Synthesis and in vitro and in vivo antitumor activity of a series of trans platinum antitumor complexes.
The synthesis of a series of platinum complexes of trans coordination geometry [centered around the general formula, trans-ammine(amine)dichlorodihydroxoplatinum(IV) plus corresponding tetrachloroplatinum(IV) or Pt(II) counterparts] is described as part of a drug discovery program to identify more effective platinum-based anticancer drugs, particularly targeted toward the circumvention of resistance to cisplatin. Complexes have been evaluated for antitumor activity using in vitro and in vivo tumor models. In vitro against a panel of cisplatin-sensitive and -resistant human tumor cell lines (predominantly ovarian), many of the trans platinum complexes studied (e.g., 1, R = cyclohexyl) exhibited comparable potency to cisplatin and also overcame acquired cisplatin resistance, where resistance was due mainly to either reduced drug uptake or enhanced platinum-DNA adduct removal. Moreover, 14 trans complexes showed significant in vivo antitumor activity against the subcutaneous murine ADJ/PC6 plasmacytoma model; all were platinum(IV) complexes, 13/14 possessing axial hydroxo ligands the other possessing axial ethylcarbamato ligands. Where tested, all of their respective platinum(II) or tetrachloroplatinum(IV) counterparts were inactive. Notably, three dihydroxoPt(IV) complexes (18, 29, 34) (R = c-hexyl, c-heptyl, and 1-adamantyl) retained some efficacy against a cisplatin-resistant variant of the ADJ/PC6. Compounds 18 (trans-[PtCl2(OH)2NH3-(RNH2)]) R = c-C6H11, 22, R = Me3C, 27, R = n-C6H13, 28, R = PhCH2, and 36 (trans-[PtBr2(OH)2NH3(c-C6H11NH2)]) also produced evidence of antitumor activity (> 5 days growth delay) against subcutaneously grown advanced stage human ovarian carcinoma xenografts. These data demonstrate that a series of trans-ammine(amine)dichlorodihydroxoplatinum(IV) complexes are active in vivo against both murine and human subcutaneous tumor models and represent potential leads to a new generation of platinum-based anticancer drug.
Kelland
L R
LR
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, Surrey, United Kingdom.
Barnard
C F
CF
Evans
I G
IG
Murrer
B A
BA
Theobald
B R
BR
Wyer
S B
SB
Goddard
P M
PM
Jones
M
M
Valenti
M
M
Bryant
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010954:Plasmacytoma / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C089656:JM 335; D009944:Organoplatinum Compounds; D002945:Cisplatin