Antitumor properties of some 2-[(dimethylamino)methyl]phenylgold(III) complexes.
Four analogues of the gold(III) complex [AuCl2(damp)] (1) (damp = 2-[(dimethylamino)methyl]phenyl) have been evaluated for antitumor activity. The compounds have structural features in common with cisplatin which was included as a comparison in the study. In vitro, against a panel of cell lines established from tumors of different tissue types, the gold complexes showed broadly similar growth inhibitory properties with some selectivity to the HT1376 bladder cell line. In a panel of human ovarian carcinoma cell lines, non-cross-resistance to cisplatin was observed, for the complexes, in an acquired cisplatin-resistant line. In vivo, using subcutaneously implanted xenografts derived from the HT1376 bladder and CH1 ovarian cell lines, [Au(acetato)2(damp)] (3) and [Au(malonato)(damp)] (5) (administered intraperitoneally) gave significant tumor inhibition. Mechanistic studies performed with compound 3 showed marked differences to cisplatin. Thus, much higher concentrations of the gold compound were required to affect Col E1 plasmid mobility, and an alkaline elution study showed that 3 did not cause interstrand DNA cross-links in SK-OV-3 cells. Exposure of SK-OV-3 cells to 3 induced only relatively minor changes in cell cycle distribution. Furthermore 3 was only marginally active in vivo against the cisplatin-sensitive murine ADJ/PC6 plasmacytoma. In summary, the gold-(III) complexes 3 and 5 exhibited selective cytotoxicity in vitro and showed in vivo antitumor activity against human carcinoma xenografts. Also, although 3 has some structural similarity to cisplatin, its mode of action appears to be different.
Buckley
R G
RG
Biomedical Department, Johnson Matthey Technology Centre, Sonning Common, Reading, Berkshire, United Kingdom.
Elsome
A M
AM
Fricker
S P
SP
Henderson
G R
GR
Theobald
B R
BR
Parish
R V
RV
Howe
B P
BP
Kelland
L R
LR
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001596:Benzylamines; D050607:Organogold Compounds; D009942:Organometallic Compounds; C103092:2-((dimethylamino)methyl)phenylgold(III) dichloride