Research identifies first step in design of new anti-cancer drugs
New research has identified a first step in the design of a new generation of anti-cancer drugs that include an agent to inhibit resistance to their effectiveness.
The research, by a team co-led by Professor Martin Michaelis of the University of Kent, in conjunction with Professor Jindrich Cinatl of the Goethe University, Frankfurt am Main, Germany, could pave the way for tailored combinations of drugs that would provide more effective treatment for patients suffering from therapy-resistant cancers.
Drug resistance is the major reason for the failure of anti-cancer therapies and patient deaths. Despite major improvements in cancer treatment in recent decades, cures are still mostly achieved by early cancer detection and local therapy using surgery and radiotherapy. Once cancer cells have spread throughout the body and formed metastases (secondary tumours), the prognosis remains grim with 5-year survival rates being below 20%.
Effective systemic drug therapies are needed therefore to improve the outcomes of patients diagnosed with metastatic disease. However, many cancers are characterised by intrinsic resistance, where there is no therapy response from the time of diagnosis, or acquired resistance, where there is an initial therapy response but cancer cells eventually become resistant.
Arguably, the most important resistance mechanism in cancer cells is the action of so-called ATP-binding cassette (ABC) transporters, drug pumps that act as a mechanism to move anti-cancer drugs from cancer cells. Of these, ABCB1 (also called multi-drug resistance gene 1 (MDR1) or P-glycoprotein) is the most relevant one. Previous attempts to target ABCB1 as part of anti-cancer therapies have failed.
A major reason for this is that ABCB1 is expressed at many sites in the body, particularly at tissue barriers such as the gastro-intestinal barrier and the blood brain barrier. This has meant in the past that agents that inhibited ABCB1 were not specific to the interaction of the desired anti-cancer drug with the ABCB1 on cancer cells but affected the body distribution of many different drugs and food constituents, resulting in toxic side-effects.
The new research demonstrates that certain inhibitors of ABCB1 specifically interfere with the ABCB1-mediated transport of certain anti-cancer drugs. This provides a first step towards the design of tailored combinations of anti-cancer drugs and ABCB1 inhibitors that specifically cause the accumulation of anti-cancer drugs in ABCB1-expressing cancer cells but do not affect the body distribution of other drugs or food constituents.
In addition to Professor Michaelis, of Kent's School of Biosciences, and Professor Cinatl and their laboratory members, the team included Dr Mark Wass (University of Kent), Professor Manfred Schubert-Zsilavecz (Goethe University), Dr Taravat Ghafourian (University of Sussex), and Professor Michael Wiese (University of Bonn) and members of their research groups.
The research, entitled Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport, was published in Oncotarget. See here: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path=7345&author-preview=5o1 -ends-
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Goethe University is a research-oriented university in the European financial centre of Frankfurt, founded in 1914 with purely private funds by liberally-oriented Frankfurt citizens. It is dedicated to research and education under the motto "Science for Society" and to this day continues to function as a "citizens' university". Many of the early benefactors were Jewish. Over the past 100 years, Goethe University has done pioneering work in the social and sociological sciences, chemistry, quantum physics, brain research and labour law. It gained a unique level of autonomy on 1 January 2008 by returning to its historic roots as a privately-funded university. Today, it is among the top ten in external funding and among the top three largest universities in Germany, with three clusters of excellence in medicine, life sciences and the humanities.