Research interests
Alfred Schinkel has a broad interest in the genes and proteins responsible for resistance to anti-cancer drugs. Using knockout and transgenic mouse models his team is providing a broader understanding of drug resistance and the way the body handles drugs, thus supporting optimization of clinical chemotherapy.
We study how drugs move around the body, which is a very important aspect of how efficiently they treat disease. One of the main problems in the cancer field is the resistance that arises in tumors to drugs. Once this has occurred in a patient, the tumor is often resistant to many different drugs, including ones to which the patient has not yet been exposed.
It was found that this can be due to overexpression of molecules named multidrug transporters that can occur in the membranes of tumor cells. These proteins can actively pump large numbers of drugs from the cell. We and other researchers discovered that they are present in normal tissues too, for example in the gut.
A typical example, P-glycoprotein, is present in the small blood vessels of the brain where it prevents toxins and other substances crossing from the blood into brain tissue.
Consequently P-glycoprotein will normally prevent drugs from getting to small cancer metastases in the brain. In the gut lining, P-glycoprotein and other pumps protect the body against food toxins. This can prevent certain drugs from being absorbed at high enough concentrations to work against tumors, and forces them to be administered intravenously.
Blocking these pumps might thus improve chemotherapy in various ways.
Drugs that block these pumps have been developed, and our collaborators, Jan Schellens and Jos Beijnen, are now testing them in clinical trials to see if these can safely allow anti-cancer drugs such as topotecan and paclitaxel to enter the body via the oral route.
We are currently extending our research to drug-uptake and drug-metabolizing systems, as these may be equally important for drug efficacy, and can be inhibited as well.
Selected publications
Van Herwaarden, A.E., and Schinkel, A.H. (2006). The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol. Sci. 27; 10-16.
Jonker, J.W., Merino, G., Musters, S., Van Herwaarden, A.E., Bolscher, E., Wagenaar, E., Mesman, E., Dale, T.C., and Schinkel, A.H. (2005). The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat. Med. 11; 127-129.
Jonker, J.W., Wagenaar, E., Van Eijl, S., and Schinkel, A.H. (2003). Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/ Slc22a2]) in mice abolishes renal secretion of organic cations. Mol. Cell. Biol. 23; 7902-7908.
Jonker, J.W., Buitelaar, M., Wagenaar, E., van der Valk, M.A., Scheffer, G.L., Scheper, R.J., Plösch, T., Kuipers, F., Oude Elferink, R.P.J., Rosing, et al. (2002). The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc. Natl. Acad. Sci. USA 99; 15649-15654.
More publications by Alfred Schinkel on PubMed
Biographic sketch
Co-workers
» Vacancies