title: The synthetic retinoid RO 13-6307 induces neuroblastoma differentiation in vitro and inhibits neuroblastoma tumour growth in vivo.
abstract: Retinoids modulate cell proliferation, differentiation and apoptosis in a variety of tumour cells including leukaemia and neuroblastoma, a childhood tumour of the sympathetic nervous system. 13-cis retinoic acid is in clinical use against minimal residual disease in neuroblastoma, where the effect seems to depend on dose, scheduling and tumour mass. Novel retinoids are searched for, to improve potency and lower toxicity. We investigated the effect of the synthetic retinoid Ro 13-6307 on neuroblastoma growth in vitro on SK-N-BE(2) and SH-SY5Y cells. Furthermore, effects on tumour growth and the toxicity profile were investigated in a rat xenograft model. Effects of Ro 13-6307 were compared to 13-cis RA (retinoic acid) in vitro and in vivo. Neuroblastoma cells treated with 1 microM Ro 13-6307 exhibited neuronal differentiation, decreased proliferation and accumulation of cells in G1 phase in at least the same magnitude as 5 microM 13-cis RA. No apoptosis was detected in vitro. Treatment of nude rats with neuroblastoma using Ro 13-6307, 0.12 mg p.o. daily, decreased neuroblastoma growth in vivo, in terms of tumour volume during treatment and tumour weight at sacrifice (p < 0.05). In contrast, Ro 13-6307, 0.08 mg p.o. daily, resulted in no significant reduction in tumour growth. All rats treated with Ro 13-6307 gained less weight than control rats, but they exhibited no other signs of toxicity. The toxicity profile of Ro 13-6307 was similar to what we found with 13-cis RA. Our preclinical results suggest that Ro 13-6307 may be a candidate retinoid for clinical oral therapy of neuroblastoma in children.
authors.affiliation: Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden. frida.ponthan@ks.se
authors.forename: Frida
authors.initials: F
authors.lastname: Ponthan
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.forename: Lena
authors.initials: L
authors.lastname: Klevenvall
authors.forename: Juan
authors.initials: J
authors.lastname: Castro
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D015474:Isotretinoin / Q000494:pharmacology; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; C077135:Ro 13-6307; D015474:Isotretinoin