Forsøksdyr: Establishment, Characterization and Evaluation of cancer models for efficacy studies (copy)

Godkjenningsdato 24.04.2018

I. The purpose of the experiment/project:
The purpose of this experiment is to establish several in vivo models for further use of this models for novel test item evaluation.

II. The expected adverse effects on the animals:
Three main adverse effect for the mice in this experiments are ulcerations of the tumors, cachexia and metastasis. To eliminate the adverse effects, we will daily follow the mice well being, sacrificing the animals with the fist signs of ulcer or 10% weight reduction. For the metastatic disease, we selected the cell line that has not been know to cause detectable metastasis during the time period of subcutaneous tumor growth. Else, animals will be immediately sacrificed with first signs of distress.

III. The expected scientific benefits or benefits for society:
This experiment aims to select the optimal tumor model satisfying the criteria mentioned below. Selection of the optimal model follow reduction and refinement principles, as an optimal model will allow use of fewer animals without noticeable impact on animal health, provide a quicker path towards the studies for regulatory approval and generate a toolbox of well characterized tumor models for future projects and new targets.

Unlike models that can be suitable for in vitro studies, models for in vivo studies should be carefully selected with regards to tumor growth, vascularity and immune response. Delivery of the conjugate drug to the tumor depends on two parameters - the amount of target protein on the surface of the cells and the perfusion of the tumor. We aim to establish several tumor models with different expression profile and vascular network and permeability of these blood vessels. As immune response in the animal following treatment that plays along the drug in tumor killing, using mice with intact immune system make the model more similar to the one that can be found in humans. Such models are typically isographts, mouse tumor in the mouse of the same strain.

IV. The number of animals and species:
In this study we aim establish models expressing different levels of different targets relevant for out targeted thorium conjugates projects. We will establish up to 10 new human-derived xenografts (200 athymic nude mice), up to 10 mouse syngeneic models in immune competent Balb/c mice (200 mice), up to 10 mouse syngeneic models in immune competent C57Bl6 mice (200 mice) and up to 6 mouse syngeneic models in immune competent CBA mice (120 mice).

V. How will the requirements for 3R be accomplished by the experiment/project:
All the models considered to be established will undergo evaluation consisting of literature search for identification of whether the cell line is suitable for the model, various in vitro tests such as binding assays, in vitro efficacy etc. and project value evaluation. No models will be established unless necessary for biodistriburtion/efficacy studies. Information from model development studies will be used to find the optimal treatment timing, growth rate and termination allowing to reduce the number of mice in efficacy study due to reduced variation in data.