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Experimental Therapeutics, Preclinical Pharmacology |
Departments of Medicine [C. M. W., T. S., J. G.], Radiation Oncology [J. W. M., N. L. O.], and Dermatology [D. K. F., H. M.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4937
Photodynamic
therapy (PDT) using the silicon phthalocyanine photosensitizer Pc 4
[HOSiPcOSi(CH3)2(CH2)3N-(CH3)2]
is an oxidative stress associated with induction of apoptosis in
various cell types. We assessed the effectiveness of Pc 4-PDT on SW480
colon cancer xenografts grown in athymic nude mice. Animals bearing
xenografts were treated with 1 mg/kg body weight Pc 4 and
48 h later were irradiated with 150 J/cm2 672-nm light
from a diode laser delivered at 150 mW/cm2. Biochemical
studies were performed in xenografts resected at various time points up
to 26 h after Pc 4-PDT treatment, whereas tumor size was evaluated
over a 4-week period in parallel experiments. In the tumors resected
for biochemical studies, apoptosis was visualized by activation of
caspase-9 and caspase-3 and a gradual increase in the cleavage of the
nuclear enzyme poly(ADP-ribose) polymerase (PARP) to a maximum of
60% of the total PARP present at 26 h. At that time all Pc
4-PDT-treated tumors had regressed significantly. Two signaling
responses that have previously been shown to be associated with Pc
4-PDT-induced apoptosis in cultured cells, p38 mitogen-activated
protein kinase and p21/WAF1/Cip1, were examined. A marked increase in
phosphorylation of p38 was observed within 1 h after Pc 4-PDT
without changes in levels of the p38 protein. Levels of p21 were not
altered in the xenografts in correspondence with the presence of mutant
p53 in SW480 cells. Evaluation of tumor size showed that tumor growth
resumed after a delay of 9–15 days. Our results suggest that:
(a) Pc 4-PDT is effective in the treatment of SW480
human colon cancer xenografts independent of p53 status;
(b) PARP cleavage may be mediated by caspase-9 and
caspase-3 activation in the Pc 4-PDT-treated tumors; and
(c) p38 phosphorylation may be a trigger of apoptosis in
response to PDT in vivo in this tumor model.
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