The novel atypical retinoid ST1926 is active in in vitro and in vivo models of human neuroblastoma
Authors: Angela Maria Di Francesco, Daniela Meco, Anna Shirley Riccardi, Giuseppe Barone, Claudio Pisano, Loredana Vesci, Maurizio D’Incalci, Riccardo Riccardi
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

672 

Retinoic acid therapy represents an important component of treatment for residual disease of stage IV neuroblastoma after chemotherapy. However, more suitable retinoid-related molecules with less toxicity, improved pharmacokinetics and greater efficacy could lead to significant improvements in the clinical response of neuroblastoma patients. Recently, the novel related adamantyl retinoid ST1926 ( E -3-(4-hydroxy-3-adamantylbiphenyl-4-yl)acrylic acid), showed to be a strong inducer of apoptosis with a potent anti-proliferative activity on a large panel of human tumor cells. In preclinical studies, ST1926 showed also an interesting antitumor activity after oral administration in both hematological and solid tumors. The present study deals with the evaluation of the antitumor activity of the drug in preclinical models of human neuroblastoma. A panel of five neuroblastoma cell lines with two morphologically and biochemically distinct phenotypes, were selected for the antiproliferative studies: SK-N-DZ, SK-N-BE(2)c, SHSY-5Y (N-type); SHEP-1 and SK-N-AS (flat substrate adherent, S-type). The paired cell lines SK-N-DZwt/Pt (sensitive and resistant to cisplatin) were also studied. We evaluated: a) short-term cytotoxicity by cell count and MTT assay; b) clonogenic survival; c) influence of antioxidant on the antiproliferative activity of the drug; d) induction of morphological differentiation in SHSY-5Y cells; e) induction of strand-breakage and DNA damage by alkaline single-cell gel electrophoresis assay; f) in vivo antitumour efficacy in CD1 nu/nu male mice bearing SK-N-DZ or SK-N-BE(2)c xenografts. In the in vitro cytotoxicity studies, exponentially growing cells were continuously exposed to increasing doses of the drug. The IC50 values were between 0.18 and 0.20μM in the short term assay and about 0.1μM in the clonogenical assay. No difference in cell sensitivity to the drug was observed in the paired cell lines SK-N-DZwt/Pt. Pre-treatment with vitamin E did not alter the antiproliferative effects of ST1926 in our model, suggesting that oxidative stress is not involved in the cytotoxic pathway of the drug in neuroblastoma. ST1926 did not induce morphological differentiation in SHSY-5Y cells. DNA strand breaks efficiency was time-dependent and reached about 20% of Tail% at the dose of 1.2 and 2.4μM. In the in vivo study, ST1926 was administered orally at 15-20-25 mg/kg/d doses and qdx3/wx3w schedule. The SK-N-DZ xenograft was more sensitive to the drug than SK-N-BE(2)c and showed a dose-dependent tumour regression which reached a TVI of 90% at the highest dose used. Overall, the drug was well tolerated and toxicity was negligible. In conclusion, ST1926 appears active in neuroblastoma and it may have a clinical potential either as a single agent or in combination therapy in the treatment of neuroblastoma. Supported by: AIRC, FOP, CNR-MIUR Project (law 449/97).