Efficiency of 5-ALA mediated photodynamic therapy on hypoxic prostate cancer: A preclinical study on the Dunning R3327-AT2 rat tumor model

摘要

Objectives: To evaluate photodynamic therapy (PDT) using 5-ALA-induced protoporphyrin IX (PPIX) in an in vivo hypoxic tumor model and its monitoring using MRI. Materiel and methods: Dunning R3327-AT2 tumors were grafted in the neck of Copenhagen rats. PDT using 150mg 5-ALA/kg i.v. was performed by focal interstitial illumination of the photosensitized tumor (λ = 633nm; fluence = 100J/cm~2). MRI at baseline and 2 days after treatment (T1, T2 and dynamic gadolinium enhanced sequences) were performed. Necrosis volumes were determined on post-procedure MRI. Tumors were resected 2 days post-PDT and obtained necrosis was determined histopathologically. Intra-tumoral PPIX distribution was evaluated using confocal microscopy and tissue porphyrin quantification. Results: Twenty rats were treated divided into three groups: continuous (n = 7), fractionated illumination (n = 7), and a control group receiving only light or only ALA or neither (n = 6). Baseline MRI confirmed the hypoxic character of tumors. Necrosis volumes determined on post-treatment MRI were not reproducible and presented with important geometric and volumetric variability. Average necrosis volumes of 0.39cc (0-0.874cc) in the continuous group, 0.24cc (0.107-0.436cc) in the fractionated group and 0.012cc (0-0.071 cc) in the control group were observed. Intra-tumoral PPIX distribution was heterogeneous and PPIX quantification revealed low intra-tumoral concentration. Conclusion: Necrosis volumes induced by 5-ALA-mediated PDT were highly variable and non reproducible, probably because of lack of intra-tissular oxygen. Photosensitizer was poorly represented inside the tumor and its distribution was heterogeneous. Our study suggests that 5-ALA-mediated PDT might not be the best management option for hypoxic prostatic adeno-carcinoma.