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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2012

01-12-2012 | Original Article

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

Authors: Daniela Meco, Angela Maria Di Francesco, Gabriella Cusano, Federica Bucci, Filomena Pierri, Valentina Patriarca, Anna Rita Torella, Claudio Pisano, Riccardo Riccardi

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2012

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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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Metadata
Title
Preclinical evaluation of the novel 7-substituted camptothecin Namitecan (ST1968) in paediatric tumour models
Authors
Daniela Meco
Angela Maria Di Francesco
Gabriella Cusano
Federica Bucci
Filomena Pierri
Valentina Patriarca
Anna Rita Torella
Claudio Pisano
Riccardo Riccardi
Publication date
01-12-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-012-1973-0

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