title: Toxicodynamic evaluation of a cisplatin-chondroitin sulfate complex using a perfused kidney and human proximal tubular cells.
abstract: Cisplatin (CDDP) is an anticancer drug. The clinical limitations associated with CDDP have stimulated the development of macromolecular drug-carrier systems, in attempts to decrease its toxicity. A complex (CDDP-CSA-23) between CDDP and chondroitin sulfate (CSA), a natural polysaccharide with a mean molecular weight of 23 kDa, proved to have the same anticancer activity as CDDP. A toxicodynamic study was performed on perfused kidneys to determine the effect of CDDP-CSA-23 on renal functions and the extent of platinum accumulation. The results showed that CDDP-CSA-23 attenuates the reduction in urine flow and creatinine clearance induced by CDDP. Moreover, significantly lower amounts of platinum were excreted into the urine in the case of CDDP-CSA-23, compared with CDDP alone. Meanwhile, CDDP-CSA-23 effectively retarded the rapid perfusion of platinum into kidney tissues, as occurs when CDDP is being perfused alone. The cytoprotective effects of CDDP-CSA on human proximal tubular (HK-2) cells were examined by measuring the growth of HK-2 cells in the presence of CDDP or CDDP-CSA-23. Interestingly, CDDP-CSA-23 was found to have a significantly reduced cytotoxicity, compared to CDDP. These results suggest that CDDP-CSA-23 greatly decreased the negative effects of CDDP on glomerular filtration and tubular transport in kidneys at early stages of its administration.
authors.affiliation: Department of Biopharmaceutics, Kumamoto University, Kumamoto, Japan.
authors.forename: Jing-Shi
authors.initials: JS
authors.lastname: Zhang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nonoguchi
authors.forename: Sumio
authors.initials: S
authors.lastname: Hirata
authors.forename: Hakaru
authors.initials: H
authors.lastname: Seo
authors.forename: Teruko
authors.initials: T
authors.lastname: Imai
authors.forename: Ayaka
authors.initials: A
authors.lastname: Suenaga
authors.forename: Victor Tuan
authors.initials: VT
authors.lastname: Giam Chuang
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004338:Drug Combinations; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010477:Perfusion / Q000379:methods*; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D002809:Chondroitin Sulfates; D003404:Creatinine; D002945:Cisplatin