Forsøksdyr: Evaluation of changes in tumor permeability following treatment with TTC

Godkjenningsdato 22.05.2018

Godkjenningsperiode 22.05.2018-21.05.2022

I. The purpose of the experiment/project:
The purpose of this experiment is to evaluate changes in tumor permeability following treatment of subcutaneous tumors of human xenografts in athymic nude mice.

II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment 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 first 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:
Tumor microenvironment, including irregular blood vessels, vessel permeability and, as a result, increased intratumoural pressure are important for delivery of drugs into the tumors. Several types of drugs are being introduced to normalize blood vessels, reducing interstitial pressure and enabling better delivery of therapeutic agents. Reduction of intratumoural pressure can be also achieved by killing the cancer cells leading to decreased cell density. in this study we hypothesize that first dose of alpha-emitting therapeutics (TTC) will alter tumor permeability even in tumor with low TTC uptake from circulation. Increased tumor permeability will allow increased tumor uptake of the following doses of TTC. Such effect are known for small molecular therapeutics like common cytotoxic drugs with some tumor penetration. However, for high molecular therapeutics, for example antibody based therapy with this effect can be limited. For TTCs, with alpha particles penetrating up to 40 um, effect can be achieved without tumor uptake, only through a bystander effect. In this study we aim to investigate effect of multiple dosing on tumor penetration for tumors with initially low, medium and high uptake.

IV. The number of animals and species:
In this study we aim to use 3 different models with different initial tumor physiology, and thus different uptake of TTC. All the models will be performed in NMRI athymic nude mice. For all the models we will conduct pharmacokinetic and efficacy studies, requiring 120 mice per model, requiring in total 360 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. Moreover, all the model were characterized in both pharmacokinetic and efficacy study with a single treatment. 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.