Resistance to radiotherapy or chemotherapy is a common cause of treatment failure in high-risk leukemias. We evaluated whether selective nanoirradiation of DNA with Auger electrons emitted by 5-123 I-iodo-49-thio-29-deoxyuridine ( 123 I-ITdU) can induce cell kill and break resistance to doxorubicin, b-, and g-irradiation in leukemia cells. Methods: 49-thio-29-deoxyuridine was radiolabeled with 123/131 I and purified by high-performance liquid chromatography. Cellular uptake, metabolic stability, DNA incorporation of 123 I-ITdU, and the effect of the thymidylate synthase (TS) inhibitor 5-fluoro-29-deoxyuridine (FdUrd) were determined in HL60 leukemia cells. DNA damage was assessed with the comet assay and quantified by the olive tail moment. Apoptosis induction and irradiation-induced apoptosis inhibition by benzoylcarbonylVal-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) were analyzed in leukemia cells using flow cytometry analysis. Results: The radiochemical purity of ITdU was 95%. Specific activities were 900 GBq/mmol for 123 I-ITdU and 200 GBq/mmol for 131 I-ITdU. An in vitro cell metabolism study of 123 I-ITdU with wild-type HL60 cells demonstrated an uptake of 1.5% of the initial activity/10 6 cells of 123 I-ITdU. Ninety percent of absorbed activity from 123 I-ITdU in HL60 cells was specifically incorporated into DNA. 123 I-ITdU caused extensive DNA damage (olive tail moment . 12) and induced more than 90% apoptosis in wild-type HL60 cells. The broad-spectrum inhibitor of caspases zVAD-fmk reduced 123 IITdU-induced apoptosis from more than 90% to less than 10%, demonstrating that caspases were central for 123 I-ITdU-induced cell death. Inhibition of TS with FdUrd increased DNA uptake of 123 I-ITdU 18-fold and the efficiency of cell kill about 20-fold. In addition, 123 I-ITdU induced comparable apoptotic cell death (.90%) in sensitive parental leukemia cells and in leukemia cells resistant to b-irradiation, g-irradiation, or doxorubicin at activities of 1.2, 4.1, 12.4, and 41.3 MBq/mL after 72 h. This finding indicates that 123 I-ITdU breaks resistance to b-irradiation, g-irradiation, and doxorubicin in leukemia cells. Conclusion: 123 I-ITdU-mediated nanoirradiation of DNA efficiently induced apoptosis in sensitive and resistant leukemia cells against doxorubicin, b-irradiation, and g-irradiation and may provide a novel treatment strategy for overcoming resistance to conventional radiotherapy or chemotherapy in leukemia. Cellular uptake and cell kill are highly amplified by inhibiting TS with FdUrd.

Synthesis and polymerization data of a series of new sulfur-containing C 1 -symmetric metallocenes,rac-[1-(9-η 5 -fluorenyl)-2- (8), are reported. The characteristic structural feature of these complexes is the 2-methyl-1H-benzo[b]indeno[4,5-d]thiophene moiety (3: MBIT), which was derived from dibenzothiophene. In the case of 7a-c the MBIT unit shows a "back" orientation, whereas in 8 it is directed to the "front" of the tetrahedral metallocene dichloride species, which was unambiguously illustrated by X-ray structure analysis. Propylene polymerization experiments revealed higher activity and stereoselectivity for 7a/MAO compared to 8/MAO. The catalysts 7a,8/MAO were found to operate under different polymerization mechanisms indicated by a diverse correlation of tacticity and polymerization temperature. Crystalline, flexible polypropylenes with tacticities ranging from 65 e [mmmm] e 90 and molecular weights up to 2 × 10 5 g mol -1 were obtained for 7a/MAO, whereas experiments using 8/MAO produced low tacticity, waxy materials. To achieve ultrahigh molecular weight isotactic polypropylene plastomers (M w up to 1.5 × 10 6 g mol -1 ), further investigations on the hafnium dimethyl complex 7c/[(C 6 H 5 ) 3 C + ][(C 6 F 5 ) 4 B -] in liquid propylene were performed.

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3'-Deoxy-3'-(18)F-fluorothymidine (FLT) was developed in 1998 by Shields and co-workers because monitoring of treatment response would be facilitated by imaging agents able to provide measures of tissue and tumour proliferation. Since then, FLT metabolism has been clarified in more detail in cell culture and experimental animal tumour models and also in clinical studies. Recently, FLT has increasingly been used for the assessment of response to anticancer treatment, mainly in tumour xenograft SCID mouse models; in contrast, clinical data are scarce. In this article we briefly summarise the intermediary metabolism of FLT and its application as an anticancer treatment response probe. The potential value and limitations of FLT as a highly promising proliferation imaging probe and its use for monitoring of treatment response are discussed.