Our bodies have a system for controlling which genes are active, a field known as epigenetics. One of the main ways this occurs is through DNA methylation, a process where chemical tags called methyl groups attach to our DNA. These tags act like switches, turning genes “on” or “off” to ensure cells function correctly.
In some diseases, particularly cancer, this process goes awry. The machinery that adds these methyl groups can become overactive, silencing genes that protect us from disease. When these protective genes are silenced, it can lead to uncontrolled cell growth. To combat this, drugs called DNA methyltransferase inhibitors (DNMTis) were developed to correct the malfunction, allowing protective genes to turn back on.
How DNA Methyltransferase Inhibitors Work
DNA methyltransferase inhibitors function as molecular impostors. They are classified as nucleoside analogs, meaning their chemical structure is very similar to cytosine, one of the fundamental building blocks of DNA. Because of this resemblance, the cancer cell is tricked into incorporating these fraudulent molecules into its new strands of DNA during cell replication.
Once the inhibitor is embedded in the DNA, it sets a trap. When a DNMT enzyme comes along to perform its methylation function, it attempts to act on the imposter nucleoside. Due to the inhibitor’s slightly different chemical structure, the enzyme becomes covalently and irreversibly bound to it. This action is like a key breaking off inside a lock; the enzyme is permanently stuck and can no longer function.
The trapped enzyme is then targeted for degradation and removed by the cell. This process leads to a state called passive demethylation, where with each subsequent round of cell division, the newly synthesized DNA lacks the methyl tags that were suppressing the beneficial genes. The result is the reawakening of tumor suppressor genes, which can then resume their job of controlling cell growth and promoting cell death in the cancerous cells.
Approved Medical Uses
The primary clinical success for DNA methyltransferase inhibitors has been in the treatment of specific blood cancers. They are an established therapy for myelodysplastic syndromes (MDS), a group of disorders where the bone marrow does not produce enough healthy blood cells. Clinical studies have shown that these drugs can improve survival rates and quality of life for patients with higher-risk MDS by correcting the abnormal methylation patterns that drive the disease.
These inhibitors are also a treatment for certain patients with acute myeloid leukemia (AML), particularly older adults who may not be candidates for more intensive chemotherapy. In this context, DNMTis can help to control the proliferation of leukemia cells and induce periods of remission.
While their impact on blood cancers is well-documented, the use of DNMTis for solid tumors, such as lung or colon cancer, has been less effective when used alone. Their application for these types of cancers is currently concentrated in the realm of clinical trials and ongoing research.
Types of DNA Methyltransferase Inhibitors
The most widely used DNA methyltransferase inhibitors belong to a class of drugs known as nucleoside analogs. These medications are designed to mimic the natural building blocks of DNA, which allows them to be integrated into the genetic material of rapidly dividing cancer cells. The two foundational drugs in this category are azacitidine (marketed as Vidaza) and decitabine (marketed as Dacogen).
While both azacitidine and decitabine are structurally similar, there is a difference in their cellular processing. Decitabine is incorporated exclusively into DNA. Azacitidine, on the other hand, is incorporated into both RNA (a related molecule involved in protein production) and DNA, with the majority ending up in RNA. This distinction may contribute to subtle differences in their side effect profiles and mechanisms of action.
Both drugs are administered via injection or intravenously, though a newer oral combination of decitabine with another medication has been developed to improve patient convenience. Researchers are also actively developing non-nucleoside inhibitors, which would block DNMT enzymes through different mechanisms and potentially offer a more targeted approach with fewer side effects.
Potential Side Effects
Treatment with DNA methyltransferase inhibitors can be accompanied by a range of side effects, which are carefully monitored by healthcare providers. The most common adverse effect is myelosuppression. This is a condition where the bone marrow’s ability to produce new blood cells is reduced.
Myelosuppression can lead to several complications. Anemia from a shortage of red blood cells causes fatigue and weakness. A low white blood cell count, known as neutropenia, increases the body’s susceptibility to infections. A deficit in platelets, called thrombocytopenia, can lead to easier bruising and bleeding.
Beyond effects on the bone marrow, patients may experience other common side effects like fatigue, nausea, and vomiting. For drugs administered by injection, reactions at the injection site, such as redness or swelling, can also occur. Supportive care measures, such as blood transfusions or growth factor medications, are often employed to manage myelosuppression and help patients tolerate the therapy.
Emerging Research in Treatment
The field of DNA methyltransferase inhibitors is evolving, with research focused on expanding their use beyond hematological cancers. A primary area of investigation is their application in treating solid tumors. While DNMTis have shown limited success on their own in these cancers, clinical trials are exploring their use in combination with other therapies.
One promising strategy is pairing DNMTis with immunotherapy, such as checkpoint inhibitors. The rationale is that by reactivating certain genes, DNMTis can make cancer cells more “visible” to the immune system, thereby priming them for attack by immunotherapy drugs.
This priming effect occurs through several mechanisms. DNMTis can increase the expression of tumor-associated antigens on the surface of cancer cells, flagging them for immune recognition. They can also induce a viral mimicry state within the tumor by activating ancient viral DNA embedded in our genome, triggering an anti-viral immune response that also targets the cancer.
Researchers are also developing next-generation DNMTis. These newer agents are designed to be more stable in the body, more specific in their targeting of cancer cells, or to have a more favorable side-effect profile, potentially making treatment more effective and tolerable.