Effect of tumor host microenvironment on photodynamic therapy in a rat prostate tumor model.
OBJECTIVE
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.


METHODS
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/cm(2) at 50 mW/cm(2), 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/cm(2) at 50 mW/cm(2), 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.
Chen
Bin
B
Thayer School of Engineering, 80000 Cummings Hall, Dartmouth College, Hanover, NH 03755, USA. bin.chen@dartmouth.edu
Pogue
Brian W
BW
Zhou
Xiaodong
X
O'Hara
Julia A
JA
Solban
Nicolas
N
Demidenko
Eugene
E
Hoopes
P Jack
PJ
Hasan
Tayyaba
T
D000818:Animals; D004195:Disease Models, Animal; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011166:Porphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D012039:Regional Blood Flow; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000077362:Verteporfin
D017319:Photosensitizing Agents; D011166:Porphyrins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077362:Verteporfin; D010100:Oxygen