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Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator

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Summary

Platinum(II) metallointercalators represent a new class of DNA-damaging antitumor complexes active in cisplatin- and oxaliplatin-resistant cell lines. In the first part of our work, we have screened in vitro a serie of 18 metallointercalators with the structure [Pt(AL)(IL)]2+ where AL = ethylenediamine (EN) or diaminocyclohexane in R,R- (RR) or S,S- (SS) configuration ; and IL = 1,10-phenanthroline with different degree of methylation : no methylation (PHEN), mono-methylated in position 4 (4ME) or 5 (5ME), or di-methylated in positions 4 and 7 (47ME) or in positions 5 and 6 (56ME) or tetramethylated in positions 3,4,7 and 8 (3478ME). Eight compounds: PHENEN, 56MEEN, 47MERR, 56MERR, 4MESS, 5MESS, 47MESS and 56MESS exhibited significant cytotoxic effect, equivalent or higher than cisplatin, oxaliplatin or carboplatin in the human HCT8 colon and IGROV1 ovarian cancer cell lines for both 1 and 24 h incubation time. The high cytotoxicity of the most active compound, the 56MESS, could be related to the hydrophobicity of the phenanthroline ligand that increases cellular uptake in human HCT8, HT29 (colon) and IGROV1 (ovarian) as well as in rat PROb colon cell lines. Unfortunately, intravenous or intraperitoneal administration of 56MESS had no antitumoral activity in BD-IX rats with peritoneal carcinomatosis induced by an intraperitoneal PROb cells inoculation. Moreover, 56MESS displayed nephrotoxicity at pharmacological dose. Thus, these data query the in vivo/in vitro correlation and reconsider the place of the in vivo screening to select adequate candidate drug for further preclinical and clinical developments.

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Acknowledgments

This work was supported by the Nievre committees of the French National League against cancer. The authors thank Dr Laurence Duvillard and Dr François Girodon for the biological analyses, Annie Fromentin and Amandine Bataille for their technical assistance as well as Jean-Luc Beltramo for platinum measurements. This collaborative project was supported by the University of Western Sydney’s International Science Linkage and Research grants.

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Authors and Affiliations

  1. Faculties of Medicine and Pharmacy, INSERM, UMR 866, University of Burgundy, 7 Bd Jeanne d’Arc, BP 87900, 21079, Dijon Cedex, France

    Johnny Moretto, Bruno Chauffert, François Ghiringhelli & Florence Bouyer

  2. Department of Haematology, Dijon University Hospital, 2 Bd Maréchal de Lattre de Tassigny, 21000, Dijon, France

    Johnny Moretto

  3. School of Biomedical and Health Sciences, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW, 1797, Australia

    Janice R. Aldrich-Wright

  4. GF Leclerc Regional Anticancer Centre, 1 rue Pr Marion, BP 77980, 21079, Dijon Cedex, France

    Bruno Chauffert & François Ghiringhelli

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  1. Johnny Moretto
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Correspondence to Florence Bouyer.

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Moretto, J., Chauffert, B., Ghiringhelli, F. et al. Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator. Invest New Drugs 29, 1164–1176 (2011). https://doi.org/10.1007/s10637-010-9461-z

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