Local photodynamic therapy (PDT) of rat C6 glioma xenografts with Pd‐bacteriopheophorbide leads to decreased metastases and increase of animal cure compared with surgery

Abstract

Photodynamic therapy (PDT), locally applied to solid C6 rat glioma tumors in the foot of CD1 nude mice, eradicated the primary tumor and also decreased the rate of groin and lung metastases. Pd-Bacteriopheophorbide (Pd-Bpheid), a novel photosensitizer synthesized in our laboratory, was used in our study. The primary lesion in the hind leg was treated by an i.v. injection of 5 mg/kg of Pd-Bpheid and immediate illumination (650 -800 nm, 360 J/cm 2 ). This protocol and the surgical amputation of the leg were compared for local and metastasis responses. Following PDT, hemorrhage, inflammation with tumor necrosis and flattening were observed and histologically verified in the photodynamically treated tumor. Whereas local tumor control rates were up to 64% following PDT, in surgically treated animals, local tumor control was absolute. The rates of metastases in the groin and the lungs were at least 12-fold lower in the photodynamically treated animals compared with untreated or surgerytreated groups. The overall cure rates after PDT or surgery were 36% and 6%, respectively, at 8 weeks. These findings suggest that local PDT with Pd-Bpheid, which acts primarily on the tumor vasculature, efficiently eradicates the solid C6 tumors. In addition, the local PDT of the primary lesion has beneficial therapeutic effects on remote C6 metastasis, which is not obtained with surgery. It is therefore suggested, that although surgery is highly efficient for the immediate removal of the primary tumor, it lacks such systemic, therapeutic effects on distant metastases. Pd-Bpheid-PDT may thus offer a potentially superior curative therapy for C6 glioma tumors in the limb by eradicating the target tumor and by reducing the rate of metastasis in the groin and lung, possibly due to innate immunity. © 2002 Wiley-Liss, Inc. Key words: photodynamic therapy; surgery; Pd-bacteriopheophorbide; C6 glioma tumor; metastasisPhotodynamic therapy (PDT) is based on the destruction of tumors by cytotoxic reactive oxygen species (ROS) produced upon local tumor illumination in patients administered with a photosensitizer. 1-3 Following health agency approval for photofrin-based PDT in many countries, this anti-cancer treatment modality entered clinical use for the local treatment of an increasing number of indications including skin, esophageal, lung, gastric, cervical and bladder cancers. 4 PDT is usually considered a local anti-tumor treatment modality. However, reports from several laboratories suggest that PDT also induces beneficial systemic effects. Following in vitro hematoporphyrin-based PDT, adhesiveness and metastatic potential decline in DHD-K12-cultured colon carcinoma cells. Moreover, intravenous or s.c. injection of these PDT-treated cells to rats resulted in a reduced number of lung metastases compared with untreated cell injection. 5,6 Although this observation may be due to local photodynamic damage, the potential beneficial effect may be viewed as systemic. Other in vivo studies showed that local PDT with various photosensitizers mediates ...

Effect of 5-ALA-PDT on VEGF and PCNA expression in human NPC-bearing nude mice

“…Some reports have shown that PDT can markedly inhibit distant metastasis of tumors in vivo (10,20,31), while others suggest that PDT can facilitate metastasis (31). In this research we did observe distant metastasis and blood vessel infiltration under the microscope in tumor tissue, indicating the metastatic characteristic behavior of CNE2 cells after ALA-PDT.…”

“…In the preliminary study we found that nude mice bearing CNE2 NPC tumors have distant metastasis following 5-ALA (aminolevulinic acid)-PDT (data not shown). However, reports from several other laboratories suggest that PDT decreases metastasis compared to results obtained with surgery (19,20). Following in vitro HPD (hematoporphyrin)-based PDT, adhesion to extracellular matrix (ECM) and metastatic potential declined in DHD-K12-cultured colon carcinoma cells (21), and the same research group observed similar results in vivo (22).…”

CD8+ T cell-mediated control of distant tumours following local photodynamic therapy is independent of CD4+ T cells and dependent on natural killer cells

“…To address this hypothesis the effect of PDT treatment of s.c. tumours on the growth of established lung tumours in immuno-competent mice bearing concomitant s.c. and lung tumours was examined. Previous studies that have examined the effect of local PDT on distant tumours have done so in the absence of an intact immune system (Schreiber et al, 2002), were unable to detect control of distant disease (van Duijnhoven et al, 2003), performed PDT before establishment of distant tumours (Momma et al, 1998), or have not discerned a mechanism by which PDT inhibits the growth of tumours outside the treatment field (Gomer et al, 1987;Blank et al, 2001;Castano et al, 2003). In the current study, we demonstrate that control of the growth of tumours present outside the treatment field is dependent upon an intact immune system, is mediated by CD8 þ T cells and is accompanied by induction of anti-tumour immune memory responses.…”

Contrast-Aided Diagnostic Ultrasound Does Not Enhance Lung Metastasis in a Mouse Melanoma Tumor Model

“…Established methods were used to test for enhanced lung metastasis, which have been used for the study of metastasis resulting from therapeutic or diagnostic manipulation of tumors implanted on the hind leg. 11,[20][21][22] A suspension of 1 million cells in 0.05 mL was injected subcutaneously on the right hind leg of each mouse under ether anesthesia. Treatment was applied after 10 days of tumor growth.…”