Photodynamic therapy with the phthalocyanine photosensitizer Pc 4 of SW480human colon cancer xenografts in athymic mice

Photodynamic therapy (PDT) using the silicon phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)(2)(CH2)(3)N-(CH3)(2)] is an oxidative stress associat ed with induction of apoptosis in various cell types. We assessed the effec tiveness 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 il radiated with 150 J/cm(2) 672-nm light from a diod e laser delivered at 150 mW/cm(2). Biochemical studies were performed in xe nografts resected at various time points up to 26 h after Pc 4-PDT treatmen t, whereas tumor size was evaluated over a 4-week period in parallel experi ments, In the tumors resected for biochemical studies, apoptosis was visual ized 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 max imum of similar to 60% of the total PARP present at similar to 26 h, At tha t time all Pc 4-PDT-treated tumors had regressed significantly, Two signali ng 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 p 38 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 correspond ence with the presence of mutant p53 in SW480 cells. Evaluation of tumor si ze 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 co lon cancer xenografts independent of p53 status; (b) PARP cleavage may be m ediated by caspase-9 and caspase-3 activation in the Pc 4-PDT-treated tumor s; and (c) p38 phosphorylation may be a trigger of apoptosis in response to PDT in vivo in this tumor model.