Studies on the mechanism of sulofenur and LY295501 toxicity: effect on the regulation of cytosolic calcium in relation to cytotoxicity in normal and tumorigenic rat kidney cell lines.
Treatment of NRK-52E (normal) and H/1.2-NRK-52E (Harvey-ras transfected NRK-52E) rat kidney epithelial-like cells with two Eli Lilly antitumor compounds, sulofenur and LY295501 (15.6 microM-1000 microM) resulted in concentration- and time-dependent cell killing. Cytosolic Ca2+ became elevated in both cell lines in the presence of extracellular Ca2+ but only minimally in its absence. Both drugs were more toxic to the tumorigenic cells than to the normal cells, but LY295501 was significantly more toxic to both cells. The similarity in toxic response by both cell lines suggests a similar mechanism of toxic action for both drugs. Since LY295501 is highly toxic to tumorigenic cells but has a manageable dose-limiting toxicity it shows excellent potential for use in chemotherapy.
Phelps
P C
PC
Department of Pathology, University of Maryland School of Medicine, Baltimore 21201, USA.
Best
C J
CJ
Berezesky
I K
IK
Merriman
R L
RL
Tanzer
L R
LR
Boder
G B
GB
Trump
B F
BF
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001572:Benzofurans / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009374:Neoplasms, Experimental / Q000503:physiopathology; D010671:Phenylurea Compounds / Q000633:toxicity*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001572:Benzofurans; D010671:Phenylurea Compounds; D013453:Sulfonylurea Compounds; C094382:N-(5-(2,3-dihydrobenzofuryl)sulfonyl)-N'-(3,4-dichlorophenyl)urea; D002118:Calcium; C058179:sulofenur