Studies of radionuclide-based products and relevant combinations for treatment of peritoneal cancer
I) The purpose of the experiment/project:
This project has two main focuses: (1) To evaluate intraperitoneal treatment of peritoneal cancers with alpha-emitting radionuclides with different half-lives and combined with different carriers, and (2) investigate the combination of intraperitoneal radionuclide therapies with another class of anticancer agent that might have synergistic effect with alpha-radiation.
II) The expected adverse effects on the animals:
The main expected adverse effects for the mice are related to tumor growth.The intraperitoneal tumor models can cause moderate discomfort and/or influence normal behavior in the advanced stage of the disease. The mice will be closely monitored so that the pre-defined study specific humane endpoints are respected. In addition, transient weight loss and slight reduction in hematological parameters may occur for some of the treatments, but time to recovery should be maximum two weeks.
III) The expected scientific benefits or benefits for society:
There is a large unmet medical need for patients with cancer that has spread into the peritoneal cavity. Intraperitoneal therapy with alpha-emitting radionuclides may enable efficient treatment of such disease. We have previously developed Radspherin®, where microparticles function as a carrier for the alpha-emitter radium-224 which is now being investigated in phase I clinical trials. In this project, we will generate data of head-to-head comparisons of Radspherin® and new candidate compounds, consisting of different carriers labeled with other alpha-emitting radionuclides. These studies are important to enhance our understanding of aspects for optimizing intraperitoneal radionuclide therapy. Further, if an increased therapeutic effect can be demonstrated in the animal studies where intraperitoneal radionuclide therapy is combined with anticancer agents already approved for clinical use, this can potentially expand the patient population benefiting from the treatment in the future.
IV) The number of animals and species:
We are requesting 580 female, athymic nude mice to accomplish the proposed research objectives.
V) How will the requirements for 3R be accomplished by the experiment/project:
In vitro experiments, including cell assays, are performed prior to initiation of animal studies. These studies are an important basis for selection of which test items/combination treatments to be evaluated in vivo, but can not be used to completely replace studies in animals. All experiments have been planned in order to use the minimum number of animals while at the same time ensure reliability of the generated data. The participants in the study have experience with the tumor models and techniques from previous FOTS IDs (9884 and 7274), and we have refined and improved our criteria for humane endpoints in the tumor bearing mice. Our aim is to carry out the study causing minimal distress for the mice by frequent monitoring and sound selection of humane endpoints.
This project has two main focuses: (1) To evaluate intraperitoneal treatment of peritoneal cancers with alpha-emitting radionuclides with different half-lives and combined with different carriers, and (2) investigate the combination of intraperitoneal radionuclide therapies with another class of anticancer agent that might have synergistic effect with alpha-radiation.
II) The expected adverse effects on the animals:
The main expected adverse effects for the mice are related to tumor growth.The intraperitoneal tumor models can cause moderate discomfort and/or influence normal behavior in the advanced stage of the disease. The mice will be closely monitored so that the pre-defined study specific humane endpoints are respected. In addition, transient weight loss and slight reduction in hematological parameters may occur for some of the treatments, but time to recovery should be maximum two weeks.
III) The expected scientific benefits or benefits for society:
There is a large unmet medical need for patients with cancer that has spread into the peritoneal cavity. Intraperitoneal therapy with alpha-emitting radionuclides may enable efficient treatment of such disease. We have previously developed Radspherin®, where microparticles function as a carrier for the alpha-emitter radium-224 which is now being investigated in phase I clinical trials. In this project, we will generate data of head-to-head comparisons of Radspherin® and new candidate compounds, consisting of different carriers labeled with other alpha-emitting radionuclides. These studies are important to enhance our understanding of aspects for optimizing intraperitoneal radionuclide therapy. Further, if an increased therapeutic effect can be demonstrated in the animal studies where intraperitoneal radionuclide therapy is combined with anticancer agents already approved for clinical use, this can potentially expand the patient population benefiting from the treatment in the future.
IV) The number of animals and species:
We are requesting 580 female, athymic nude mice to accomplish the proposed research objectives.
V) How will the requirements for 3R be accomplished by the experiment/project:
In vitro experiments, including cell assays, are performed prior to initiation of animal studies. These studies are an important basis for selection of which test items/combination treatments to be evaluated in vivo, but can not be used to completely replace studies in animals. All experiments have been planned in order to use the minimum number of animals while at the same time ensure reliability of the generated data. The participants in the study have experience with the tumor models and techniques from previous FOTS IDs (9884 and 7274), and we have refined and improved our criteria for humane endpoints in the tumor bearing mice. Our aim is to carry out the study causing minimal distress for the mice by frequent monitoring and sound selection of humane endpoints.