Cancer Letters

Cancer Letters

Volume 197, Issues 1–2, 18 July 2003, Pages 185-192
Cancer Letters

Retinoid therapy of high-risk neuroblastoma

https://doi.org/10.1016/S0304-3835(03)00108-3Get rights and content

Abstract

Retinoids are derivatives of vitamin A that include all trans-retinoic acid (ATRA), 13-cis-retinoic acid, (13-cis-RA), and fenretinide (4-HPR). High levels of either ATRA or 13-cis-RA can cause arrest of cell growth and morphological differentiation of human neuroblastoma cell lines, and phase I trials showed that higher and more sustained drug levels were obtained with 13-cis-RA relative to ATRA. A phase III randomized trial showed that high-dose, pulse therapy with 13-cis-RA given after completion of intensive chemoradiotherapy (with or without autologous bone marrow transplantation) significantly improved event-free survival in high-risk neuroblastoma. The cytotoxic retinoid 4-HPR achieved multi-log cell kills in neuroblastoma cell lines resistant to ATRA and 13-cis-RA, and a pediatric phase I trial has shown it to be well tolerated. Cytotoxicity of 4-HPR is mediated at least in part by increasing tumor cell ceramide levels and combining 4-HPR with ceramide modulators increased anti-tumor activity in pre-clinical models. Thus, further clinical trials of 4-HPR in neuroblastoma, and of 4-HPR in combination with ceramide modulators, are warranted.

Introduction

Neuroblastoma has the highest rate of spontaneous regression of any human tumor and even metastatic neuroblastomas have been shown to spontaneously mature to a benign tumor known as ganglioneuroma. These clinical observations have stimulated studies of neuroblastoma differentiation in vitro. A variety of agents have been shown to induce neurite outgrowth of human neuroblastoma cell lines, including retinoic acid, cyclic AMP elevating agent, and nerve growth factor [1].

Section snippets

Retinoic acid

One of the most potent differentiation inducers for human neuroblastoma in vitro is retinoic acid (RA) [2]. Treatment of both MYCN gene-amplified and non-amplified human neuroblastoma cell lines with all-trans-retinoic acid (ATRA) caused a marked decrease in MYCN RNA expression and arrest of cell proliferation [3], [4]. In some cell lines, 10 days of ATRA treatment caused a prolonged growth arrest that persisted for >60 days after drug removal and the growth arrest correlated with decreased

RA receptors

The differentiation and growth arrest of malignant cells produced by RA are likely mediated by one or more of the two families of RA receptors (RARs; RA receptor (RAR) or retinoid X receptor (RXR)) which have been cloned and sequenced: RAR α, β, γ and RXR α, β, γ [5]. All belong to the steroid/thyroid hormone family of transcription factors and possess discrete DNA-binding and RA binding domains. As depicted in Fig. 1, RA binds to the RARs, causing conformational changes that promote binding to

13-cis-RA

The in vitro work with RA prompted investigators to determine if retinoids could be effective against tumors in a clinical setting. In the mid-1980’s the only retinoid available for clinical use was 13-cis-retinoic acid (13-cis-RA), which had been shown to induce differentiation in promyelocytic leukemia and had been used in trials with some objective responses in both promyelocytic leukemia, myelodysplastic syndrome, cutaneous T-cell lymphoma (mycosis fungoides), and advanced squamous

Fenretinide

A synthetic retinoid made in the late 1960’s, N-(4-hydroxyphenyl) retinamide or fenretinide (4-HPR) has been reported to inhibit the growth of neuroblastoma cell lines in vitro with 1–10 μM concentrations in a dose dependent manner [18] and 4-HPR was highly active against retinoic-acid resistant neuroblastoma cell lines at 5–10 μM drug levels [19]. In contrast to 13-cis-RA and ATRA, 4-HPR does not induce maturational changes, but is cytotoxic, causing both apoptosis and necrosis [20]. Toxicity

Conclusions

In vitro studies led to clinical trials that have defined a dose of 13-cis-RA which was tolerable in patients after myeloablative therapy, and a phase III trial that showed post-consolidation therapy with high-dose, pulse 13-cis-RA improved EFS for patients with high-risk neuroblastoma. However, there are still many high-risk neuroblastoma patients who have tumors that do not respond to 13-cis-RA, even when 13-cis-RA is used in a state of complete response to prior therapy. Given the

Acknowledgements

Supported in part by the Neil Bogart Memorial Laboratories of the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research and by National Cancer Institute Grant CA81403.

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