Modelo matemático de distribuição larga de dose limiar em tumores submetidos a múltiplas sessões de terapia fotodinâmica / Mathematical model for broad distribution of threshold dose in tumors treated with multiple photodynamic therapy sessions

AUTOR(ES)
DATA DE PUBLICAÇÃO

2010

RESUMO

Photodynamic therapy is a well known treatment option for many types of malignant and nonmalignant lesions. This technique causes cell damage through a photochemical reaction, generating oxidative agents responsible for tumor cell killing. In several cases, multiple PDT-sessions are needed to promote cancer eradication. However, several clinical studies have been reported an increase of tumor resistance after a PDT-session. We present a theoretical model to describe the effects caused by successive PDT sessions based on the consequences of a partial response caused by the threshold dose distribution within the hypothetical tumor. In this model, we assume that this threshold dose distribution is represented by a Modified Gaussian Distribution. In terms of threshold dose, higher values imply higher resistance to PDT. If the distribution is broad, the treatment cannot result in the killing of all tumor cells. The survival cell fraction promotes a tumor regrowth with different characteristics compared to the original cell population. We applied the model in a hypothetical tumor to exemplify the idea here presented. The qualitative analysis extracted from our theoretical model shows a behavior that is in agreement with results obtained in our results from in vitro experiments and several clinical observations. To investigate the occurrence of a selection of higher threshold dose cells, an experiment that evaluated the response of tumor cells after multiple sessions of photodynamic therapy was carried out. To simulate this procedure, successive sessions of PDT in hepatocellular carcinoma cells (HepG2) were performed. A time interval between PDT-sessions was respected to allow surviving cells division, resulting in a new cell culture. The photosensitizer used in the experiments was Photogem® and a 630 ± 10nm irradiation was performed. The result of in vitro experiments provided evidence of increasing resistance of HepG2 cells after successive PDT-sessions. This increase is predicted by the theoretical model and may be related to variations in the tumor cell population, which is expressed by the variation of the distribution of threshold dose, according to the model. However, the increased PDT resistance of the cell population provided by the theoretical model is more pronounced than the one experimentally observed. Based on tumor cell variability, the simulations demonstrated that insufficient light dose can induce an increase in tumor resistance to further PDT sessions. This model maybe used to evaluate which type of threshold dose distribution we can find in real tumors, and the consequences caused by light attenuation observed from the illuminated surface and deeper tumor regions. This proposed model shows relative agreement to clinical literature. However, further experimental observations shall improve the model here presented. The idea presented in this study shall motivate further studies to identify the importance of cell threshold distribution in tumors submitted to PDT techniques.

ASSUNTO(S)

modelo teórico photodynamic therapy tumor response cancer cells variability resposta tumoral theoretical model threshold dose distribution variabilidade celular terapia fotodinâmica distribuição de dose limiar de luz

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