Synthesis and activity of a trinuclear platinum complex: [{trans-PtCl(NH3)2}2mu-{trans-Pt(3-hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in ovarian cancer cell lines.
This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 plasmid DNA have been determined. TH1 is found to be significantly more cytotoxic than cisplatin - two times more active than cisplatin against the parent cell line A2780, thirteen times more active against the cisplatin-resistant cell line A2780(cisR) and 11.5 times more active against the cell line A2780(ZD0473R). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH1 are 1.98 and 0.5. The results suggest that TH1 has been able to significantly overcome resistance in A2780(cisR) and A2780(ZD0473R) cell lines. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH1 should bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin.
Tayyem
Hasan
H
Discipline of Biomedical Sciences, Cumberland Campus, C42, The University of Sydney, East Street, PO Box 170, Lidcombe, NSW, Australia.
Huq
Fazlul
F
Yu
Jun Qing
JQ
Beale
Philip
P
Fisher
Keith
K
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010957:Plasmids / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin