DKFZ: Combination of low-dose chemotherapy and antibodies reduces the development of metastases
Mice with malignant tumors who received low-dose chemotherapy in combination with an antibody against a central control protein of blood vessel cells develop fewer metastases and survive longer. This is the result of a study by the German Cancer Research Center (DKFZ) and the Medical Faculty of Heidelberg University. According to the scientists, the combination therapy even works several times against the settlement of metastases. In this way, it prevents blood vessels from supplying the newly formed metastases. At the same time, the treatment reduces the number of certain immune cells, which in turn promote the settlement of cancer cells, according to a message from the DKFZ.
New therapy fights metastases and is gentler on the patient. If a tumor is surgically removed, the patient is considered cancer-free. However, the malignant tumor has often spread. To combat these cancer cells, doctors usually advise chemotherapy. However, this treatment is extremely stressful for the patient. In addition, the cells are undetectable and it is therefore not clear which patient actually benefits from chemotherapy. "This is a big dilemma for many cancer patients: Should they choose high-dose chemotherapy with all the serious side effects or accept a higher risk of metastases instead?" Says Professor Hellmut Augustin from the DKFZ. His research group therefore looked for more gentle methods that prevent the development of metastases.
In doing so, the scientists took into account new research findings that attribute the wall cells of the blood vessels (endothelial cells) to great importance for tumor growth. The background to this is the process of angiogenesis, in which tumor cells cause blood vessels to form new capillaries that supply the tumor and promote its growth.
In addition, the endothelial cells themselves also form factors that promote the growth of tumors. The researchers around Augustin therefore not only wanted to prevent the formation of vessels in the tumors, but also to suppress the production of these growth factors. They chose the molecule angiopoietin-2 as the starting point for their study, which is formed by endothelial cells and plays an important role in angiogenesis.
Mice lived longer thanks to the new therapy against metastases. The researchers conducted their investigation on mice to which breast or lung cancer cells had been transferred. After the tumors reached an early stage of growth, they were surgically removed. Then the experimental animals received different types of chemotherapy. Some mice were also treated with a blocking antibody against angiopoietin-2.
As it turned out, chemotherapy alone was not effective. In combination with the antibody, however, the mice developed significantly fewer metastases than the untreated animals. The most effective was a combination therapy with the antibody and a so-called metronomic chemotherapy, in which the cytostatic substances are administered permanently in low doses. In contrast to conventional high-dose chemotherapy, metronomic chemotherapy does not primarily work against the tumor cells themselves, but prevents the settlement of certain cells from the bone marrow in the tumor, which also promote tumor growth. The animals treated with this combination therapy lived longer than the mice that received only the antibody.
Inhibition of angiopoietin-2 prevents immigration of cancer-promoting immune cells into the vicinity of the tumor . Blocking angiopoietin-2, on the other hand, caused far fewer cancer-promoting immune cells to migrate into the tumor environment.
"With our combination therapy, we are therefore working against the settlement of metastases from several sides: on the one hand, we throttle their vascular supply. On the other hand, we prevent tumor-promoting macrophages from settling, which create an inflammatory environment and thus prepare the ground for a permanent settlement of the cancer cells, ”explains Augustin. “Of course, we cannot predict whether the results of these preclinical examinations can be transferred one-to-one to humans, but we learned a lot from our experiments how metastases develop. We now want to translate the knowledge into a clinical application. ”(Ag)
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