Bonnet-Duquennoy Mathilde, Papon Janine, Mishellany Florence, Labarre Pierre, Guerquin-Kern Jean-Luc, Wu Ting-Di, Gardette Maryline, Maublant Jean, Penault-Llorca Frédérique, Miot-Noirault Elisabeth, Cayre Anne, Madelmont Jean-Claude, Chezal Jean-Michel, Moins Nicole
Univ Clermont 1, Clermont-Ferrand, France.
Int J Cancer. 2009 Aug 1;125(3):708-16. doi: 10.1002/ijc.24413.
In recent years, there has been dramatic worldwide increase in incidence of malignant melanoma. Although localised disease is often curable by surgical excision, metastatic melanoma is inherently resistant to most treatments. In this context, targeted radionuclide therapy could be an efficient alternative. After pharmacomodulation study, we selected a quinoxaline derivative molecule (ICF01012) for its high, specific and long-lasting uptake in melanoma with rapid clearance from nontarget organs providing suitable dosimetry parameters for targeted radiotherapy. Aim of this study was to investigate, in vivo, efficacy of [(131)I]ICF01012 on nonmetastatic B16F0, metastatic B16Bl6 or human M4Beu melanoma tumours. First, colocalisation of ICF01012 with melanin by SIMS imaging was observed. Second, we showed that treatment drastically inhibited growth of B16F0, B16Bl6 and M4beu tumours whereas [(131)I]NaI or unlabelled ICF01012 treatment was without significant effect. Histological analysis and measure of PCNA proliferation marker expression showed that residual B16 tumour cells exhibit a significant loss of aggressiveness after treatment. This effect is associated with a lengthening of the treated-mice survival time. Moreover, with B16Bl6 model, 55% of the untreated mice had lung metastases whereas no metastasis was counted on treated group. Our data demonstrated a strong anti-tumoural effect of [(131)I]ICF01012 for radionuclide therapy on murine and human in vivo pigmented melanoma models, whatever their dissemination profiles and their melanin content be. Further studies will attempt to optimise therapy protocol by increasing the balance between the anti-tumoural effect and the safety on non-target organs.
近年来，全球恶性黑色素瘤的发病率急剧上升。尽管局限性疾病通常可通过手术切除治愈，但转移性黑色素瘤对大多数治疗方法具有内在抗性。在这种情况下，靶向放射性核素治疗可能是一种有效的替代方法。经过药物调节研究，我们选择了一种喹喔啉衍生物分子（ICF01012），因为它在黑色素瘤中具有高、特异性和持久的摄取，并且能从非靶器官快速清除，为靶向放射治疗提供了合适的剂量学参数。本研究的目的是在体内研究[(131)I]ICF01012对非转移性B16F0、转移性B16Bl6或人M4Beu黑色素瘤肿瘤的疗效。首先，通过二次离子质谱成像观察到ICF01012与黑色素的共定位。其次，我们表明该治疗显著抑制了B16F0、B16Bl6和M4beu肿瘤的生长，而[(131)I]NaI或未标记的ICF01012治疗则没有显著效果。组织学分析和PCNA增殖标志物表达的测量表明，治疗后残留的B16肿瘤细胞的侵袭性显著降低。这种效果与治疗小鼠的存活时间延长有关。此外，在B16Bl6模型中，55%的未治疗小鼠有肺转移，而治疗组未发现转移。我们的数据表明，[(131)I]ICF01012对放射性核素治疗小鼠和人类体内色素性黑色素瘤模型具有强大的抗肿瘤作用，无论它们的扩散情况和黑色素含量如何。进一步的研究将试图通过提高抗肿瘤作用与非靶器官安全性之间的平衡来优化治疗方案。
