nitrate was added to improve the water-solubility. A new series of [Pt (trans-ι-DACH) (DPPE)].2NO$_3$(PC) was evaluated for its cytotoxic activity on MKN-45 human gastric adenocarcinoma cells and normal primary cultured kidney cells. PC has demonstrated high levels of cytotoxicity against MKN-45/S, MKN-45/ADR and MKN-45/CDDP cells. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells, and human renal cortical tissues, determined using the MTT assaying technique, the ($^3$H)-thymidine uptake and the glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum (II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new clinically available anticancer chemotherapeutic agents.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1995.04a
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• pp.124-124
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• 1995

Cisplatinum is often effective in cancer treatment, but potent nephrotoxicity limits its clinical use. We have, therefore, developed new anticancer drugs that contain platinum. We have synthesized six new platinum compounds based on Figure 1. Drugs were initially administrated at 5${\times}$10$\^$-4/M with 48 hours exposure in monolayer cultures of primary rabbit proximal tubular cells and human renal cortical cells with the M.T.T. endpoint to measure toxicity. Drug concentrations of 10$\^$-3/M, 10$\^$-4/M, and 10$\^$-5/M with 72 hours exposure were used for human renal cortical tissues in 7 weeks histoculture with toxicity measured by the glucose-consumption endpoint. From these studies, we determined that the new platinum drugs have lower nephrotoxicity than cisplatinum. Drugs D, E, and H. have lower nephrotoxicity than the other new drugs. We are currently measuring the anticancer efficacy of drugs D, E, and H.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.4
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• pp.359-366
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• 2001

We have synthesized a novel platinum(II) coordination complex containing cis-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,3-dichloropropane (DCP) as a leaving group. A new series of [Pt(cis- DACH)(DCP)](PC) was evaluated for its cytotoxic activity on MKN-45 human gastric adenocarcinoma cells and normal primary cultured kidney cells. The new platinum complex has demonstrated high efficacy in the cytotoxicity against MKN-45/P, MKN-45/ADM and MKN-45/CDDP cell-lines. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined by MTT assay, the $[^3H]-thymidine$ uptake and glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new, clinically available anticancer chemotherapeutic agents.

• Biomolecules & Therapeutics
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• v.8 no.3
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• pp.228-234
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• 2000

We have synthesized a novel platinum(II) coordination complex containing trans-ι-1,2-diaminocy-clohexane (DACH) as a carrier ligand and 1,2-dichloroethane (DCE) as a leaving group. A new series of [Pt(trans-ι-DACH)(DCE)](PC) was evaluated for its cytotoxic activity on MKN-45 human gastric adenocar-cinoma cells and normal primary cultured kidney cells. The new platinum complex has demonstrated high efficacy in the cytotoxicity against MKN-45/P, MKN-45/ADM and MKN-45/CDDP cell-lines. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined by MTT assay, the [$^3H$]-thymidine uptake arid glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new, clinically available anticancer chemotherapeutic agents.

• Biomolecules & Therapeutics
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• v.5 no.2
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• pp.125-132
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• 1997

Cisplatin, a platinum-complex, is currently one of the most effective compounds used in the treat-ment of solid tumors. However, its use is limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and improving selective cytotoxicity. We synthesized new Pt (II) complex analogue containing 1,2-diaminocyclohexane (DACH) as carrier ligand and 1,2-bis (diphenylphosphino) ethane (DPPE) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of [Pt(cia-DACH)(DPPE)] . $2NO_3$ (PC) was synthes-ized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $_{13}$carbon nuclear magnetic resonance (NMR)] .PC demonstrated acceptable and significant antitumor activity against SKOV-3 and OVCAR-3 human ovarian carcinoma cell lines as compared with that of cisplatin. The cytotoxicity of PC in normal cells was found quite less than that of cisplatin using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), ($^3$H)thymidine uptake and glucose consumption tests in rabbit renal proximal tubular cells, human renal cortical cells and tissues. In conclusion, PC is considered to be more selective cytotoxicity toward human ovarian cancer cells than normal human/rabbit kidney cells.

• Biomedical Science Letters
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• v.10 no.4
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• pp.341-346
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• 2004

Tumor necrosis factor-α (TNF-α) or its mRNA expression are increased in acute nephrosis of various types including ischemia/reperfusion injury. This study was undertaken to determine whether pentoxifylline (PTX), an inhibitor of TNF-α production, provides a protective effect against hypoxia-induced cell injury in rabbit renal cortical slices. To induce hypoxia-induced cell injury, renal cortical slices were exposed to 100% N₂ atmosphere. Control slices were exposed to 100% O₂ atmosphere. The cell injury was estimated by measuring lactate dehydrogenase (LDH) release and p-aminohippurate (PAH) uptake. Exposure of slices to hypoxia increased the LDH release in a time-dependent manner. However, when slices were exposed to hypoxia in the presence of PTX, the LDH release was decreased. The protective effect of PTX was dose-dependent over the concentrations of 0.05∼1 mM. Hypoxia did not increase lipid peroxidation, whereas an organic hydroperoxide t-butylhydroperoxide (tBHP) resulted in a significant increase in lipid peroxidation. PTX did not affect tBHP-induced lipid peroxidation. Hypoxia decreased PAH uptake, which was significantly attenuated by PTX and glycine. tBHP-induced inhibition of PAH uptake was not altered by PTX, although it was prevented by antioxidant deferoxarnine. The PAH uptake by slices in rabbits with ischemic acute renal failure was prevented by PTX pretreatment. These results suggest that PTX may exert a protective effect against hypoxia-induced cell injury and its effect may due to inhibition of the TNF-α production, but not by its antioxidant action.

• YAKHAK HOEJI
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• v.40 no.2
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• pp.218-224
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• 1996

This laboratory has recently reported the synthesis and in vitro antitumor activity of PT(II) complexes containing ethylenediamine and diphosphine. In view of the reports of others, cisplatin is toxic to the kidney since the kidney's vulnerability to PT(II) complexes may originate in its ability to accumulate and retain platinum to a greater degree than other organs. The in vitro cytotoxicity of these synthetic PT(II) complexes on the primary cultured proximal tubular cells of rabbit kidney and renal cortical cells of human kidney was investigated. Three endpoints for cytotoxicity tests were evaluated:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), $^3H$-thymidine uptake and the glucose consumption tests. The rank order of sensitivity exhibited $^3H$-thymidine uptake>MTT>glucose consumption test. The agents with diphosphine leaving group were significantly less cytotoxic than cisplatin. Moreover, 1,2-bis(diphenylphosphino)ethane (DPPE) exhibited less cytotoxicity than 1.3-bis (diphenylphosphino)propane (DPPP) against on rabbit and human cultured kidney cells. Based on these results, the decreased nephrotoxicity of these new complexes over cisplatin appeared to be partially attributable to a leaving group of DPPP and DPPE. This novel class of platinum compound represents a valuable lead in the development of a "third-generation" agent.