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Investigational New Drugs

, Volume 22, Issue 1, pp 3–16 | Cite as

Inhibition of Cell Growth, Induction of Apoptosis and Mechanism of Action of the Novel Platinum Compound cis-Diaminechloro-[2-(Diethylamino) Ethyl 4-Amino-Benzoate, N4]-Chloride Platinum (II) Monohydrochloride Monohydrate

  • Maria A. Mariggiò
  • Sergio Cafaggi
  • Massimo Ottone
  • Brunella Parodi
  • Maria O. Vannozzi
  • Vaclav Mandys
  • Maurizio Viale
Article

Abstract

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4′-6-diamidine-2′-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique.

When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue.

Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.

DPR growth inhibition apoptosis cell lines mechanism of action 

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Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Maria A. Mariggiò
    • 1
  • Sergio Cafaggi
    • 2
  • Massimo Ottone
    • 3
  • Brunella Parodi
    • 2
  • Maria O. Vannozzi
    • 3
  • Vaclav Mandys
    • 4
  • Maurizio Viale
    • 3
  1. 1.Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Patologia Generale e Oncologia SperimentaleUniversità di BariItaly
  2. 2.Dipartimento di Chimica e Tecnologie Farmaceutiche e AlimentariUniversità di GenovaItaly
  3. 3.Lab. di Farmacologia TossicologicaIstituto Nazionale per la Ricerca sul CancroGenovaItaly
  4. 4.Department of Pathology, Third Faculty of MedicineCharles University in PragueCzech Republic

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