title: Platinum coordination complexes which circumvent cisplatin resistance.
abstract: In the search for a platinum complex capable of oral administration, the poor bioavailability of established drugs has been circumvented by the discovery of a novel class of platinum (IV) ammine/amine dicarboxylate dichlorides. These compounds, when administered orally to mice carrying the ADJ/PC6 plasmacytoma, exhibit antitumor selectivities far superior to those of cisplatin or carboplatin (given intraperitoneally). Oral activity comparable to that of intraperitoneal cisplatin and carboplatin has also been demonstrated in a panel of human ovarian tumor xenografts. Platinum (IV) ammine/amine dicarboxylates retain cytotoxicity in cultures of L1210/cisplatin and L1210/tetraplatin acquired resistant cells. This property does not translate into a cisplatin-resistant variant of the ADJ/PC6 tumor, in the example of JM221. This result reflects experience with tetraplatin, a drug currently in phase I study, which is comparably ineffective against an ADJ/PC6/cisplatin variant. It is a moot point whether either L1210 or ADJ/PC6/cisplatin-resistant variants are clinically predictive screening models, since this issue must be determined ultimately by clinical study. We have attempted to resolve this dichotomy through the establishment of human ovarian carcinoma lines, both in vitro and in vivo, where there is evidence that response to platinum coordination complexes in the several models reflects that of the donor patient's tumor to platinum-based clinical therapy. The data herein for platinum (IV) ammine/amine dicarboxylates in these models gives encouragement to the notion that these novel compounds may be of value as oral therapeutic agents, whilst also providing an important lead to the discovery and development of a new generation of platinum drugs possessing broad clinical utility.
authors.affiliation: Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
authors.forename: K R
authors.initials: KR
authors.lastname: Harrap
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.forename: P M
authors.initials: PM
authors.lastname: Goddard
authors.forename: R M
authors.initials: RM
authors.lastname: Orr
authors.forename: S E
authors.initials: SE
authors.lastname: Morgan
authors.forename: B A
authors.initials: BA
authors.lastname: Murrer
authors.forename: M J
authors.initials: MJ
authors.lastname: Abrams
authors.forename: C M
authors.initials: CM
authors.lastname: Giandomenico
authors.forename: T
authors.initials: T
authors.lastname: Cobbleigh
mesh_terms: D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010954:Plasmacytoma / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D002945:Cisplatin