title: Human primary renal cells as a model for toxicity assessment of chemo-therapeutic drugs.
abstract: Chemo-therapeutic drugs act on cancerous and normal cells non-selectively and often cause organ impairments during treatment. Improving safety or reducing toxicity becomes an important challenge for developing better anticancer drugs. In the present study, effects of selected anticancer drugs (camptothecin, doxorubicin, colchicine, paclitaxel, cisplatin, and carboplatin) on cell viability and proliferation was investigated. The anti-proliferative activity of each drug on cancer cells (human hepatoma HepG2) and human primary renal proximal tubule cells (hRPTECs and LLC-PK1) was determined with the [(3)H]thymidine incorporation assay. Results indicated all six drugs blocked cell proliferation in cancer and normal cells. When the anti-proliferation potency was ranked in hRPTECs based on EC50 values, camptothecin is the most potent, followed by doxorubicin, paclitaxel, colchicine, cisplatin and carboplatin. Cytotoxicity of drugs to hRPTECs was assessed with the ATP bioluminescence assay. Doxorubicin and cisplatin were known to induce nephrotoxicity in vivo and they were indeed cytotoxic to hRPTECs in our study with EC50 values at 11.2 and 39.6 microM. All other drugs are not cytotoxic in the concentrations tested. These drugs typically displayed separation of EC50s between potency (anti-proliferation) and cytotoxicity. The dose separation provides a concentration range for each drug to act on cell proliferation without induction of significant cytotoxicity. Our results suggest that hRPTEC system can serve as an in vitro model for assessing potential nephrotoxicity of chemo-therapeutic drugs.
authors.affiliation: Department of Pharmacology, Berlex Biosciences, Richmond, CA 94804, USA. wei-wei_li@berlex.com
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Marilyn
authors.initials: M
authors.lastname: Lam
authors.forename: David
authors.initials: D
authors.lastname: Choy
authors.forename: Andrew
authors.initials: A
authors.lastname: Birkeland
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Post
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents