One of the oldest cancer drugs in use is methotrexate. It is used to treat a variety of solid and blood cancers, but it can also cause side effects that, in some cases, are so severe that treatment needs to be stopped.
Methotrexate stops cells from producing folate, an important nutrient used to make DNA and proteins. When folate is not produced or available, the cell is unable to make DNA and dies. By stopping folate production, methotrexate is often very effective at eradicating cancer cells, but the same reaction happens in healthy cells, resulting in severe side effects. Researchers have been looking for ways to make the drug more effective, allowing doctors to prescribe a lower dose that does not result in toxic side effects to healthy cells.
A team of researchers based at the Massachusetts Institute of Technology recently used genetic technology to look at the genes involved in how cancer cells respond to methotrexate, with the goal of understanding the mechanisms involved in the drug’s activity and making it more effective.
Dietary supplement may improve drug effectiveness
The researchers used a powerful genetic technology called CRISPR to look for genes involved in how cancer cells respond to methotrexate, ultimately identifying two. In this study, they focused their efforts on a gene called FTCD.
They found that when FTCD levels were reduced, cancer cells were more sensitive to methotrexate. FTCD is important in breaking down an essential amino acid called histidine, and it uses the nutrient folate in the process.
Their results suggest that when less FTCD was available, more folate remained in cells, allowing the cells to survive. On the other hand, when more FTCD is available, it uses up more folate to break down histidine, leaving less of the nutrient for the vital tasks of DNA and protein building. Already folate-starved, these cells become hyper sensitive to methotrexate.
Since increasing FTCD gene activity in cells is not currently a practical treatment, the researchers explored whether increasing the amount of histidine available – and needing to be broken down – might be another way to use up more folate and improve sensitivity to methotrexate. Combining a low-dose methotrexate treatment with a histidine-rich diet was more effective than low-dose methotrexate alone in shrinking tumour size in mice, with no increased side effects.
Histidine is found in a variety of foods and is easy to add to a diet. As a result, adding more histidine to an individual’s diet could be an inexpensive way to improve methotrexate effectiveness, meaning that lower doses can be used and side effects lessened.
Untangling the mechanics of how cancer drugs work is complicated, but new technology is helping to suggest ways of improving effectiveness and reducing side effects of existing cancer drugs. In this case, research could help to give an old cancer drug new life by combining it with a dietary supplement to make it more effective with fewer side effects.
Eileen Hoftyzer, BSc