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Effect of Tumor Host Microenvironment on Photodynamic Therapy in a Rat Prostate Tumor Model

¹ Thayer School of Engineering, Dartmouth College and ² Department of Diagnostic Radiology, Dartmouth Medical School, Hanover, New Hampshire; ³ Division of Biostatistics, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center and ⁴ Department of Surgery, Dartmouth Medical School, Lebanon, New Hampshire; and ⁵ Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Brian W. Pogue or Bin Chen, Thayer School of Engineering, 8000 Cummings Hall, Dartmouth College, Hanover NH 03755. Phone: 603-646-3861; Fax: 603-646-3856; E-mail: pogue{at}dartmouth.edu or bin.chen{at}dartmouth.edu.

Purpose: Tumor host microenvironment plays an important role in tumor growth, metastasis, and response to cancer therapy. In this study, the influence of tumor host environment on tumor pathophysiology, photosensitizer distribution, and photodynamic therapy (PDT) treatment effect was examined in the metastatic at lymph node and lung (MatLyLu) rat prostate tumor.

Experimental Design: MatLyLu tumors implanted in different host environment [i.e., orthotopically (in the prostate) or s.c.] were compared for difference in vessel density, average vessel size, vascular permeability, tumor vascular endothelial growth factor production, and tumor oxygenation. Uptake of photosensitizer verteporfin in tumors in both sites was determined by fluorescence microscopy. To compare tumor response to PDT, both orthotopic and s.c. MatLyLu tumors were given the same doses of verteporfin and laser light treatment, and PDT-induced tumor necrotic area was measured histologically.

Results: Orthotopic MatLyLu tumors were found to grow faster, have higher vessel density and more permeable vasculature, have higher vascular endothelial growth factor protein levels, and have lower tumor hypoxic fraction than the s.c. tumors. Uptake of photosensitizer verteporfin in the orthotopic tumor was higher than in the s.c. tumors at 15 minutes after injection (1 mg/kg, i.v.), and became similar at 3 hours after injection. For the vascular targeting PDT treatment (0.25 mg/kg verteporfin, 50 J/cm² at 50 mW/cm², 15 minutes drug-light interval), there was no significant difference in PDT-induced tumor necrotic area between the orthotopic and s.c. tumors, with 85% to 90% necrosis in both types of tumors. However, tumor necrosis induced by the cellular targeting PDT (1 mg/kg verteporfin, 50 J/cm² at 50 mW/cm², 3 hours drug-light interval) was significantly different in the orthotopic (64%) versus the s.c. (29%) tumors.

Conclusions: Tumor host environment can significantly affect photosensitizer verteporfin distribution and PDT treatment effect. Verteporfin-PDT regimen targeting tumor cells is more sensitive to such influence than the vascular targeting PDT. Our study showed the importance of tumor host environment in determining tumor physiologic properties and tumor response to PDT. To obtain clinically relevant information, orthotopic tumor model should be used in the experimental studies.

Key Words: photodynamic therapy (PDT) • verteporfin • tumor microenvironment • tumor vasculature • tumor oxygenation • tumor response

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