Reduction of cisplatin nephrotoxicity by sodium selenite. Lack of interaction at the pharmacokinetic level of both compounds.

Administration of sodium selenite (Na2SeO3) 1 hr before cis-diamminedichloroplatinum(II) (referred to herein as cisplatin) can protect against the nephrotoxicity of cisplatin. The pharmacokinetic aspects of this interaction were studied in rodents with radiolabeled selenite and cisplatin. Total [75Se]selenium in plasma consisted of [75Se] selenium in plasma proteins and [75Se]selenite in plasma ultrafiltrate. After a short distribution phase, the elimination of [75Se]selenite and total [75Se]selenium proceeded biphasically in the rat, with an initial plasma elimination half-life of [75Se]selenite of 22 +/- 2 min. Coadministration of cisplatin had no effect on the initial nor on the much slower terminal elimination phase of [75Se]selenite nor of total [75Se] selenium. Sodium selenite, in doses protecting against the nephrotoxicity of cisplatin, did not significantly affect areas under the plasma concentration time curve from 0-6 hr nor the initial plasma half-lives of [195mPt]cisplatin (t1/2, 28 +/- 2 min) and total [195mPt]platinum (t1/2, 30 +/- 3 min) in plasma. The much slower terminal elimination phases in plasma and the cumulative urinary excretion of [195mPt] cisplatin and total [195mPt]platinum were neither influenced by sodium selenite. Sodium selenite does not react chemically with cisplatin in vitro. Apparently, bioactivation of selenite is required for its protective effect in vivo. Distribution studies in a mice tumor model indicated that [75Se]selenium is concentrated strongly in the kidney and that the bioactivation of selenite also most likely occurs primarily in the kidneys. We conclude that sodium selenite protects rodents against cisplatin-induced nephrotoxicity without influencing the systemic availability of cisplatin and total platinum.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of lipid peroxidation in the nephrotoxicity of cisplatin.

The possible role of lipid peroxidation in the nephrotoxicity of the antitumour drug cisplatin was studied in vitro. In contrast to Adriamycin, cisplatin did not induce lipid peroxidation in rat kidney microsomes containing a NADPH-generating system. Pretreatment of rat kidney microsomes with cisplatin did not reduce the activity of a microsomal glutathione (GSH)-dependent protective factor against lipid peroxidation induced by Fe(2+)-ascorbate. However, pretreatment of rat kidney microsomes with 0.1 mM N-ethyl maleimide (NEM) did reduce this GSH-dependent protection. Cisplatin also did not reduce the activity of a cytosolic GSH-dependent protective factor against Fe(2+)-ascorbate-induced lipid peroxidation. The results of our experiments indicate that, in contrast to Adriamycin, cisplatin does not induce lipid peroxidation in vitro in various test systems. It also does not destroy microsomal and cytosolic GSH-dependent protective factors against lipid peroxidation.

The influence of ebselen on the toxicity of cisplatin in LLC-PK1 cells.

LLC-PK1 cells have been used as an in vitro model to study the nephrotoxicity of the antitumor drug cisplatin. A concentration-dependent cytotoxicity of cisplatin, measured as lactate dehydrogenase leakage and amount of protein remaining attached to the culture plate, was observed. At a cisplatin concentration of 0.4 mM cell viability was reduced to 21% after 72 hr. Ebselen, a seleno-organic compound capable of forming selenol intermediates through reaction with thiols, was found to protect LLC-PK1 cells against cisplatin-induced toxicity at low concentrations (5-15 microM). The ebselen-induced protection against cisplatin toxicity in this in vitro test system apparently correlates well with a similar protection previously observed in vivo in mice and rats.

The mechanism of interaction between cisplatin and selenite.

Cisplatin is a widely used antitumor drug, highly effective in the treatment of several tumors. Cisplatin exerts its antitumor activity through an interaction with DNA, which results in the formation of bidentate adducts. An important side-effects of cisplatin is nephrotoxicity. Selenite can reduce the nephrotoxicity of cisplatin without reducing the antitumor activity of the drug. We have studied the mechanism of selenite protection against cisplatin-induced nephrotoxicity. The protection correlates with higher levels of selenium in the kidney (about eight times) and with higher levels of glutathione in the kidney, both compared to tumors. Selenite is metabolized into selenols, specifically into methylselenol and glutathionylselenol; this bioactivation of selenite into selenols is a glutathione-dependent process. HPLC with on-line radioactivity detection of 195mPt showed that methylselenol is capable of forming a complex with cisplatin in vitro. 1H-NMR gave evidence that the complex contains one or more Pt-Se-CH3 bonds. Attempts to obtain further structural information by Desorption Chemical Ionization and Fast Atom Bombardment mass-spectrometry failed. It is proposed that the formation of a cisplatin-selenol complex also takes place in vivo, especially in the kidney, thereby preventing cisplatin exerting its nephrotoxic activity.

Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen.

2-Phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) is classified as a relatively nontoxic selenium compound, probably because of its bound selenium moiety. In thiol-rich tissues, such as the kidneys, ebselen is converted into selenol intermediates. Selenols are nucleophilic agents which might be able to react with platinum compounds. The influence of ebselen on cis-diamminedichloroplatinum(II) (cisplatin)-induced nephrotoxicity in mice was assessed, using single doses of both compounds. Ebselen prevented cisplatin-induced elevations of blood urea nitrogen and serum creatinine levels and morphological kidney damage in BALB/c mice. This protective effect of ebselen was dose dependent: at a cisplatin dose of 14.5 mg/kg, maximal protection was achieved when a single dose of 10 mg of ebselen/kg was administered 1 h before cisplatin. Administration of ebselen, 10 mg/kg, 1 h after cisplatin also protected against severe nephrotoxicity. Treatment with ebselen did not reduce the antitumor activity of cisplatin against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. However, this reduction of cisplatin-induced nephrotoxicity would be of little clinical value if it was achieved at toxic doses of ebselen. Ebselen, 10 mg/kg, did not induce blood urea nitrogen, serum creatinine, serum glutamic pyruvate transaminase, or serum glutamic oxalate elevations in the mice. These results are in agreement with the reported low toxicity of ebselen, which is now in Phase I clinical trials as an antiinflammatory drug. The present results indicate that ebselen may provide protection against cisplatin-induced nephrotoxicity, when it is given before or after cisplatin. This might open new perspectives in cancer chemotherapy.

Platinum distribution in intraperitoneal tumors after intraperitoneal cisplatin treatment.

The spatial distribution of platinum (Pt) in the kidney was studied by an autoradiographic technique, in which cisplatin (CDDP) was replaced by 195mPt-labeled CDDP, and by proton-induced X-ray emission (PIXE). Although both studies demonstrated comparable spatial distribution patterns, PIXE had the advantage that Pt concentrations could be determined quantitatively, in contrast to the relative information obtained by the autoradiographic technique. Using PIXE, the distribution of Pt in i.p. tumors was studied after i.p. administration of CDDP. The highest Pt concentrations were always found on the periphery of tumors, indicating that the periphery was exposed to a higher drug concentration than the center. Dose was correlated to the concentration of CDDP at both the center and the periphery (r = 0.99). The Pt concentration in the periphery was usually higher by a factor of 2-3 after i.p. administration than after i.v. treatment, whereas in the center of the tumor no concentration difference could be detected. The penetration depth of CDDP lay between 1 and 2 mm and was calculated from the differences in Pt concentration after i.p. and i.v. treatment. This indicates that the effective advantage of i.p. chemotherapy with CDDP in cases of cancers limited to the peritoneal cavity is accentuated at the periphery of the tumor.

Determination of 75Se-labelled selenite and metabolites in plasma and urine by high-performance liquid chromatography with on-line radioactivity detection.

A reversed-phase ion-pair high-performance liquid chromatographic method with on-line radioactivity detection for the simultaneous determination of 75Se-labelled selenite and metabolites has been developed. With this system a good resolution of various radiolabelled selenium complexes can be achieved. The detection limit of the radioactivity detector (signal-to-noise ratio = 3) is 49 pg of selenium (specific activity of 3 GBq/mg selenium) per millilitre of urine or plasma ultrafiltrate. The detector response is independent of both the chemical structure of the selenium complexes and the matrix composition of the samples. This method may serve as a reference system for other high-performance liquid chromatographic systems with less specific and sensitive detectors.

Determination of cisplatin and related platinum complexes in plasma ultrafiltrate and urine by high-performance liquid chromatography with on-line radioactivity detection.

A reversed-phase ion-pair chromatographic method with on-line radioactivity detection for the simultaneous determination of 195mPt-labelled cisplatin and related platinum complexes has been developed. With this system a good resolution of various radiolabelled platinum complexes can be achieved. The detection limit of the radioactivity detector is 10 ng of cisplatin (specific activity of 15 MBq/mg cisplatin) per millilitre of urine or plasma ultrafiltrate. The detector response is independent of both the chemical structure of the platinum complexes and the matrix composition of the samples. This method may serve as a reference system for other high-performance liquid chromatographic systems with less specific and sensitive detectors.

Selenium-induced protection against cis-diamminedichloroplatinum(II) nephrotoxicity in mice and rats.

The influence of selenium on cis-diamminedichloroplatinum(II) (c-DDP) nephrotoxicity in mice and rats was assessed, using single doses of both compounds. Sodium selenite, 2 mg of selenium per kg, given 1 h before c-DDP, greatly reduced blood urea nitrogen and creatinine levels and morphological kidney damage in both BALB/c mice and Wistar rats, while administration 1 h after c-DDP did not. Liver toxicity of selenium was evaluated by measuring serum glutamic pyruvate transaminase and serum glutamic oxalate transaminase and by routine histology. No liver damage was observed in animals treated with sodium selenite, 2 mg of selenium per kg, and physiological saline or c-DDP. Pretreatment with sodium selenite did not reduce the antitumor activity of c-DDP against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. The present results indicate that sodium selenite may provide protection against c-DDP nephrotoxicity, when it is given before c-DDP. Moreover, selenium has an antineoplastic activity against several tumors. The combination of these qualities may open new perspectives in cancer chemotherapy.

Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy.

Chemotherapy i.p. is increasingly being tested as a treatment modality for cancer limited to the peritoneal cavity. We have developed a rat tumor model in which penetration and distribution of cis-diamminedichloroplatinum(II) into intraperitoneal tumors have been studied. The platinum concentration in intraperitoneal tumor nodules, measured by two techniques, flameless atomic absorption spectroscopy and proton-induced X-ray emission, was always higher after i.p. treatment than i.v. Further, platinum concentrations were higher at the periphery of the tumor after i.p. administration than after i.v., while platinum concentrations in the center of the tumor nodules were identical. No difference was detected in platinum concentrations in s.c. tumors nor in the total area under the curve (plasma) after i.p. and i.v. administration of cis-diamminedichloroplatinum(II), suggesting that the higher drug concentration measured in peritoneal tumors after i.p. administration is due to direct diffusion of the drug from the peritoneal cavity.

Cisplatin-induced changes of selenium levels and glutathione peroxidase activities in blood of testis tumor patients.

Haematocrit and glutathione peroxidase activity in blood, as well as selenium levels in blood, erythrocytes and plasma, were determined in 15 patients during four courses of cisplatin combination treatment for testicular teratoma. The haematocrit steadily declined, necessitating frequent blood transfusions during or after treatment. For patients without blood transfusions during treatment the reduction of the haematocrit averaged 40%. Glutathione peroxidase activity in blood declined also; for patients without blood transfusion the reduction was 30%, which is fully explained by the decrease of the haematocrit. The enzyme activity per volume of erythrocytes remained constant during the treatment. Erythrocyte selenium level did not change significantly, but plasma selenium levels of all patients dropped within each course of chemotherapy, and progressively with each subsequent course. Between cycles the levels were largely restored to almost normal values. These results may be explained by a decreasing availability of selenium in the body to maintain the normal plasma level, due to increased retention of cisplatin in tissues and subsequent alteration of selenium metabolism.