Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation.

Abstract

The MTD of cis-RA given on this intermittent schedule was 160 mg/m2/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels. Monitoring of serum calcium and cis-RA levels is indicated in future trials.

Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

“…In addition, certain neuroblastoma cells underwent apoptosis in response to ATRA (Piacentini et al, 1992;Takada et al, 2001;Nagai et al, 2004). Consistent with these observations, 13-cis-RA treatment after intensive chemotherapy improved an event-free survival rate of the patients with aggressive neuroblastomas with 17% increase (Villablanca et al, 1995;Matthay et al, 1999). Although the antitumor effects of RA alone on aggressive neuroblastoma are limited, RA treatment has an advantage that it carries no severe side effects.…”

Interferon-? cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells

“…61 Based on observations that RA can also induce differentiation of neuroblastoma cell lines in vitro, 16 -18 RA has been used for several clinical trials in neuroblastoma patients with variable results. [37][38][39][40] However, a recent study using high-dose 13-cis RA treatment after myeloablative therapy and autologous bone marrow transplantation showed encouraging results. 41 Since differentiation and/or growth arrest induced by RA, TPA or vitamin D 3 was shown to be potentiated by IFN-␥ in several cell types, [42][43][44][45][46][47] the aim of our investigation was to determine whether IFN-␥ would synergize with RA or TPA to induce differentiation and growth inhibition in neuroblastoma cells.…”

“…Our results together with those of Wuarin et al 50 and a publication by Cornaglia et al, 48 reporting that combined therapy with RA and IFN-␥ inhibited tumor formation of LA-N-5 cells injected in nude mice, suggest that RA and IFN-␥ in combination may be of therapeutical interest. Presently both RA [37][38][39][40] and IFN-␥ 62 have been used as single agents in clinical trials for cancer therapy. This is a good basis for combination therapy with the 2 agents.…”

“…Long-term remissions were observed occasionally in neuroblastoma patients in clinical trials using all-trans-RA or 13-cis RA. [37][38][39][40] However, high-dose 13-cis RA treatment after autologous bone marrow transplantation showed encouraging results in a recent study. 41 Studies of cell types other than neuroblastoma have demonstrated that IFN-␥ potentiates differentiation and/or growth arrest induced by RA or vitamin D 3 in acute promyelocytic leukemia and myelomonocytic tumor cells [42][43][44][45] and in mammary and cervical carcinoma cells.…”

Differentiation of neuroblastoma cells by phorbol esters and insulin-like growth factor 1 is associated with induction of retinoic acid receptor β gene expression

“…Among the agents that induce neuroblastoma cell di erentiation retinoic acid (RA) appears to be quite potent (Haussler et al, 1983). This has led to clinical trials of retinoids to treat neuroblastoma and other neoplastic diseases (Gudas et al, 1994;Villablanca et al, 1995). Phorbol esters, which activate protein kinase C and act as tumor promoters in other cell types also promote di erentiation of neuroblastoma cells as judged by morphology and expression of neuronal markers (Bjelfman et al, 1990;Pahlman et al, 1991).…”