Forsøksdyr: Preventing brain metastases by stabilizing the blood-brain barrier


Godkjenningsdato 23.01.2018

Background
Malignant brain tumors are associated with poor patient prognosis, and current treatments are not effective. To study brain metastases, appropriate preclinical models are needed. We have established unique animal models for studying metastatic progression, either by injecting human metastatic tumor cells into the left cardiac ventricle of immunodeficient mice, or by injecting the same cells subcutaneously into nod/scid mice. We will now study how the blood-brain barrier (BBB) affects the metastatic properties of tumor development in the brain.

We aim to study whether a vascular destabilization of the BBB is a prerequisite for successful formation of brain metastases. If so, is a strategy where stabilization of the BBB is performed, sufficient to prevent formation of brain metastases.

Expected harm to animals
The compound that we want to test on the mice (AKB-9785), do not cause any harm to the animals, as shown previously in animal studies. Injections and imaging is causing mild harm to the animals, while tumor growth in the brain will cause moderate harm to the animals.

Expected benefit for science and society
We hope to achieve an improved treatment of patients with brain metastases.

How many and kind of animals to be used
78 nod/scid mice.

How the demand on RRR is to be achieved
We need to use animal models in our research, as in vitro models do not reflect the 3D structural behavior and physiological conditions in animals, and these conditions are crucial for intracranial tumor growth. Therefore, in vitro experiments are not sufficient to obtain our aim, which is to bring new treatment into the clinic.
Refinement: The injection techniques used, is causing mild harm to the animals. We use 2 trained people during the injections, one responsible for the injections, and the other responsible for animal care. The animals are placed onto a heating pad, and we use ultrasound guidance during intracardiac injections, which ensure fast and accurate injections. During imaging, two trained persons are present, one to prepare and monitor the animals, and the other to operate the imaging instrumentation. Heating is used. The imaging procedures do not cause any harm to the animals.
Regarding tumor development; the animals are monitored daily by trained people, and weighed twice/week. Regular imaging as described is important, as this will reveal tumor burden before detecting any symptoms in animal behavior. The last two weeks before sacrifice, the animals show progressive signs of discomfort, and analgetics will be considered.
Reduction: We are using ultrasound-guided injections of tumor cells into the left cardiac ventricle of the mice, which increases our success rate from previous 80% (when we did free-hand injections) to 100%. Thus, we can cut down the number of animals in each experimental group with 2 animals (from 14 to 12 animals).