Use of cancer drug explored

“A promising new drug may be able to treat more types of cancer than first thought,” according to BBC News. The website said that new research has found that the drug methotrexate can selectively kill cells with a particular genetic mutation associated with a number of cancers. 

This was a highly complex and promising scientific study that may have implications for research into a number of cancers as the drug was found to selectively kill cells deficient in the MSH2 protein involved in repairing damaged or mis-replicated DNA. The researchers found that methotrexate may have a role in destroying affected cells, but this is only of relevance to cancers associated with the MSH2 genetic mutation, particularly in people with a certain type of hereditary (non-polyposis) colorectal cancer. It is also unclear what role this drug could play in the treatment of people with this genetic mutation, or those who have already developed cancer because of this mutation, and so a trial is currently underway in selected people.

Methotrexate, which is already used to treat some cancers and inflammatory conditions, can be a highly toxic drug. It is prescribed under specialist supervision with regular monitoring and normal doses for other medical conditions are only once a week.

Where did the story come from?

The research was carried out by Sarah Martin and colleagues of the Cancer Research UK Gene Function and Regulation Group, The Breakthrough Breast Cancer Research Centre and The Institute of Cancer Research in the UK. The study was supported by grants from Cancer Research UK, Breakthrough Breast Cancer, and NHS funding of the NIHR Biomedical Research Centre.

The study was published in the peer-reviewed medical journal Molecular Medicine.

What kind of scientific study was this?

This laboratory research was on cells and featured a number of tests related to the MSH2 gene. MSH2 is believed to code for a protein involved in the removal of mismatched DNA base pairs, a mutation that can sometimes occur during normal DNA replication. MSH2 mutations lead to a lack of this protein and are known to predispose to several cancers, including hereditary non-polyposis colon cancer, a condition where a person develops numerous polyp growths in the bowel that have a risk of becoming cancerous. These individuals are also at higher risk of certain other cancers elsewhere in the body.

The aim of the study was to identify new ways to treat cancers that resulted from this mismatch process and led the researchers to examine various drugs and molecules to see which would destroy cells lacking a functional MSH2 protein. The researchers took human endometrial cancer cells that had mutations in the MSH2 gene and performed various experiments. They then compared these cells with human endometrial cancer cells that had their MSH2 function restored.

The cells were then exposed to 1120 different substances and the resulting effects on their viability were assesed. The majority of these chemicals were currently marketed drugs, including methotrexate. The drug methotrexate was identified as one that could strongly select and destroy those cells that had MSH2 mutations by producing oxidative lesions in the DNA.

What were the results of the study?

The drug methotrexate was found to target both cells with a functional MSH2 protein and those that were deficient in MSH2. However, cells that had functional MSH2 were able to clear the damaging oxidative lesions quite quickly, while in cells that had deficient MSH2, the oxidative lesions persisted.

To confirm that methotrexate was causing the oxidative lesions, the researchers tested drugs that counteract the effects of methotrexate. They found that the antioxidant selenium reduced the accumulation of oxidative lesions in the MSH2-deficient cells. They also confirmed methotrexate acted by the inhibition of the enzyme dihydrofolate reductase (DHFR), by administering methotrexate to cells but adding folic acid, the natural substrate that is acted upon by the DHFR enzyme. They found that folic acid reduced the lethal effects of methotrexate. They further connfirmed this finding by silencing DHFR in cells, which led to an accumulation of oxidative lesions in the cell.

What interpretations did the researchers draw from these results?

The researchers say that while methotrexate has frequently been used for many years to treat cancer, their findings suggest that the drug may have a particular role in the treatment of a subset of patients who have cancers which are characterised by mutations in the MSH2 gene.

What does the NHS Knowledge Service make of this study?

This is highly complex scientific research that may have important implications for future research. Despite media reports, the drug discussed, methotrexate, is not strictly new as it already used to treat some forms of cancer. The breakthrough in research is based on seeing how the drug interacts with a particular genetic mutation that is associated with a number of cancers, and which causes a deficit of the MSH2 protein involved in the repair of damaged DNA. Researchers compared various drugs for their ability to target cells with this particular deficit, and found that methotrexate may have a role in destroying the affected cells.

It should be noted that these findings are only of relevance to those cancers associated with this mutation, in particular, people with the condition of hereditary non-polyposis colorectal cancer (of whom only 40% are estimated to have this mutation).

 Also, the current research aimed to initially identify an approved drug that could then be entered into clinical trials of people who have cancers as a result of mutations of the MSH2 gene; this research was not a trial itself. A trial using methotrexate in a specific group of people is now said to be underway.

Methotrexate can be a highly toxic drug and is currently used in people with certain cancers and some cases of rheumatoid arthritis, inflammatory bowel disease and psoriasis. In all of these cases it would only be used under specialist prescription and supervision. Methotrexate can affect liver and kidney function, cause lung problems and suppress the bone marrow leading to a drop in blood count, in addition to causing various other adverse side effects. In may also adversely interact with other drugs.

Normally doses are only given once per week (either by tablet or injection), and people taking the drug require close and regular monitoring. The trial currently underway is in 29 people with metastatic colorectal cancer and involves weekly injections of methotrexate. It is due to be completed in 2014.