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The characterization and significance of the complement system activated by photodynamic therapy in the treatment of solid tumors

University of British Columbia

Photodynamic therapy (PDT) is approved by health agencies throughout the developed world for the treatment of a variety of diseases, and continues to gain recognition as a treatment for neoplastic lesions. During PDT a light-sensitive drug (photosensitizer) is excited locally in tissue with light of appropriate wavelength. The transfer of energy from the excited photosensitizer to molecular oxygen (O2) results in the production of reactive oxygen species (ROS) that inflict damage to various cell components resulting in the disruption of tissue homeostasis. The aim of this project was to ascertain whether the complement (C) system is engaged in a PDT-treated solid tumor and if this plays a role in overall tumor response to treatment. The following summarizes the findings of this dissertation. C activation in response to PDT-inflicted tumor injury proceeds via the antibody-independent alternative pathway and results in significantly elevated levels of the fluid phase C protein C3 in both serum and Lewis lung carcinoma tumors. Other indications of C activity are the presence of the C3 breakdown fragment C3b and assembly of the membrane-inserted complex containing proteins C5b through C9. In mice bearing PDT-treated EMT6 tumors, a multitude of signals are released from the treated lesion into circulation to promote immune cell trafficking. Although a variety of inflammatory mediators such as IL-1β, IL-6, TNF-α, and histamine promote neutrophilia in mice following PDT the most significant effect was demonstrated by C. Blocking C activity prior to PDT also resulted in a significant decrease in tumor cures. A C3 knockout model (C3 k.o.) was employed to address the impact of the loss of C function on the long-term control of Lewis lung carcinoma tumors by PDT. Results suggest that the relevance of C activity may depend on the mechanism of action of the photosensitizer of choice and subsequent levels of tumor oxygen during light activation. Enhanced tumor O2 levels during treatment theoretically increased the probability of ROS production. Understanding the mechanism of how the C system responds to PDT-induced injury could lead to methods of improving the overall therapeutic benefit of treatment and gain wider acceptance for clinical applications.

Thesis/Dissertation

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2009-11-27

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http://hdl.handle.net/2429/15874

Pathology

University of British Columbia

UBCV

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