125I 标记胸腺嘧啶核苷类似物 5-碘-4'-硫代-2'-脱氧尿苷的 Auger 电子发射体对抗多发性骨髓瘤——靶向内放射治疗。

Auger electron emitter against multiple myeloma--targeted endo-radio-therapy with 125I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine.

机构信息

Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm, Germany.

出版信息

Nucl Med Biol. 2011 Oct;38(7):1067-77. doi: 10.1016/j.nucmedbio.2011.02.018. Epub 2011 Apr 21.

DOI:10.1016/j.nucmedbio.2011.02.018

PMID:21982576

Abstract

INTRODUCTION

Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue (125)I-labeled 5-iodo-4'-thio-2'-deoxyuridine ([(125)I]ITdU).

METHODS

Cellular uptake and DNA incorporation of [(125)I]ITdU were determined in fluorodeoxyuridine-pretreated KMS12BM, U266, dexamethasone-sensitive MM1.S and -resistant MM1.R cell lines. The effect of stimulation with interleukin 6 (IL6) or insulin-like growth factor 1 (IGF1) on the intracellular incorporation of [(125)I]ITdU was investigated in cytokine-sensitive MM1.S and MM1.R cell lines. Apoptotic cells were identified using Annexin V. Cleavage of caspase 3 and PARP was visualized by Western blot. DNA fragmentation was investigated using laddering assay. Therapeutic efficiency of [(125)I]ITdU was proven by clonogenic assay.

RESULTS

[(125)I]ITdU was shown to be efficiently incorporated into DNA of malignant cells, providing a promising mechanism for delivering highly toxic Auger radiation emitters into tumor DNA. [(125)I]ITdU had a potent antimyeloma effect in cell lines representing distinct disease stages and, importantly, in cell lines sensitive or resistant to the conventional therapeutic agent, but was not toxic for normal plasma and bone marrow stromal cells. Furthermore, [(125)I]ITdU abrogated the protective actions of IL6 and IGF1 on MM cells. [(125)I]ITdU induced massive damage in the DNA of malignant plasma cells, which resulted in efficient inhibition of clonogenic growth.

CONCLUSION

These studies may provide a novel treatment strategy for overcoming resistance to conventional therapy in multiple myeloma.

摘要

简介

多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，其特征是恶性、终末分化的 B 细胞在骨髓中积聚。尽管治疗取得了进展，但 MM 仍然是一种无法治愈的疾病。因此，迫切需要新的治疗方法。由于放射性药物的 DNA 选择性靶向，正电子发射放射性药物是靶向纳米辐射治疗的理想选择。在此，我们评估了亲电子发射放射性药物[125I]标记的 5-碘-4'-硫代-2'-脱氧尿苷([125I]ITdU)在多发性骨髓瘤中的治疗潜力。

方法

在氟脱氧尿苷预处理的 KMS12BM、U266、地塞米松敏感 MM1.S 和耐药 MM1.R 细胞系中，测定[125I]ITdU 的细胞摄取和 DNA 掺入。在细胞因子敏感的 MM1.S 和 MM1.R 细胞系中，研究白细胞介素 6 (IL6)或胰岛素样生长因子 1 (IGF1)刺激对[125I]ITdU 细胞内掺入的影响。用 Annexin V 鉴定凋亡细胞。用 Western blot 检测 caspase 3 和 PARP 的裂解。通过梯状电泳研究 DNA 片段化。通过集落形成实验证明[125I]ITdU 的治疗效果。

结果

结果表明，[125I]ITdU 能有效地掺入恶性细胞的 DNA 中，为将高毒性正电子发射体递送至肿瘤 DNA 提供了一种很有前途的机制。[125I]ITdU 对代表不同疾病阶段的细胞系具有很强的抗骨髓瘤作用，重要的是，对常规治疗药物敏感或耐药的细胞系也具有抗骨髓瘤作用，但对正常血浆和骨髓基质细胞没有毒性。此外，[125I]ITdU 消除了 IL6 和 IGF1 对 MM 细胞的保护作用。[125I]ITdU 导致恶性浆细胞的 DNA 受到严重损伤，从而有效地抑制了集落形成生长。