Delivering a double blow to cancer cells

10 Dec 2009

A promising method for delivering anti-cancer drugs specifically to cancer cells while being less damaging to normal cells has been developed by researchers at the University of Aberdeen, and is reported today  in The Biochemical Journal. In addition to the predicted toxic effects of killing the cancer cells by damaging their DNA, the putrescine-anthracene compound being tested also demonstrated an unexpected bonus by depleting the cancer cells’ reserves of essential growth compounds.

Dr Heather Wallace and her colleagues used small molecules called polyamines to deliver cytotoxic (cell-killing) drugs to cultures of human leukaemia cells in laboratory tests. Polyamines are essential for cell growth and, as cancer cells grow quickly they need increased supplies of these molecules. The polyamines are taken inside the cell by a dedicated chemical pathway that does not seem to be too specific about what extra is attached to the polyamine – meaning that the research team could adapt the very small polyamine, putrescine, by attaching the anti-cancer cell drug anthracene to it to form Ant4, a putrescine-anthracene conjugate.

Ant4 was taken up by the cancer cells in preference to normal, naturally occurring polyamines. This was the first time that cells from a human origin have been shown to take up the Ant4 complex as its uptake into cancer cells has previously only been demonstrated in hamster cell cultures. Once inside the cancer cells Ant4 killed them within 24 hours by damaging their DNA and causing the inbuilt “cell death” mechanism to operate. However, the researchers also found an additional killing mechanism at work. The Ant4 complex seemed to deprive the cancer cells of the internal supplies of polyamines that they had already built up, again causing them to die.

“Ant4 may be a double-edged sword”, said Dr Wallace, “As well as having conventional cytotoxic effects on cancer cells, it also seems to destroy them by depleting their own internal polyamine reserves. We are investigating the mechanisms behind this as it may help us to develop other polyamine-conjugates as a potent chemotherapeutic combination to deliver cytotoxic drugs directly to the cancer cells and minimise damage to surrounding, normal cells.”