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Part 2 of 3: Chasing a moving target 


By Simon Fogarty



A tough obstacle: The body's own defense system
'The so-called ‘War against Cancer’ started with US President Richard Nixon’s National Cancer Act of 1971. It turned out to be many battles on many fronts as cancer was confirmed to be not one but a myriad of diseases. Not only that, but each cancer cell in a given patient has a different genetic make-up. It can differ in itsresponse to treatment and also its ability to develop resistance.As Dr. Michael Gottesman, one of the pioneers in resistance research, put it in his review of 2002: “To paraphrase Tolstoy in the opening lines of Anna Karenina, normal cells are all alike in their response to drugs, but cancer cells each respond in their own way.”

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The development of more targeted anticancer drugs is ongoing. It has been driven by breakthroughs in our understanding of the molecular mechanisms that lead to out-of-control division of cancer cells. This has also brought deeper insight into how cancer cells become resistant to treatment.

The mechanisms of resistance

Resistance of cancer cells to drugs is a question of the survival of the fittest – a Darwinistic mechanism similar to the development of antibiotic resistance in bacteria. If a particular cancer cell happens to have a property that enables it to avoid being killed by the drug then it will be selected for and continue to multiply. This natural law normally protects the organism, but in the case of cancer treatment can be fatal.

There are many mechanisms of resistance, including:

  • Mutations in, or loss of, a drug receptor on the cell surface
  • Reduced activation of pro-drug forms
  • Drug inactivation – for example, drugs can be inactivated by being conjugated to glutathione, a powerful anti-oxidant that protects the cell against the damaging effects of reactive oxygen species.
  • Evasion of the programmed cell-death ‘apoptotic’ pathway - the natural mechanism developed to rid the body of cancer cells

However, perhaps the most studied form of resistance involves drug metabolism. This includes uptake, efflux or ejection of the drug from the cell, and detoxification or breakdown by thebody.

The cellular mechanisms for uptake and ejection of drugs are particularly important and can lead to multidrug resistance. This is where the affected cells acquire the ability to resist the effect of many drugs.

Dr. Michael Gottesman, now at the National Cancer Institute in the USA, and his colleagues discovered an example of this: P-glycoprotein (P-gp), a cell-surface protein that pumps drugs out of the cell. It was a groundbreaking discovery, which led to a massive research effort to understand the extent of drug efflux mechanisms.

Several pumps, or ABC transporters, have since been discovered. These are capable of forcing out all known anticancer agents and can result in multi-drug resistance (MDR). Like so many other mechanisms that defeat treatment, these efflux pumps are the evolutionary result of the body’s fight for survival – in this case the need to pump out foreign and potentially toxic substances, or xenobiotics, from the cell.

Knowledge is power, and in the final part of this series we will look at a few examples of how resistance to anticancer drugs is being overcome, and take a glimpse into the future of cancer treatment.

Next in this three-part series:  Let’s make this personal

 

About the author

Simon Fogarty

Simon has a broad background in drug discovery automation covering all areas from assay development to design of automation systems. He is enthusiastic about the life sciences and constantly strives to provide practical working solutions to researchers. After working in both pharma/biotech and life science instrumentation sectors for a number of years he joined Tecan in 2008. At Tecan Simon is Director of the Application Sciences Group the USA.