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

Ickenstein, Ludger M.; Edwards, Katarina; Sjöberg, Stefan; Carlsson, Jörgen; Gedda, Lars

doi:10.1016/j.nucmedbio.2006.06.002

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 6 , Pages 773-783, August 2006

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

Ludger M. Ickenstein
- Department of Physical and Analytical Chemistry, Uppsala University, P.O. Box 579, 75121 Uppsala, Sweden
Katarina Edwards
- Department of Physical and Analytical Chemistry, Uppsala University, P.O. Box 579, 75121 Uppsala, Sweden
Stefan Sjöberg
- Department of Biochemistry and Organic Chemistry, Uppsala University, P.O. Box 576, 75123 Uppsala, Sweden
Jörgen Carlsson
- Rudbeck Laboratory, Division of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, 75185 Uppsala, Sweden
Lars Gedda
- Rudbeck Laboratory, Division of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, 75185 Uppsala, Sweden
- Rudbeck Laboratory, Division of Experimental Urology, Department of Surgery, Uppsala University, 75185 Uppsala, Sweden
- Corresponding author. Rudbeck Laboratory, Division of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, 75185 Uppsala, Sweden. Tel.: +46 18 4713431; fax: +46 18 4713432.

Received 24 March 2006; received in revised form 19 May 2006; accepted 1 June 2006.

Abstract

Introduction

Auger 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.

Methods

¹²⁵I 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 Discussion

The 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.