A novel 125I-labeled daunorubicin derivative for radionuclide-based cancer therapy

IntroductionAuger electron emitters, such as 125I, are getting increasingly wider recognition as alternatives to current anticancer treatments. The effectiveness of Auger electrons is strongly dependent on their proximity to DNA and is therefore considered as harmless outside the nucleus.Methods125I or 127I was conjugated with Comp1, Comp2 or Comp3 — three derivatives of the chemotherapeutic drug daunorubicin. Their capacity factors, DNA-binding constants and exclusion parameters, and the degree of DNA fragmentation after incubating isolated DNA with our 127I- or 125I-conjugated daunorubicin derivatives were determined. Human breast adenocarcinoma (SK-BR-3) cells were incubated with the derivatives; fluorescent microscopy and autoradiography images were generated; and cell growth was monitored.Results and DiscussionThe capacity factor of 127I-Comp1 was similar to those of daunorubicin and doxorubicin, whereas lower capacity factors of 127I-Comp2 and 127I-Comp3 suggested reduced interactions with lipid membranes. DNA exclusion parameters and binding constants of 127I-Comp1 and 127I-Comp2, but not of 127I-Comp3, were similar to those of doxorubicin. Fluorescent microscopy and autoradiography images of SK-BR-3 cells revealed that 127I-Comp1 and 125I-Comp1 accumulated in tumor cell nuclei, whereas 127I-Comp2 and 127I-Comp3 were present predominantly in other cell compartments. The binding of 125I-Comp1 to isolated chromosomal DNA led to major fragmentation. Incubation of SK-BR-3 cells with 125I-Comp1 inhibited cell growth, whereas doxorubicin or 127I-Comp1 administered at the same concentration had no effect on cell growth. Our results thus suggest that 125I-Comp1 has the potential to become a new tool for anticancer therapy.