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.
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