Replacement of an NH3 by an Iminoether in Transplatin Makes an Antitumor Drug from an Inactive Compound
- Marc Leng†,1,
- Daniel Locker1,
- Marie-Josèphe Giraud-Panis1,
- Annie Schwartz1,
- Francesco P. Intini2,
- Giovanni Natile2,
- Claudio Pisano3,
- Angelina Boccarelli4,
- Domenico Giordano4 and
- Mauro Coluccia4
- 1Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France (M.L., D.L., M.G.P., A.S.); 2Department of Pharmaceutical Chemistry, Bari, Italy (F.P.I., G.N.); 3Department of Oncology, Sigma-tau, Pomezia, Italy (C.P.); and4Department of Biomedical Sciences and Human Oncology, Bari, Italy (A.B., D.G., M.C.)
Abstract
To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH3 by an iminoether group,trans-[PtCl2{Z-HN=C(OMe)Me}(NH3)] andtrans-[PtCl2{E-HN=C(OMe)Me}(NH3)] complexes (differing in the Z or Econfiguration 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 IC50 values being 103, 37, and 215 μM, 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 mixedZ 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 mixedZ 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.
Footnotes
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Send reprint requests to: Mauro Coluccia, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mailmauro.coluccia{at}dimo.uniba.it
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↵† Marc Leng worked to the last of his days on this paper, giving the most important contribution to its realization. Unfortunately, Marc died of cancer in May 2000, but neither our long collaboration nor our friendship are interrupted, because we will always remember the joy of staying together.
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This work was supported in part by grants from Ligue Contre le Cancer Loiret, Agence Nationale pour la Recherche sur le Sida, Association pour la Recherche sur le Cancer, and European Union Cost D8/0007/97 and BMH4-CT97-2485 contracts.
- Abbreviations:
- cisplatin and transplatin
- cis- and trans-diamminedichloroplatinum(II)
- mixed E and mixed Z
- trans-dichloro(ammine)(E-iminoether)platinum(II) andtrans-dichloro(ammine)(Z-iminoether)platinum(II)
- ICL
- interstrand cross-link
- bp
- base pairs
- ri
- input molar ratio of drug over nucleotide residues
- dsDNA
- double-stranded DNA
- HMG1
- high mobility group 1
- %T/C
- mean survival time (%) of treated animals versus controls
- %TWI
- percentage of tumor weight inhibition of treated mice versus controls
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
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- Received June 26, 2000.
- Accepted September 6, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
