Establishment, Characterization and Evaluation of cancer models for efficacy studies in NSG mice

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

II. The expected adverse effects on the animals:
The 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 well being of the mice, sacrificing the animals with the fist signs of ulcer or the occurence of more than 10% weight reduction. For the metastatic disease, we will select the cell lines that have 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 of new test items 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 and vascularity. 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. The NOD Scid gamma (NSG) mouse strain will be chosen for tumor models that will not grow or have low tumor take in more immunocompetent mice, and further passage xenografts from the NSG mice to other mouse strains.

IV. The number of animals and species:
In this study we aim to establish models expressing different levels of different targets relevant for our targeted thorium conjugates projects. We will establish up to 10 new tumor models in NSG mice (10 models x 12 mice= a total of 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, various in vitro tests such as binding assays, in vitro efficacy etc. and project value evaluation. No models will be established unless necessary for further biodistribution/efficacy studies of our test items. 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 upcoming efficacy studies due to reduced variation in data.