In vivo testing of beta-sitosterol analogues
1. Background
Brain metastasis is associated with extremely poor patient prognosis, and current treatments are not effective. In order to study cancer metastasis, more appropriate preclinical models are needed. We have established a unique human metastasis model for studying metastatic progression, where we inject human metastatic tumor cells into the left cardiac ventricle of immunodeficient mice. We have done a detailed characterisation of the blood-brain barrier (BBB) in the tumor model. We are currently sharing our model and knowledge with several other research groups (in UK, Germany, USA, The Netherlands).
We have previously shown that the plant phytosterol beta-sitosterol effectively inhibits brain metastasis in vitro and in vivo. We have an ongoing collaboration with a research group at MD Anderson Cancer Center (Houston, TX), who has synthesized 30 beta-sitosterol analogues for us. The idea is to try to maximixe in vivo uptake, solubility and treatment effects by modulating the chemical structure of beta-sitosterol.
We have initial in vitro data, showing promising results for two of these compounds (WP1760 and WP1787). We would now like to test these two compound further in vivo.
2. Aim of the research
The aim of this project is to bring our research into a phase 1 clinical trial on cancer metastasis patients. The current application thus describes a set of important experiments, in order to achieve this.
3. Expected harm to the animals
Moderate. The compound that we want to test on animals, have previously been used on patients to treat other conditions than cancer, and no side effects were found Kippl et al, Br J Urol 1997). The intracardial injection technique is to our experience tolerated well by the animals. However, due to increasing tumor burden in the brain, the mice will from around week 5 to various degree show reduced activity, loss of weight and increased tumor burden on MRI, which will be closely monitored according to our score sheet”.
4. Expected benefit for science and society
If successful, we hope to achieve a new and better treatment of cancer patients with metastatic spread to the brain.
5. How many and kind of animals to be used
We plan to use up to a total of 48 nod/scid mice and and 48 nude rats in our experiments.
6. 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 metastatic spread of cancers in patients. Therefore, we are of the opinion that in vitro experiments are not sufficient to obtain our aim, which is to bring new treatment into the clinic.
Brain metastasis is associated with extremely poor patient prognosis, and current treatments are not effective. In order to study cancer metastasis, more appropriate preclinical models are needed. We have established a unique human metastasis model for studying metastatic progression, where we inject human metastatic tumor cells into the left cardiac ventricle of immunodeficient mice. We have done a detailed characterisation of the blood-brain barrier (BBB) in the tumor model. We are currently sharing our model and knowledge with several other research groups (in UK, Germany, USA, The Netherlands).
We have previously shown that the plant phytosterol beta-sitosterol effectively inhibits brain metastasis in vitro and in vivo. We have an ongoing collaboration with a research group at MD Anderson Cancer Center (Houston, TX), who has synthesized 30 beta-sitosterol analogues for us. The idea is to try to maximixe in vivo uptake, solubility and treatment effects by modulating the chemical structure of beta-sitosterol.
We have initial in vitro data, showing promising results for two of these compounds (WP1760 and WP1787). We would now like to test these two compound further in vivo.
2. Aim of the research
The aim of this project is to bring our research into a phase 1 clinical trial on cancer metastasis patients. The current application thus describes a set of important experiments, in order to achieve this.
3. Expected harm to the animals
Moderate. The compound that we want to test on animals, have previously been used on patients to treat other conditions than cancer, and no side effects were found Kippl et al, Br J Urol 1997). The intracardial injection technique is to our experience tolerated well by the animals. However, due to increasing tumor burden in the brain, the mice will from around week 5 to various degree show reduced activity, loss of weight and increased tumor burden on MRI, which will be closely monitored according to our score sheet”.
4. Expected benefit for science and society
If successful, we hope to achieve a new and better treatment of cancer patients with metastatic spread to the brain.
5. How many and kind of animals to be used
We plan to use up to a total of 48 nod/scid mice and and 48 nude rats in our experiments.
6. 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 metastatic spread of cancers in patients. Therefore, we are of the opinion that in vitro experiments are not sufficient to obtain our aim, which is to bring new treatment into the clinic.