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The Role of Microvascular Damage in Photodynamic Therapy: The Effect of Treatment on Vessel Constriction, Permeability, and Leukocyte Adhesion¹

Department of Surgery, Division of Surgical Oncology [V. H. F., T. J. W., S. A. W.], and Department of Mathematics [P. B. C.], James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40292

Intravital microscopy of the rat cremaster muscle was used to evaluate changes in vessel constriction, vessel permeability, and leukocyte adhesion during and after photodynamic therapy (PDT). Animals were given Photofrin doses of 0–25 mg/kg i.v. 24 h before treatment. Cremaster muscles were exposed to 135 J/cm² light at 630 nm. Animals given 5 mg/kg Photofrin showed no vessel constriction or increase in vessel permeability to albumin. Doses of 10 and 25 mg/kg Photofrin caused a dose-related constriction of arterioles which was observed within the first minutes of illumination at the higher drug dose. After the initial constriction, arteriole response to PDT was biphasic in nature, with some vessels relaxing to nearly control levels while others remained fully constricted. Constriction of venules occurred only at the highest porphyrin dose studied (25 mg/kg) and was delayed in comparison to arteriole constriction. Photofrin doses which produced arteriole constriction also caused an increase in venule permeability to albumin, which occurred shortly after the start of light treatment and was progressive with time. Leakage began at specific sites along the venule wall but became uniform along the entire length of the venule by 1 h after treatment. Changes in the adherence of polymorphonuclear leukocytes to venule endothelium were also observed with PDT. Photofrin doses of 25 mg/kg and 45 J/cm² light were sufficient to cause polymorphonuclear leukocytes to become adherent to the vessel wall. A second group of animals was given indomethacin trihydrate to examine the involvement of cyclooxygenase products such as thromboxane in vessel response to PDT. Animals given 5 mg/kg indomethacin intraarterially 1 h before light treatment showed no constriction of arterioles or venules at all Photofrin and light doses studied. No increases in venule permeability to albumin were seen in this group of animals. This suggests that cyclooxygenase products including thromboxane are important in causing vessel constriction and changes in permeability during PDT. The initiating event which causes the release of these vasoactive agents remains unknown.

¹ Supported by PHS Grants CA51771 and CA47377, awarded by the National Cancer Institute, Department of Health and Human Services, by the Department of Surgery, and the James Graham Brown Cancer Center.

² To whom requests for reprints should be addressed, at Department of Surgery, University of Louisville, James Graham Brown Cancer Center, 529 South Jackson Street, Louisville, KY 40292.

Received 12/ 4/91. Accepted 7/ 7/92.

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