13‐cis‐retinoic acid (NSC 122758) in the treatment of children with metastatic neuroblastoma unresponsive to conventional chemotherapy: Report from the childrens cancer study group

Abstract

The Childrens Cancer Study Group evaluated daily oral 13-cis-retinoic acid to determine its therapeutic efficacy in 28 children with advanced neuroblastoma refractory to conventional therapy. Cheilitis and fissured lips were the most common side effects; however, fewer than 50% of the patients experienced any toxicity. Two of twenty-two evaluable children demonstrated positive response to therapy. In one case, a child received the drug for 11 months. Seventeen patients demonstrated progressive disease within 28 days of the start of treatment. Three other patients with stable disease, or removed from study at day 28, were considered nonresponsive. Our data demonstrate that, when given as a single daily oral dose of 100 mg/m2, 13-cis-retinoic acid does not have significant activity in children with advanced neuroblastoma.

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.…”

Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma – a study of the United Kingdom Children's Cancer Study Group

“…The retinol derivative 13-cis-retinoic acid (13-cisRA) is now an established component of the treatment of high-risk neuroblastoma, despite the fact that early phase II trials conducted with low-dose 13-cisRA showed limited clinical benefit in patients with recurrent disease (Reynolds et al, 1991;Finklestein et al, 1992;Kohler et al, 2000). When 13-cisRA was administered as a highdose (160 mg m À2 day À1 ), intermittent regimen in a Children's Cancer Group phase III randomised trial, a significant improvement in 3-year event-free survival (EFS) was observed (Matthay et al, 1999).…”

Effect of Retinoids on Growth Inhibition of Two Canine Melanoma Cell Lines.

“…In addition to their well-established anti-carcinogenic activity [2,3,6,18], retinoids have been shown to inhibit the proliferation of a considerable number of cultured cells, including human and murine melanoma cells [8,15,16,19,24,27,28].…”