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Induction of Tumor Necrosis by -Aminolevulinic Acid and 1,10-Phenanthroline Photodynamic Therapy¹

Laboratory of Immunophysiology, Department of Animal Sciences [N. R., S. A., K. W. K.], Laboratory of Plant Pigment Biochemistry and Photobiology, Department of Horticulture [C. A. R.], and Department of Veterinary Pathobiology, College of Veterinary Medicine [J. S., J. F. Z.], University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

-Aminolevulinic acid (ALA) causes cells to accumulate protoporphyrin IX (Proto) and heme. Exposure to light in vitro causes intracellular Proto to initiate formation of singlet oxygen molecules, leading to self-destruction. This photoactivated destruction by ALA in vitro is enhanced by addition of the tetrapyrrole modulator 1,10-phenanthroline (Oph), which increases cellular accumulation of Proto. Here we significantly extend this idea by evaluating the efficacy of ALA and Oph photodynamic therapy of solid tumors in vivo. Methylcholanthrene-induced fibrosarcoma (Meth-A) cells were used, which lead to the formation of solid tumors when implanted into syngeneic recipients. Initially, suspensions of Meth-A cells were treated in vitro with combinations of ALA and Oph. Meth-A cells in suspension accumulated 6-fold greater amounts of Proto (P < 0.05) after 3-h incubation with ALA and Oph than when incubated with ALA alone, and were also more susceptible to subsequent photoactivated cell lysis in vitro. Similarly, solid Meth-A tumors grown in syngeneic BALB/c mice accumulated significant (P < 0.05) amounts of Proto 3 h after in vivo treatment with ALA, and Oph synergized with ALA to significantly (P < 0.05) enhance the induction of Proto in these tumors. ALA and Oph-based phototreatment of mice bearing Meth-A solid tumors resulted in necrosis of tumors, as determined by a significant reduction in both size and histopathology, with little damage to surrounding normal tissue. These data directly demonstrate the experimental usefulness of Proto modulators for ALA-based photodynamic therapy in the treatment of solid tumors in vivo and provide a rationale for their potential application in a multitude of tumor types.

¹ This research was supported in part by the J. P. Trebellas Photobiotechnology research endowment (to C. A. R.) and by NIH Grant AG-06246 (to K. W. K.).

² To whom requests for reprints should be addressed, at Laboratory of Immunophysiology, 207 Plant and Animal Biotechnology Laboratory, 1201 West Gregory Drive, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Phone: (217) 333-5142; Fax: (217) 244-5617.

Received 6/ 6/95. Accepted 11/13/95.

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