Activity and DNA binding of new organoamidoplatinum (II) complexes.
Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)2L2 and Class 2, Pt(NRCH2CH2NR2')L(X)] and their antitumour activity examined by a range of in vitro, cellular and animal studies. All Class 1 compounds exhibited activity comparable to cisplatin in mouse leukemia L1210 cells, but were at least 8-fold more active against the cisplatin-resistant L1210/R line. The lead compound 1a (R=p-HC6F4) caused nearly complete tumour regression in the ADJ/PC6 mouse tumour model. Compound 1a exhibited similar DNA reactivity to cisplatin, resulting in virtually identical DNA sequence specificity as cisplatin, and had similar time and concentration dependency of interstrand crosslinks. Compared with cisplatin, la showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans amine ligands, and further study of both classes of compounds is warranted.
Talarico
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Pharmacology and Developmental Therapeutics Unit, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.
Phillips
D R
DR
Deacon
G B
GB
Rainone
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S
Webster
L K
LK
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001345:Autoradiography; D001665:Binding Sites; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism; D003432:Cross-Linking Reagents; D018736:DNA Adducts / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015507:Drugs, Investigational / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D015507:Drugs, Investigational; C057270:cisplatin-DNA adduct; D002945:Cisplatin