| Summary: | 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. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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