Cytotoxic effect in vivo and in vitro of CHS 828 on human myeloma cell lines.
CHS 828 is a pyridyl cyanoguanidine with promising antitumor activity both in vitro and in vivo, and has previously been found especially active against tumor cells obtained from patients with B cell chronic lymphocytic leukemia. In the present study the cytotoxic effect in vitro of CHS 828 was investigated on a panel of 10 human myeloma cell lines using the fluorometric microculture cytotoxicity assay. CHS 828 induced a concentration-dependent, but variable decrease in tumor cell survival in the cell line panel with inhibitory concentrations 50% (IC50) in the range 0.01-0.3 microM. These concentrations are below those achievable in vivo. There was no detectable dependence on P-glycoprotein-mediated or GSH-associated drug resistance and the drug showed low to moderate cross-resistance with standard drugs, including melphalan, vincristine and doxorubicin. Furthermore, sensitivity to CHS 828 showed no apparent relationship to growth factor dependence, tumor progression or phenotypic variability. CHS 828 was also tested in vivo using a hollow fiber model in rats with three of the cell lines. The results indicate a high cytotoxic activity of CHS 828. Overall, the results show a high cytotoxic activity of CHS 828 in the myeloma models, which might warrant its further development against myeloma.
Hovstadius
Peter
P
Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden. peter.hovstadius@medsci.uu.se
Lindhagen
Elin
E
Hassan
Sadia
S
Nilsson
Kenneth
K
Jernberg-Wiklund
Helena
H
Nygren
Peter
P
Binderup
Lise
L
Larsson
Rolf
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003486:Cyanides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005470:Fluorometry / Q000379:methods; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine