Forsøksdyr: Evaluation of nanomedical products in tumor models in A/J Min/+ mice.

Godkjenningsdato 10.06.2018

Godkjenningsperiode 10.06.2018-09.06.2022

The present study aims to characterize carcinogenesis and assess localization and efficacy of nanomedical products (contrast agents for MRI and potential therapeutic agents) in intestinal, cancerous lesions in A/J APC Min/+ mouse model. The study group has long experience using this model to address various aspects of colorectal cancer initiation, promotion, and progression.

To reduce the experimental period, Azoxymethane (AOM) will be used to enhance the intestinal tumor load. Thus, age and dose dependent susceptibility to AOM-induced tumorigenesis in this model will be characterized initially. The carcinogenic potential of AOM in different doses and at different ages is determined by scoring the number, size and spatial distribution of small lesions and tumors.

The accumulation of the nanomedical products (contrast agent for MRI and potential therapeutic agents) in intestinal cancerous lesions is determined by chemical analysis by Spago Nanomedical, and by histology and immunohistochemistry. The efficacy of the contrast agent for MRI is determined by MRI. The efficacy of the nanomedical product for therapeutic agents is determined by a reduction in number and size of lesions and tumors.

This mouse line is characterized by development of intestinal lesions spontaneously. The lesions normally do not affect the well-being of the animals within the experimental study period. Although the AOM enhances the prevalence of intestinal lesions, it is not expected that the wellbeing of the animals will be affected. The animals are closely monitored, and if the lesions become severe and animals develop clinical symptoms (rectal bleeding, discomfort), the animals will be euthanized. The diets will be available ad libitum. Handling of the animals will be kept to a minimum, only allowing ear-marking, weaning, weighing and moving when the cages are cleaned.

The expected scientific and societal value of this study are the characterization of carcinogenesis in the A/J APC (Min/+) mouse model, which is highly relevant for increasing knowledge about carcinogenesis in human colorectal cancer. In addition, this study contributes to the development of nanomedical products that selectively accumulates in tumors, which enables MRI diagnostics and therapeutic agents for destruction of cancer cells with increased precision and reduced side effects compared to the existing treatments.

In total, 1000 A/J (Min/+) and 150 A/J wildtype are included.

The A/J APC (Min/+) mouse model is well suited to study the susceptibility for formation of intestinal lesions, as well as tumor distribution, diagnostics and treatment. Due to the similarity between the gene defect in this mouse model and in human sporadic colorectal cancer, the model is used for studying carcinogenesis, diagnostics and treatment in colorectal cancer in humans. Although in vitro studies are helpful tools within cancer research, such studies do not enable reliable predictions regarding carcinogenesis, diagnostics and treatment, which are the main endpoints in these studies. After careful consideration, the performance of animal experiments provide the only possibility to include the entirety of physiological processes.