Preferential Tumor Targeting and Selective Tumor Cell Cytotoxicity of 5-[131/125I]Iodo-4′-Thio-2′-Deoxyuridine

Breaking the Invulnerability of Cancer Stem Cells: Two-Step Strategy to Kill the Stem-like Cell Subpopulation of Multiple Myeloma

“…This effect is due to the generation of high ionization density clusters at the location of emission, which predominantly induce double-strand breaks (DSB), representing highly cytotoxic forms of DNA damage (16). As shown previously in a leukemia SCID mouse model, pretreatment with a nontoxic dose of FdUrd resulted in increased incorporation of 125 I-ITdU into the leukemia cells by blocking the key enzyme thymidylate synthase followed by a depletion of the cellular thymidine triphosphate pool (14,15). The predominant increase in 125 I-ITdU incorporation was observed in tumor tissue leading to extensive tumor damage, whereas only moderate injury occurred in normal tissues (14).…”

Hedgehog signaling sensitizes Glioma stem cells to endogenous nano-irradiation

“…Our in vitro data clearly show the selective and efficient targeting of activated GSC by nano-irradiation. Regarding an in vivo application of FdUrd and [I-125]ITdU, we previously demonstrated a massive apoptosis induction in the tumor tissue, and only moderate damage in normal proliferating tissues like the spleen and small intestine crypt cells [18]. Considering the unique characteristic of the Auger electron emitters (e.g.…”

“…Due to the 4′-thio substitution ITdU displays resistance against enzymatic cleavage of the C–N glycosidic bond by thymidine phosphorylase (TP). Importantly, ITdU was shown to be rapidly incorporated into nuclear DNA through the thymidine salvage pathway providing a promising mechanism for delivering Auger radiation emitters such as I-123 and I-125 into tumor DNA [17, 18]. However, the application of ITdU is impaired by high background activity due to thymidylate synthase (TS) mediated deiodination of ITdU and generation of I-125 metabolites [17, 19].…”

“…The conditioning of tumor cells with a selective TS inhibitor fluorodeoxyuridine (FdUrd) efficiently blocked the dehalogenation of [I-125]ITdU and increased the substrate flux through the thymidine salvage pathway as indicated by the 18-fold increased DNA uptake of [I-125]ITdU, resulting in roughly 20-fold increased apoptosis induction in malignant cells [20]. Similarly, in an acute leukemia HL60 xenografted SCID mouse model, the FdUrd pre-treatment considerably increased the selectivity of ITdU towards tumor by increased cellular uptake and the incorporation into the DNA in malignant cells [18]. As a consequence, [I-125]ITdU preferentially induced apoptosis in tumor cells, whereas the viability of cells in normal proliferating tissues remained basically unaffected.…”

Molecular and cellular effects of Auger emitters: 2008–2011

“…To circumvent the catabolism of 125 IdU and promote its incorporation into DNA via the salvage pathway, incorporation of a new thymidine analog was tested (Morgenroth et al 2008). Th e new thymidine analog, 5-iodo-4 ′ -thio-2 ′ -deoxyuridine (ITdU) was found to be resistant to cleavage of the glycosidic bond and was found to be more rapidly incorporated into DNA in human myeloid leukemia cells (HL60) or in a tumor model in SCID mice.…”