Naturally reducing drug 'friendly fire'

By Mike Nagle

- Last updated on GMT

Related tags: Cells, Cancer

A new technique mimics Nature to mark cancer tumours for
destruction by the immune system while leaving healthy cells alive,
and could potentially lead to anticancer drugs with fewer side
effects.

Scientists at the University of Wisconsin-Madison have attached a molecule to tumours, which is then recognised by immune system antibodies and the cell is killed. By mimicking Nature's way of recognising cells, the team hope their drug could have fewer side effects than established chemotherapies. The many debilitating side effects of chemotherapy are often caused when a drug kills healthy cells as well as tumour cells. Therefore, drug developers are constantly on the look out for new techniques for delivering anticancer drugs preferentially to tumour cells, and so avoiding this 'friendly fire'. "This study suggests that the cell recognition mode we used can direct an endogenous immune response to destroy cancer cells selectively,"​ said Professor Laura Kiessling. "We think this could lead to a new class of therapeutic agents not only for cancer but also for other diseases involving harmful cells." ​ Cancer cells often have higher levels of certain receptors on their surface than normal cells. The tumours can be preferentially targeted by combining a deadly anticancer drug with another molecule that binds strongly to one of these receptors. However, even if the target is only found in low levels on healthy cells, the strong binding leads to a kind of one-shot, one-kill effect where healthy cells are also killed. Contrastingly, cell recognition in living systems involves binding agents that only attach weakly to targets - the agent needs to bind to several receptors at once to stick to the cell. This cuts down on cases of mistaken identity because if the agent attaches to the wrong type of cell, it can be easily displaced. Prof Kiessling decided to develop a drug which mimicked this natural process. They took a molecule that binds to a receptor called integrin, which is found in higher levels in cancer cells. However, instead of attaching a toxic anticancer drug, they attached a carbohydrate called alpha-Gal. The body naturally produces an antibody to alpha-Gal - called anti-Gal. However, the two only bind together weakly, and so an immune response only occurs if anti-Gal can bind to several alpha-Gal molecules at once. In a series of cell based experiments, Kiessling's drug only recognised and killed cells where integrin was found in high levels. In cells with lower levels of the receptor, the drug still bound but the resulting levels of alpha-Gal weren't high enough to elicit an immune response. The team also attached a common anticancer drug, doxorubicin, to the same integrin binding agent. The cells were killed regardless of the amount of integrin they carried. "What we've shown is that you don't need a receptor that's found solely on tumour cells,"​ said Prof Kiessling. "You just need one that's found in significantly higher numbers on cancerous cells than on normal ones."​ The team are now looking at increasing the selectivity even further by developing agents that bind two different receptors.

Related topics: Preclinical Research

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