Raffaghello L, Pagnan G, Pastorino F, Cosimo E, Brignole C, Marimpietri D, Bogenmann E, Ponzoni M, Montaldo P G
Laboratory of Oncology, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16148 Genoa, Italy.
Cancer Lett. 2003 Jul 18;197(1-2):151-5. doi: 10.1016/s0304-3835(03)00097-1.
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In advanced disease stages, prognosis is poor and treatments have limited efficacy, thus novel strategies are warranted. The synthetic retinoid fenretinide (HPR) induces apoptosis in NB and melanoma cell lines. We reported an in vitro potentiation of HPR effects on melanoma cells when the drug is incorporated into GD2-targeted immunoliposomes (anti-GD2-SIL-HPR). Here, we investigated the antitumor activity of anti-GD2-SIL-HPR against NB cells, both in vitro and in vivo. Anti-GD2-immunoliposomes (anti-GD2-SIL) showed specific, competitive binding to, and uptake by, various NB cell lines. Moreover, anti-GD2-SIL-HPR presented increased selectivity and efficacy in inhibiting NB cell proliferation through the induction of apoptosis, compared to free drug and SL-HPR. In an in vivo NB metastatic model, we demonstrated that anti-GD2-SIL-HPR completely inhibited the development of macroscopic and microscopic metastases in comparison to controls. However, similar, but significantly less potent antitumor effect was observed also in mice treated with anti-GD2 immunoliposomes without HPR (anti-GD2-SIL-blank) or anti-GD2 mAb alone (P=0.0297 and P=0.0294, respectively, vs. anti-GD2-SIL-HPR). Moreover, our results clearly demonstrated that, although anti-GD2 mAb had a strong antitumor effect in this in vivo NB model, 100% curability was obtained only following treatment with anti-GD2-SIL-HPR (P<0.0001). Anti-GD2 liposomal HPR should receive clinical evaluation as adjuvant therapy of neuroblastoma.
神经母细胞瘤（NB）是儿童最常见的颅外实体瘤。在疾病晚期，预后较差且治疗效果有限，因此需要新的治疗策略。合成视黄酸芬维A胺（HPR）可诱导NB和黑色素瘤细胞系凋亡。我们报道，当该药物被包载于靶向GD2的免疫脂质体（抗GD2-SIL-HPR）中时，其对黑色素瘤细胞的作用在体外得到增强。在此，我们研究了抗GD2-SIL-HPR对NB细胞的体内外抗肿瘤活性。抗GD2免疫脂质体（抗GD2-SIL）显示出对多种NB细胞系的特异性、竞争性结合及摄取。此外，与游离药物和SL-HPR相比，抗GD2-SIL-HPR通过诱导凋亡在抑制NB细胞增殖方面表现出更高的选择性和疗效。在体内NB转移模型中，我们证明与对照组相比，抗GD2-SIL-HPR完全抑制了肉眼可见和显微镜下转移灶的形成。然而，在用不含HPR的抗GD2免疫脂质体（抗GD2-SIL-空白）或单独使用抗GD2单克隆抗体治疗的小鼠中也观察到了类似但明显较弱的抗肿瘤作用（分别与抗GD2-SIL-HPR相比，P = 0.0297和P = 0.0294）。此外，我们的结果清楚地表明，尽管抗GD2单克隆抗体在该体内NB模型中有很强的抗肿瘤作用，但仅在使用抗GD2-SIL-HPR治疗后才获得100%的治愈率（P<0.0001）。抗GD2脂质体HPR应作为神经母细胞瘤的辅助治疗进行临床评估。
