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

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Abstract
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. 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. 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. 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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