didimethylsulfoxide-dichloroplatinum(ii) and Kidney-Diseases

The systemic toxicity and efficacy of cisplatin (CDDP) were examined in vitro and in vivo. Procedures were performed before and after the antineoplastic agent was encapsulated into multilamellar liposomes (L-CDDP). In vitro cytotoxicity evaluation in L1210 murine leukaemia and NIH OVCAR human ovarian cancer cells showed IC50 values of 0.14 and 0.05 micrograms/ml with CDDP or L-CDDP, respectively. In vivo, mice injected intravenously with L-CDDP had plasma levels of platinum 4-fold higher than with CDDP. The t1/2 alpha was 2 h and the t1/2 beta exceeded 48 h with L-CDDP; whereas a t1/2 alpha of 15 min and t1/2 beta of 12 h was observed with CDDP. The values of platinum in liver, spleen, kidneys, lungs and heart were substantially higher in L-CDDP-treated compared to CDDP-treated mice. Cytotoxic evaluation of both agents was tested in vitro (murine L1210 leukaemia and NIH OVCAR cell line) and in vivo (male CD2F1 mice). CDDP and L-CDDP showed similar cytotoxicity in tissue culture. At the highest dose given, 12 mg/kg intraperitoneally (i.p.), L-CDDP showed higher antitumour efficacy demonstrated by an increased life span of the mice. The CDDP treatment at the highest dose was lethal to all the tumour bearing mice. The nephrotoxicity in rats (blood urea nitrogen and creatinine evaluation) of L-CDDP administered i.p. was significantly less than with CDDP. In addition, the ability of kidney slices to transport organic anions [para-aminohippurate (PAH)] and consume O2 was substantially decreased in rats treated with free CDDP compared to L-CDDP. Accordingly, the liposomal encapsulation of CDDP attenuates its nephrotoxicity, but allows maintenance of antitumour efficacy and may be a potentially effective modality in clinical settings.

Topics: Animals; Cell Survival; Drug Carriers; Female; Kidney Diseases; Leukemia L1210; Liposomes; Male; Mice; Mice, Inbred Strains; Organoplatinum Compounds; Ovarian Neoplasms; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tumor Cells, Cultured

The renal function in 26 patients with malignant tumors (19 non-small cell lung cancers, 4 small cell lung cancers, 1 malignant lymphoma, 1 esophageal cancer, 1 malignant thymoma) who were treated with 43 times combination chemotherapy including CDDP was evaluated prospectively, by measuring of creatinine clearance (Ccr), fractional excretion of beta-2-microglobulin (FE beta 2MG), urinary N-acetyl-beta-glucosaminidase (NAG), and 131I-OIH or 123I-OIH renogram. The comparison of renogram and other parameters showed significant change in renogram (23/43, 53.5%), however other parameters such as Ccr, FE beta 2MG, NAG altered in only 10.3-34.9%. After the administration of CDDP, renograms were divided into distinctive 4 patterns as follows: 1) aggravation of obstructive pattern 2) early plateau pattern in excretory phase 3) intermittent pattern in excretory phase 4) prolongation of secretory phase. We consider these patterns suggest some obstructive change of urinary tract microscopically, that is proximal tubules damage due to cellular necrosis and tubular dilatation by CDDP. 131I-OIH or 123I-OIH renogram in delayed phase is useful for detection of renal dysfunction by CDDP administration.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Iodohippuric Acid; Kidney; Kidney Diseases; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Radioisotope Renography

Renal toxicity is the major side effect of cis-dichlorodiammine platinum (CDDP) and it develops renal tubular damage. In the present study, the acute changes of urinary beta-glucuronidase (beta-GL) and alkaline phosphatase (ALP) activities following CDDP administration as indicators of its toxicity were studied in 5 patients with urological malignant tumors. The activities were measured for 11 days continuously from the day before CDDP administration. In all cases, both urinary enzyme activities increased with CDDP administration. Increase patterns of urinary beta-GL activities were similar to those of urinary NAG, but remarkably-high values of beta-GL activities were found in cases of urothelial tumors probably because urinary beta-GL derives from the kidney (lysosomes of tubular cells) and from the epithelial cells of urinary tract. Urinary ALP activities changed corresponding well with urinary gamma-glutamyl transpeptidase (gamma-GTP). This study shows that the determination of urinary beta-GL is not a significant marker of CDDP renal toxicity, especially in cases with urological malignancies, in contrast to results for urinary brush border enzyme activities such as ALP or gamma-GTP.

Topics: Aged; Alkaline Phosphatase; Female; Glucuronidase; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Organoplatinum Compounds; Reference Values