Synthesis of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) and its activity in human ovarian tumour models.
We report the synthesis and in vitro activity of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) (coded as DH3) in humour ovarian tumour models. The compound is less active than cisplatin against the parent cell line A2780 but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line. DH3 is marginally less active than cisplatin against ZD0473-resistant A2780(ZD0473R) cell line but with a much lower resistance factor than cisplatin. DH3 has higher platinum-DNA binding levels than cisplatin in the A2780 and A2780(ZD0473) cell lines and a lower value in the A2780(cisR) cell line. Even though DH3 has a lower activity than cisplatin, the higher platinum-DNA binding levels observed for DH3 than cisplatin in A2780 and A2780(ZD0473R) cell lines may not be entirely unexpected when we note that the two compounds are likely to differ in their nature of binding with DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH3 is expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The higher activity of DH3 than cisplatin in the A2780(cisR) cell line despite its lower level of platinum-DNA binding can also be seen to indicate the complexity of the situation. Although platinum-DNA binding may be an essential requirement for apoptosis, it is not sufficient to cause cell death that is actually brought about by downstream processes in the cycle. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH3 is less able to prevent BamH1 digestion than is cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than DH3.


CONCLUSIONS
DH3 is less active than cisplatin against the parent cell line A2780, but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line.
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.
Narjes
N
Deqnah
Jun Qing
JQ
Yu
Philip
P
Beale
Keith
K
Fisher
Fazlul
F
Huq
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010984:Platinum / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D011725:Pyridines; C570238:bis(2-hydroxypyridine)dichloroplatinum(II); D010984:Platinum; D002945:Cisplatin