In Vitro and In Vivo Efficacy of Photofrin® and Pheophorbide a, a Bacteriochlorin, in Photodynamic Therapy of Colonic Cancer Cells¶

Abstract

This study was designed to investigate the efficacy of photodynamic therapy (PDT) in treating colonic cancer in a preclinical study. Photofrin, a porphyrin mixture, and pheophorbide a (Ph a), a bacteriochlorin, were tested on HT29 human colonic tumor cells in culture and xenografted into athymic mice. Their pharmacokinetics were investigated in vitro, and the PDT efficacy at increasing concentrations was determined with proliferative, cytotoxic and apoptotic assessments. The in vivo distribution and pharmacokinetics of these dyes (30 mg/kg, intraperitoneal) were investigated on HT29 tumor-bearing nude mice. The inhibition of tumor growth after a single 100 J/cm2 PDT session was measured by the changes in tumor volume and by histological analysis of tumor necrosis. PDT inhibited HT29 cell growth in culture. The cell photodamage occurred since the time the concentrations of Ph a and Photofrin reached 5.10(-7) M (or 0.3 microg/mL) and 10 microg/mL, respectively. A photosensitizer dose-dependent DNA fragmentation was observed linked to a cleavage of poly(ADP-ribose) polymerase and associated with an increased expression of mutant-type p53 protein. PDT induced a 3-week delay in tumor growth in vivo. The tumor injury was corroborated by histological observation of necrosis 48 h after treatment, with a correlated loss of specific enzyme expression in most of the tumor cells. In conclusion, PDT has the ability to destroy human colonic tumor cells in vitro and in vivo. This tumoricidal effect is likely associated with a p53-independent apoptosis, as HT29 cells express only mutated p53. The current study suggests a preferential use of Photofrin in PDT of colonic cancer because it should be more effective in vivo than Ph a as a consequence of better tumor uptake.

The c-MET/PI3K Signaling Is Associated with Cancer Resistance to Doxorubicin and Photodynamic Therapy by Elevating BCRP/ABCG2 Expression

“…Pba was shown to cause mitochondria-dependent apoptosis in cultured cancer cells (Tang et al, 2009). In vivo animal models also demonstrated that Pba impedes tumor growth in colon carcinoma and hepatoma xenograft models (Hajri et al, 2002;Li et al, 2007). However, the development of PDT resistance has been displayed: colon cancer cells repeatedly exposed to PDT agents developed resistance to PDT (Singh et al, 2001).…”

The Sensitivity of Cancer Cells to Pheophorbide a-Based Photodynamic Therapy Is Enhanced by NRF2 Silencing

“…Several in vivo animal studies have supported the efficacy of Pba-PDT in preventing tumorigenesis. For instance, a liposomal preparation of Pba-PDT delayed tumor growth in a colon carcinoma HT29 xenograft [19]. Intravenous administration of 0.3 mg/kg Pba followed by light irradiation significantly inhibited tumor growth in nude mice harboring a human hepatoma xenograft [11].…”

Improved Photodynamic Efficacy of Zn(II) Phthalocyanines via Glycerol Substitution

“…Irradiation of DPBF-isopropanol solution in the absence of photosensitizers was also carried out as negative control. The singlet oxygen generation rate for each phthalocyanine was determined relative to Pha which has a singlet oxygen quantum yield of 0.52 in alcohol [24].…”