Replacement of an NH(3) by an iminoether in transplatin makes an antitumor drug from an inactive compound.
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.
Leng
M
M
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France.
Locker
D
D
Giraud-Panis
M J
MJ
Schwartz
A
A
Intini
F P
FP
Natile
G
G
Pisano
C
C
Boccarelli
A
A
Giordano
D
D
Coluccia
M
M
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
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