Melanoma therapy via peptide-targeted α-radiation
Melanoma therapy via peptide-targeted α-radiation
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DOI：
10.1158/1078-0432.ccr-05-0619
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发表时间：
2005-08-01
影响因子：
11.5
通讯作者：
Quinn, TP
中科院分区：
文献类型：
--
作者：
Miao, YB;Hylarides, M;Quinn, TP
目的：在B16/F1小鼠黑色素瘤动物模型中，评价一种独特的黑色素瘤靶向多肽与体内产生的a粒子放射性核素的偶联治疗效果。阿尔法辐射是致密的电离，导致高浓度的破坏性自由基和无法修复的DNA双链断裂。这种高线性能量转移克服了抗辐射的肿瘤细胞和氧气效应，导致黑色素瘤等肿瘤的潜在高治疗指数。实验设计：黑色素瘤靶向肽1，4，7，10-tetraazacyclodecane-1，4，7，10-tetraacetic酸(DOTA)-Re(Arg(11))CCMSH被放射性标记为Bi-212的亲本，它通过α和β衰变而衰变。结果：PB-212[DOTA]-Re(Arg(11))CCMSH对B16/F1黑色素瘤C57小鼠侧翼肿瘤有较快的摄取、滞留和全身消退。照射到肿瘤的剂量估计为61cGy/亩，Ci，Pb212。用50、100和200亩Ci的铅-212[DOTA]-Re(Arg(11))CCMSH治疗黑色素瘤小鼠，它们的平均生存期分别延长到22、28和49.8天，而安慰剂对照组的平均生存期为14.6天。接受200亩Ci剂量的小鼠中45%无病存活。结论：铅-212[DOTA]-Re(Arg(11))CCMSH治疗B16/F1黑色素瘤小鼠显著降低了肿瘤生长速度，延长了平均生存时间，在许多情况下，疾病完全缓解。PB-212-DOTA-Re(Arg(11))CCMSH似乎是一种非常有前途的放射性药物，用于黑色素瘤的靶向放射性治疗。
Purpose: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated a-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. alpha-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma.Experimental Design: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg(11))CCMSH, was radiolabeled with Pb-212, the parent of Bi-212, which decays via alpha and beta decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model.Results: Pb-212[DOTA]-Re(Arg(11))CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/mu Ci Pb-212 administered. Treatment of melanoma-bearing mice with 50, 100, and 200 mu Ci of Pb-212[DOTA]-Re(Arg(11)) CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 mu Ci doses survived the study disease-free.Conclusions: Treatment of B16/F1 murine melanoma-bearing mice with Pb-212[DOTA]-Re(Arg(11)) CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. Pb-212-DOTA-Re(Arg(11))CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.