Temporal effects of the novel antitumour pyridyl cyanoguanidine (CHS 828) on human lymphoma cells.
CHS 828, a novel pyridyl cyanoguanidine, has shown potent antitumour activity both in vitro and in vivo and is currently undergoing phase I evaluation in humans in collaboration with the European Organization for Research and Treatment of Cancer (EORTC). Here we study the temporal effects of CHS 828 on cytotoxicity, protein and DNA synthesis, cellular morphology and ultra structure using the lymphoma cell line U-937 GTB as the primary tumour model. In vitro analysis of tumour cell survival in response to CHS 828 revealed a cytotoxic effect progressively increased as a function of exposure time with maximum efficacy observed after 72 h. Activity of CHS 828 on U-937 GTB cells grown in vivo was also found. CHS 828 induced-cell death was dependent on intact protein synthesis and most cells appeared to lose their membrane integrity in the presence of a relatively well preserved nuclear structure. The results indicate that CHS 828 induced active and delayed cell death with a non-apoptotic morphology.
Martinsson
P
P
Division of Clinical Pharmacology, University Hospital, Uppsala University, S-751 85, Uppsala, Sweden. petra.martinsson@medsci.uu.se
Liminga
G
G
Dhar
S
S
de la Torre
M
M
Lukinius
A
A
Jonsson
E
E
Bashir Hassan
S
S
Binderup
L
L
Kristensen
J
J
Larsson
R
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016923:Cell Death; D002470:Cell Survival; D003486:Cyanides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000648:ultrastructure; D008854:Microscopy, Electron; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine