title: Synthesis and antitumour activity of a new trinuclear platinum compound [{cis-PtCl(NH3)2μ {trans-Pt(3-hydroxypyridine)2H2N(CH2)5NH2)2}] Cl4 in human ovarian cancer cells.
abstract: A trinuclear platinum compound with a cis-geometry for the terminal metal centers coded as QH5 has been synthesized and investigated for activity against the human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cancer cell lines. Cellular accumulation of platinum, level of platinum-DNA binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH5 is found to be more active than cisplatin against all the three cell lines and to have much lower resistant factors than cisplatin. The compound is 2.5-times more active than cisplatin against the A2780(cisR) cell line and 11.5-times more active than cisplatin against A2780(ZD0473R) cell line. When the activity of QH5 in A2780 cell line is compared with its activity in the A2780(ZD0473R) cell line, it is found to be 2.4-times more active against the resistant A2780(ZD0473R) cancer cell line than the parent A2780 cell line, thus indicating that it has been able to overcome mechanisms of resistance operating in the A2780(ZD0473R) cell lines. The higher activity of QH5 as compared to cisplatin is found to be associated with higher platinum accumulation at all time points and high level of platinum-DNA binding at 24 h in all the three human ovarian cancer cell lines. Provided QH5 has the right toxicity profile and its in vitro activity is complemented with sufficient activity in vivo, the compound may have the potential for development as a novel platinum-based anticancer drug targeted to ovarian cancer.
authors.affiliation: Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, The University of Sydney, Cumberland Campus C42, 75 East Street, Lidcombe, NSW 1825, Australia. fazlul.huq@sydney.edu.au.
authors.forename: Shahnaz A
authors.initials: SA
authors.lastname: Hamad
authors.forename: Philip
authors.initials: P
authors.lastname: Beale
authors.forename: Jun Qing
authors.initials: JQ
authors.lastname: Yu
authors.forename: Fazlul
authors.initials: F
authors.lastname: Huq
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010051:Ovarian Neoplasms; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004247:DNA
keywords: A2780; BamH1 digestion; Ovarian cancer; cisplatin; drug resistance; interstrand adducts; pBR322 plasmid DNA