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Receptor-mediated DNA-targeted photoimmunotherapy.

Abstract
We show the efficacy of a therapeutic strategy that combines the potency of a DNA-binding photosensitizer, UV(A)Sens, with the tumor-targeting potential of receptor-mediated endocytosis. The photosensitizer is an iodinated bibenzimidazole, which, when bound in the minor groove of DNA and excited by UV(A) irradiation, induces cytotoxic lesions attributed to a radical species resulting from photodehalogenation. Although reminiscent of photochemotherapy using psoralens and UV(A) irradiation, an established treatment modality in dermatology particularly for the treatment of psoriasis and cutaneous T-cell lymphoma, a critical difference is the extreme photopotency of the iodinated bibenzimidazole, approximately 1,000-fold that of psoralens. This feature prompted consideration of combination with the specificity of receptor-mediated targeting. Using two in vitro model systems, we show the UV(A) cytotoxicity of iodo ligand/protein conjugates, implying binding of the conjugate to cell receptors, internalization, and degradation of the conjugate-receptor complex, with release and translocation of the ligand to nuclear DNA. For ligand-transferrin conjugates, phototoxicity was inhibited by coincubation with excess native transferrin. Receptor-mediated UV(A)-induced cytotoxicity was also shown with the iodo ligand conjugate of an anti-human epidermal growth factor receptor monoclonal antibody, exemplifying the potential application of the strategy to other cancer-specific targets to thus improve the specificity of phototherapy of superficial lesions and for extracorporeal treatments.
AuthorsTom C Karagiannis, Pavel N Lobachevsky, Brenda K Y Leung, Jonathan M White, Roger F Martin
JournalCancer research (Cancer Res) Vol. 66 Issue 21 Pg. 10548-52 (Nov 01 2006) ISSN: 0008-5472 [Print] United States
PMID17079478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Photosensitizing Agents
  • Receptors, Transferrin
  • DNA
  • ErbB Receptors
Topics
  • Animals
  • CHO Cells
  • Cricetinae
  • DNA (metabolism)
  • Endocytosis
  • ErbB Receptors (metabolism)
  • Humans
  • Immunotherapy
  • K562 Cells
  • Photochemotherapy (methods)
  • Photosensitizing Agents (therapeutic use)
  • Receptors, Transferrin (metabolism)
  • Ultraviolet Rays

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