This website uses cookies

This websites contains videos from YouTube. This company uses cookies (third party cookies). If you do not want them to use these cookies, you can indicate so here. However, this does mean that you will not be able to watch videos on this website. We also make use of our own cookies in order to improve our website. We don’t share our data with other parties. Read more about our cookie policy

This website uses cookies to enable video and to improve the user experience. If you do not want to accept these cookies, indicate so here. Read more about our cookie policy

Ga direct naar de inhoud, het hoofdmenu, het servicemenu of het zoekveld.

Molecular Oncology: Alfred Schinkel

AlfredSchinkel.jpg

Alfred Schinkel, Ph.D.Group leader

About Alfred Schinkel

Alfred Schinkel

Our research focuses on genes and proteins that affect drug resistance or drug susceptibility in tumors, or influence the pharmacological and toxicological behavior of anticancer and other drugs and toxins, including carcinogens, in mice and man. Insight into these systems may:

  • Improve chemotherapy/pharmacotherapy approaches for cancer and other diseases
  • Increase understanding of risks and opportunities of drug-drug interactions mediated through these systems
  • Increase insight into factors determining susceptibility to toxins and carcinogens
  • Allow elucidation of physiological functions

To study the roles of the proteins involved, and their interactions, we generate and analyze knockout and transgenic mice for the relevant genes as well as appropriate in vitro systems. Most of the studied proteins can be profoundly inhibited or induced by pharmacological modulators. This affords a window of opportunity to modulate these systems to improve pharmacotherapy, but it also involves the risk of adverse drug-drug interactions. 

Active drug efflux transporters
Plasma membrane proteins of the ATP binding cassette (ABC) multidrug transporter family, including P-glycoprotein (P-gp, ABCB1), MRP2 (ABCC2) and BCRP (ABCG2), can actively export a wide range of anticancer and other drugs from cells. These proteins can cause multidrug resistance in tumor cells, and significantly influence the pharmacokinetics of many drugs, including oral availability and tissue penetration. Interindividual variation in activity of these proteins can occur due to genetic polymorphisms, and due to extensive inhibition with various compounds, which can dramatically affect toxicity and therapeutic application of drugs. Analysis of P-gp, Bcrp and Mrp2 knockout mice generated by us has yielded a wealth of information on these functions, and some insights have resulted in ongoing clinical trials in patients to optimize oral pharmacokinetics of anticancer drugs (collaboration with Schellens and Beijnen). We are currently studying overlapping physiological, pharmacological and toxicological functions of these proteins in various compound knockout mouse strains.

Major discoveries we made: 

  • P-gp and BCRP are essential elements of the blood-brain barrier, and keep many drugs out of the brain by pumping them back into the blood. They therefore are major determinants of the clinical use of many drugs, as they avoid their central nervous system (brain) effects. On the other hand, this activity may reduce efficacy of anticancer drugs against brain tumors or micrometastases partly protected by the blood-brain barrier.  
  • P-gp and BCRP can be important factors in limiting the oral availability of many drugs and toxins, as in the intestinal wall they can pump these compounds back into the intestinal lumen. This function limits the clinical use of many drugs, but it also sometimes provides important protection from natural (dietary) toxins.
  • BCRP is an important transporter in the lactating breast, where it transports and even concentrates many drugs, carcinogens and other xenotoxins, but also vitamin B2 (riboflavin) into the milk. It thus contributes to the risk of exposing suckling infants and young to drug and pesticide residues. 
  • BCRP and P-gp expression in the placenta protects the unborn fetus from exposure to drugs, pesticides and toxins present in the bloodstream of the mother. 

Drug-metabolizing enzymes
Arguably the most important factor for variable drug exposure is the Cytochrome P450 3A system (CYP3A), which metabolizes >50% of drugs. CYP3A activity can vary dramatically due to inhibition or induction by co-administered drugs or food components, and is therefore a major factor in drug-drug and drug-food interactions. To assess the in vivo impact of CYP3A, we have generated complete Cyp3a knockout mice, and mice with transgenic overexpression of CYP3A4, the primary human CYP3A enzyme. Analysis of these mice provides insight into the tissue-specific contribution of (human) CYP3A to variable drug exposure and low oral availability of drugs. These insights can be of great value to improve drug administration regimens, but also during the development of optimally efficacious drugs, for cancer and other diseases. We are currently focusing on using the insights obtained to improve the oral bioavailability of taxanes, and testing co-administration regimens to support analogous efforts in patients. 

Important discoveries we made:

  • Intestinal CYP3A activity can be far more important than hepatic CYP3A activity in limiting the oral availability of substrate drugs. 
  • P-gp and CYP3A in the intestine can collaborate efficiently in limiting the oral availability of shared substrate drugs, but they do not have an obvious synergistic mechanism of action in doing so.   

Drug uptake transporters
Many drugs need transport proteins in order to be efficiently taken up into cells. This can affect pharmacokinetically important characteristics, such as uptake of drugs from the intestinal lumen, uptake into the liver or many other tissues, and uptake into tumor cells. Hence, variable activity of the uptake transporters can affect oral availability, elimination rate and route, tissue and tumor distribution of drugs, and therefore therapeutic efficacy and risks of toxic side effects. We generated knockout mice for the organic cation transporter family (Oct/Slc22a1-2), and established its impact on tissue distribution and elimination of anticancer drugs and model compounds. More recently, the importance for drug disposition of multidrug uptake transporters of the organic anion-transporting polypeptide family (OATP/SLCO) has been studied through the generation and characterization of knockout and transgenic mice for the SLCO1A/1B family. We are currently extending this work to additional OATP drug uptake family members.

Major discoveries we made:

  • The human Rotor syndrome, a previously unexplained hereditary conjugated hyperbilirubinemia disorder, is caused by a simultaneous and complete genetic deficiency in two main liver uptake transporters, OATP1B1 and OATP1B3.
  • Efficient detoxification of bilirubin glucuronide by the liver requires functioning of an extrusion-reuptake loop across the basolateral membrane of hepatocytes ("hepatocyte hopping"). 

Clinical translation
Collaborations with the groups of J.H. Beijnen (hospital pharmacist), J.H.M. Schellens (clinical pharmacologist and doctor of internal medicine) and O. van Tellingen at the NKI-AVL allow rapid translation of obtained insights into clinical trials in cancer patients.

Co-workers

Van Hoppe, Stephanie

Stéphanie van Hoppe

PhD student

Experience

Close this window
Kort, Anita.jpg

Anita Kort

Ph.D. student

Experience

I am working as a PhD student in the groups of dr. Alfred Schinkel and prof.dr. Jos Beijnen. I started my research project with the development of bioanalytical assays to support pre-clinical experiments. Currently, I am working on in vitro and in vivo experiments in the Schinkel group where I focus on the influence of efflux transporters and drug-metabolizing enzymes on the oral availability and tissue distribution of anti-cancer drugs, primarily using knockout and transgenic mouse strains.

Close this window
Wagenaar, Els.jpg

Els Wagenaar

Technician

Experience

Close this window
Wang, Jing

Jing Wang

Phd student

Experience

Close this window
Wang, Yaogeng

Yaogeng Wang

PhD student

Experience

Close this window
Gan, Chanpei

Changpei Gan

PhD student

Experience

Close this window
Qi, Xiaozhe

Xiaozhe Qi

PhD student

Experience

My research focuses on the nephrotoxicity of ochratoxin A (OTA) and proteins that affect the transport of ochratoxin A in the kidney. Cell culture and in vivo studies are combined to explore the nephrotoxicity.

Insight into OTA-induced nephrotoxicity will help to:

  • Clarify the mechanisms of OTA toxicity.
  • Increase understanding of why the main target organ of OTA is the kidney.
  • Increase insight into the function of transporters in OTA-mediated toxicity.
  • Prevent and possibly treat OTA-induced nephrotoxicity.

For the studies, I use cell lines overexpressing transport proteins and gene knockout cell lines.

Close this window

Key publications View All Publications

  • Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.

    J Clin Invest. 2012; 122: 519-28.

    van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, et al.

    Link to PubMed
  • The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk.

    Nat Med. 2005; 11: 127-9.

    Jonker JW, Merino G, Musters S, van Herwaarden AE, Bolscher E, Wagenaar E, Mesman E, Dale TC, Schinkel AH.

    Link to PubMed
 
 

Recent publications View All Publications

  • Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis

    Int J Clin Exp Pathol. 2015 May 1;8(5):5252-62

    Sticova E, Lodererova A, van de Steeg E, Frankova S, Kollar M, Lanska V5 Kotalova R, Dedic T, Schinkel AH, Jirsa M

    link to PubMed
  • Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b

    Cancer Res. 2015 Jul 1;75(13):2729-36

    Vasilyeva A, Durmus S, Li L, Wagenaar E, Hu S, Gibson AA, Panetta JC, Mani S, Sparreboom A, Baker SD, Schinkel AH

    link to PubMed
 

Contact

  • Office manager

    Karin Hageman

  • E-mail

    k.hageman@nki.nl

  • Telephone Number

    +31 20 512 2099

Donate

'Research for the benefit of cancer patients'

Support us
Share this page