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Preclinical evaluation of the novel 7-substituted camptothecin Namitecan (ST1968) in paediatric tumour models

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Abstract

Purpose

The present study aimed to evaluate the new water soluble camptothecin analogue Namitecan (ST1968) in preclinical paediatric tumour models of the nervous system comprehensive of neuroblastoma, primitive neuroectodermal tumours/PNET and medulloblastoma where the drug was compared to Irinotecan.

Methods

Cellular sensitivity to the drug was assessed by MTT and clonogenic assays. Propidium iodide staining was used for cell cycle perturbation studies. The genotoxic effects were quantified by Comet assay, whereas apoptosis was assessed by PARP cleavage and sub-G1 accumulation. Tumour response was investigated in xenograft models in nude mice.

Results

The cellular response to Namitecan was heterogeneous with IC50 (2 h) ranging between 0.14 and 13.26 μM, whereas SN38 (the active metabolite of Irinotecan) appeared more effective (IC50: 0.03–11.7 μM). Interestingly, prolonged drug incubation times up to 72 h enhanced Namitecan cytotoxicity, with similar colony inhibition curves between the two analogues (IC50, nM-SN38: 0.9 ± 0.2; Namitecan: 0.7 ± 0.4). DNA damage, accumulation in late-S/G2 phases and induction of apoptosis appeared important players of Namitecan cytotoxicity in our models. In vivo, Namitecan was superior to Irinotecan in three out of five xenograft models, with reversible weight loss (10 %). In the sensitive SK-N-AS xenograft, Namitecan showed a high retention in tumours consistently with: high antitumour response, rapid drug-mediated DNA damage (60 % mean TailDNA after 1 h from drug inoculation), persistent cell cycle perturbation (60–40 % G2 accumulation after 48–72 h, respectively) and apoptosis. Studies with Namitecan and platinum agents in this model showed a significant enhancement of antitumour activity of the drugs combination versus single agents.

Conclusions

Our preclinical data strongly support the interest of further investigations on the well-tolerated Namitecan either as a single agent or in combination in paediatric oncology.

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Acknowledgments

This work was supported by Fondazione per l’Oncologia Pediatrica (FOP). The authors thank Sigma-Tau (Rome, Italy) for supplying Namitecan. We also thank S. Dottori (Sigma-Tau S.p.A) for its excellent technical assistance. Namitecan is under Clinical Trial sponsored by Sigma-Tau.

Conflict of interest

Dr Pisano Claudio and Dr Federica Bucci are full employed by Sigma-Tau.

Author information

Authors and Affiliations

  1. Laboratory of Pharmacology, Division of Paediatric Oncology, Catholic University of Rome, Largo A. Gemelli, 8, 00168, Rome, Italy

    Daniela Meco, Angela Maria Di Francesco, Gabriella Cusano, Filomena Pierri, Valentina Patriarca, Anna Rita Torella & Riccardo Riccardi

  2. Research and Development, Sigma Tau, Pomezia, Rome, Italy

    Federica Bucci & Claudio Pisano

Authors
  1. Daniela Meco
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  2. Angela Maria Di Francesco
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  3. Gabriella Cusano
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  4. Federica Bucci
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  5. Filomena Pierri
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  6. Valentina Patriarca
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  7. Anna Rita Torella
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  8. Claudio Pisano
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  9. Riccardo Riccardi
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Corresponding author

Correspondence to Angela Maria Di Francesco.

Additional information

Daniela Meco and Angela Maria Di Francesco equally contributed to this work.

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Meco, D., Di Francesco, A.M., Cusano, G. et al. Preclinical evaluation of the novel 7-substituted camptothecin Namitecan (ST1968) in paediatric tumour models. Cancer Chemother Pharmacol 70, 811–822 (2012). https://doi.org/10.1007/s00280-012-1973-0

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  • DOI: https://doi.org/10.1007/s00280-012-1973-0

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