Research published today in Nature has shown that supplementing with a common dietary amino acid increases the efficacy of the common chemotherapy drug methotrexate in mouse models of cancer.
Methotrexate is an old chemotherapy drug made in the 1940s, used to treat some types of cancer and a number of autoimmune diseases, such as rheumatoid arthritis.
It works by inhibiting a gene called DHFR, which allows cells to modify folate for use in cellular processes such as DNA replication and ultimately cell division.
Much like many old chemotherapy drugs, it is not specific to cancer cells, albeit faster-dividing cells are more affected by the drug. It is this lack of specificity which means that it can be very toxic, limiting its use in patients and meaning that many experience unpleasant or damaging side effects.
The research team used the gene-editing tools of CRISPR-Cas9 in methotrexate-treated leukemia cells in the lab to find genes that affect response to the drug.
They found one gene encoding a protein which was already known to be involved in transporting methotrexate into the cell, showing that their method was valid, but also found a gene which had never been associated with methotrexate sensitivity before.
“We were completely shocked to find a gene involved in histidine catabolism in our analysis. We’d never seen this gene before, we had to look up what it did,” said David Sabatini, leader of the research from the Whitehead Institute at the Massachusetts Institute of Technology.
The gene FTCD encodes an enzyme which helps break down (catabolize) histidine, an amino acid found in high levels in meat, fish and dairy and some grains.
This breakdown process also reduces folate levels in cells, but in a different manner to methotrexate itself.
The researchers then went on to use mouse models of cancer to conclude that low doses of methotrexate were more effective at reducing the size of tumors and killing cancer cells when histidine was also given to the mice.
The effect of diet on chemotherapy drugs is a busy area of research at the moment, with work published just last week showing in mice that the ketogenic diet might improve the efficacy of a class of cancer drug known as PI3K inhibitors.
If these results are similar in human clinical trials, the researchers hope that the effectiveness of methotrexate could be increased by giving simple, inexpensive dietary interventions, meaning lower doses of the agent can be prescribed and hopefully some of the worst side-effects avoided.
A key use of methotrexate is in treating children with leukemia. It's given two ways; intravenously to help clear the blood of leukemic cells but also intrathecally, meaning it is injected directly into the spinal fluid. This is to try and wipe out any leukemia cells hiding in the central nervous system which could evade therapy and come back causing relapsed disease, which is much harder to treat.
I am unfortunately no stranger to methotrexate, having undergone treatment for leukemia as a child with a cocktail of chemotherapy agents including several doses of methotrexate. I'm also not unfamiliar with the toxicity of methotrexate, having experienced a rare side-effect called stroke-like syndrome, which meant I was paralyzed down my entire left side for three days after a spinal injection of the drug, eventually making a full recovery.
Regrettably, it isn't just me who experienced this and possibly more worrying is the growing numbers of childhood leukemia survivors who appear to be having neurocognitive issues such as memory problems, which are widely believed to be due to the methotrexate.
“These are very important preclinical studies in mice and show an interesting proof of principle to use a screening tool to identify modulators of methotrexate effects,” said Mary Relling, PharmD, Chair of the Pharmaceutical Sciences Department at St. Jude Children’s Research Hospital.
Parents of children with leukaemia are understandably passionate about doing anything they can to reduce the burden of side-effects of treatment on their children, but this early study is simply not enough evidence to consider histidine supplementation and in fact, could interfere with the treatment working. Parents are already warned about folate supplementation during treatment as this does stop methotrexate working properly.
“We would be worried that families might buy the supplement and use it, potentially interfering with the treatment regimen. I urge any patient or families of patients undergoing cancer therapy to consult with their pharmacist or physician if considering supplementation,” said Relling.
Sabatini is hopeful about the prospects for supplementation improving the therapy in the future, noting that the gene for the histidine breakdown protein does not appear to be expressed in many healthy cells. Caution is however certainly warranted as it’s still possible that histidine supplementation might increase the toxicity of the drug on healthy tissues in people, contributing to side-effects that were not apparent in the mouse model.
“Every time we try to do something to improve anti-tumor efficacy, it’s generally associated with an increase in toxicity,” said Relling, urging caution.
Sabatini is also keen to stress that his work didn’t look at methotrexate in the context of arthritis or several other diseases which are also treated with the drug, but is optimistic for the future and is currently planning more research including potential human clinical trials to further evaluate the relationship between histidine and methotrexate.
“Diet could have a very big influence on histidine levels. Can we predict sensitivity to methotrexate treatment based on histidine levels in humans? This is very exciting,” said Sabatini.