Cellular pharmacology of mu-[1,2-bis(diphenylphosphino)ethane]bis[(1-thio-beta-D-gluco pyranosato-S)gold(I)]: a novel antitumor agent.
SK&F 102912 (mu-[1,2-bis(diphenylphosphino)ethane]bis[(1-thio-beta-D- glucopyranosato-S)gold(I)], [(Autg)2(dppe)]) has shown reproducible and significant activity in transplantable murine tumor models and represents a structurally unique class of antineoplastic agents. A number of in vitro studies were performed to elucidate the cellular pharmacology of this gold-containing complex. [(Autg)2(dppe)] is a potent cytotoxic agent in vitro as demonstrated by its ability to inhibit the clonogenic capacity of a variety of tumor cell lines following a brief exposure to the drug. Cell-cycle analysis using HL-60 cells showed that low concentrations (2 microM) of [(Autg)2(dppe)] induced an S-phase block and higher concentrations induced a secondary block at the G1/S boundary. [(Autg)2(dppe)] had several effects on DNA metabolism and structure including preferential inhibition in cells of DNA synthesis (relative to RNA and protein synthesis) and the production of DNA single- and double-strand breaks as measured by alkaline elution. The cytoxic mechanism of this gold complex appears to be distinct from that of the monophosphine-gold complex auranofin.
Mirabelli
C K
CK
Smith Kline and French Laboratories, Philadelphia, PA 19101.
Jensen
B D
BD
Mattern
M R
MR
Sung
C M
CM
Mong
S M
SM
Hill
D T
DT
Dean
S W
SW
Schein
P S
PS
Johnson
R K
RK
Crooke
S T
ST
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D009942:Organometallic Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002843:Chromatin; D009942:Organometallic Compounds; C056161:SK&F 102912; D001310:Auranofin; D004247:DNA