Forsøksdyr: Evaluation of pharmacokinetic properties and efficacy of stromal targeting conjugate in xenografts model

Godkjenningsdato 05.06.2018

I. The purpose of the experiment/project:
The purpose of this experiment is to evaluate pharmacokinetic properties and efficacy of 227Th labelled conjugate in xenografts models.

II. The expected adverse effects on the animals:
Three main adverse effect for the mice in this experiments are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well being, sacrificing the animals with the fist signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.

III. The expected scientific benefits or benefits for society:
The selected target is differemtially expressed in stroma of epithelial cancers. The target protein is thought to be involved in the control of epithelial carcinogenesis. Targeting it allows spesific delivery of Th227, an alpha emitting isotope. This allows killing of resistant cancer cells, especially in triple negative breast cancer where choices of targets are limited.

IV. The number of animals and species:
In this study we aim to use up to 4 different models with different expression levels of the target, 2 with medium expression (approx. 50.000 targets per cell), one with low and one with high. All the models will be performed in NMRI athymic nude mice. For all the models we will conduct pharmacokinetic and efficacy studies, requiring 170 mice per model, requiring in total 680 mice.

V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed.
All the models we earlier establish in model development studies with identification of expression level, optimal time point for treatment, study duration, potential adverse conditions, take rate and magnitude of effect. Only the required number of animals will be used in the study.
Technicians conduction the study have long experience with similar studies using well refined techniques.