METHODS AND MATERIALS: The R3327-MatLyLu rat prostate
tumor model was used in this study.
Photosensitizer verteporfin distribution was quantified by fluorescence microscopy.
Tumor blood flow changes were monitored by
laser-Doppler system and tumor hypoxia was quantified by the immunohistochemical staining for the hypoxic marker EF5. The
therapeutic effects of
PDT treatments were evaluated by the histologic examination and
tumor regrowth assay.
RESULTS: Fluorescence microscopic studies indicated that
tumor localization of
verteporfin changed from predominantly within the
tumor vasculature at 15 min after injection, to being throughout the
tumor parenchyma at 3 h after injection. Light treatment (50 J/cm(2)) at 15 min after
verteporfin injection (0.25 mg/kg, i.v.) induced significant
tumor vascular damage, as manifested by
tumor blood flow reduction and increase in the
tumor hypoxic fraction. In contrast, the vascular effect observed after the same light dose (50 J/cm(2)) delivered 3 h after administration of
verteporfin (1 mg/kg, i.v.) was an initial acute decrease in blood flow, followed by recovery to the level of control. The EF5 staining revealed no significant increase in hypoxic fraction at 1 h after
PDT using 3 h
drug-light interval. The combination of 3-h interval
PDT and 15-min interval
PDT was more effective in inhibiting
tumor growth than each individual
PDT treatment. However, it was found that the combined treatment with the sequence of 3-h interval
PDT before 15-min interval
PDT led to a superior antitumor effect than the other combinative
PDT treatments. Histologic studies confirmed that this combined treatment led to damage to both
tumor vasculature and
tumor cells. Importantly, the combined
PDT treatment did not increase normal tissue damage and tissue recovered well at 60 days
after treatment.
CONCLUSIONS: Our results suggest that targeting both
tumor vascular and cellular compartments by combining a long-interval
PDT with a short-interval
PDT can be an effective and safe way to enhance
PDT damage to
tumor tissue.