Researchers at the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI-AVL) have developed a new tumor model in mice that makes it possible to determine how a hereditary form of breast cancer becomes resistant to many of the anti-cancer drugs now being used. A pump in the cell membrane of the cancer cells pumps the drugs out of the cell. The discovery by Dr. Sven Rottenberg, Dr. Jos Jonkers and Prof. Dr. Piet Borst is in an advance on-line publication of 2 July 2007 of the Proceedings of the National Academy of Sciences.
Cellular pump
Cancer that has initially nearly disappeared through chemotherapy often rears its head again and then appears to be insensitive to further therapy. That can be caused by a pump in the cell membrane of the cancer cells that can pump the administered drugs out of the cell. That had already been discovered in cultured cancer cells, but the importance of this mechanism for actual tumors had, thus far, remained unclear. Using a new tumor model in mice that strongly resembles hereditary breast cancer in humans, Rottenberg and his colleagues can now show that pumping can also cause drug resistance in real tumors; in particular, a resistance to Adriamycine (doxorubicin) and Taxotere (docetaxel).
Research model
Up until now, there were no good laboratory animal models that made it possible to study how tumors become resistant to chemotherapy in a cancer-patient simulated situation. Over the passed few years, the NKI-AVL have, however, developed new mouse models for breast cancer, lung cancer and mesothelioma. Through the application of genetic tricks, spontaneous tumors occur in the mice that resemble cancer in humans. Scientific director of the NKI-AVL, Anton Berns, started developing these tumor models 15 years ago. Thanks to this long-term investment, the NKI-AVL now has new possibilities for studying the origin of drug resistance.
Resistance
Resistance to chemotherapy is a major problem in the fight against breast cancer. As long as tumors are confined to one place, they are often well treatable with surgery, chemotherapy or radiotherapy. It is the metastasized breast cancer cells that are life-threatening. The problem arises when cancer that has initially nearly disappeared through chemotherapy rears its head again and proves to be resistant to further therapy.
Fundamental insight
The unraveling of the mechanism of resistance to doxorubicin and docetaxel is a first step on a long road. Not all breast tumors that originate from this mouse model can ascribe their resistance to the pumping mechanism and the researchers are now busy trying to find out why these tumors become resistant. Mice are not people and the translation of fundamental insights -- from mice to man -- is a long-winded process.
Piet Borst: “These research models make it possible for us to do basic research on the mechanism of drug resistance in a more human-like situation. We hope that we will, because of this, be able to develop better methods for recognizing resistance in an early stage, to avoid it where possible and to test new drugs or combinations of existing drugs better.”