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The chemistry behind cancer drugs: searching for fewer side effects

PhD candidate Dennis Wander searches for the best of both worlds. That is to say: a cancer drug that is effective and also has minimal side effects. To this end, he makes new molecules inspired by two existing medicines. And not without result: ‘We have created a new variant that is very promising.’ Promotion on 19 November.

Dangerous side-effects

In 1969, the cancer drug doxorubicin was discovered. Despite the fact that this drug has dangerous side effects on the heart, it is still one of the most commonly used drugs to fight cancer today. 'That is because of its high effectiveness,' explains Wander of the Leiden Institute for Chemical Research. 'Since then, more than a thousand other potential drugs have been tested, but the vast majority did not exceed the effectiveness of doxorubicin.' Yet there is a downside to the drug: because it weakens the heart muscle, patients can only be treated with it to a limited extent.

The drug aclarubicin does not have these side effects, but interest in Europe remained limited because it is not more effective than its competitor. However, new insights into the effects of both drugs have now changed this.

Difference in effect

'Contrary to long-standing belief, doxorubicin and aclarubicin do not work in the same way,' says Wander. Researchers thought that both drugs worked mainly by causing fractures in the DNA, which ultimately lead to cell death. 'Like many drugs that target DNA, these effects are particularly damaging to rapidly dividing cells, such as cancer cells.'

'In 2013, however, the lab of Sjaak Neefjes, with whom we collaborate closely, discovered that only doxorubicin works this way. Both drugs, however, turned out to disconnect histones from the DNA.' Histones are proteins around which the DNA of a cell is wrapped. If they disconnect, the DNA will untie and a cell will eventually die. The fact that doxorubicin has an extra anti-cancer effect, namely the breaking of DNA, is a possible explanation for the high effectiveness of the drug, but probably also for its severe side effects.'

Lab setup of Dennis Wander

Alternative wanted

In order to better understand the differences between the two drugs, Wander developed a method to create hybrid structures: new molecules that have structures in between those of doxorubicin and aclarubicin. Wander: 'These new structures are chemically very challenging to make. By testing them, we hope to find out which structural elements of the two drugs cause their different effects. With this knowledge, we hope to ultimately contribute to an effective drug that does not harm the heart.'

Wander already gives a glimpse of the first results: 'We have made a variant of doxorubicin that, like aclarubicin, does not cause DNA fractures, but does untie histones. The first tests show that this variant still kills cancer cells, which is very interesting. We're working on a publication, so hopefully, we'll be able to tell more about it soon!'


Text: Hilde Pracht

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