title: Replacement of an NH(3) by an iminoether in transplatin makes an antitumor drug from an inactive compound.
abstract: To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH(3) by an iminoether group, trans-[PtCl(2)(Z-HN=C(OMe)Me)(NH(3)] and trans-[PtCl(2)(E-HN=C(OMe)Me)(NH(3)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC(50) values being 103, 37, and 215 microM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.
authors.affiliation: Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France.
authors.forename: M
authors.initials: M
authors.lastname: Leng
authors.forename: D
authors.initials: D
authors.lastname: Locker
authors.forename: M J
authors.initials: MJ
authors.lastname: Giraud-Panis
authors.forename: A
authors.initials: A
authors.lastname: Schwartz
authors.forename: F P
authors.initials: FP
authors.lastname: Intini
authors.forename: G
authors.initials: G
authors.lastname: Natile
authors.forename: C
authors.initials: C
authors.lastname: Pisano
authors.forename: A
authors.initials: A
authors.lastname: Boccarelli
authors.forename: D
authors.initials: D
authors.lastname: Giordano
authors.forename: M
authors.initials: M
authors.lastname: Coluccia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects; D018983:DNA Footprinting; D004262:DNA Restriction Enzymes / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000378:metabolism; D051381:Rats; D013890:Thiourea / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D006609:High Mobility Group Proteins; D009841:Oligonucleotides; C034697:transplatin; D004247:DNA; D012321:DNA-Directed RNA Polymerases; D004262:DNA Restriction Enzymes; D013890:Thiourea; D002945:Cisplatin