Retinoid therapy of high-risk neuroblastoma
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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