SN-38 is an anti-cancer compound that is effective at killing tumor cells. It is not administered directly to patients but is instead produced inside the body from a precursor drug given during chemotherapy. This conversion process allows for the delivery of a potent therapeutic agent to cancer cells while managing its effects on the body. This approach is part of a planned treatment process designed to maximize damage to cancerous tissues while minimizing harm to healthy ones.
SN-38’s Role in Cancer Treatment
The use of SN-38 in cancer therapy is based on the “prodrug” concept, where a less active compound is transformed into a more active one inside the body. Patients are administered a chemotherapy drug called irinotecan. This drug circulates through the body and, once it reaches the liver and other tissues, encounters enzymes known as carboxylesterases that convert the irinotecan molecule into SN-38.
This conversion is an important part of the treatment, as SN-38 is substantially more potent than its parent drug. It is estimated to be 100 to 1,000 times more cytotoxic, or cell-killing, than irinotecan itself. However, this conversion process is not perfectly efficient, as studies indicate that often less than 8% of the initial irinotecan dose becomes SN-38.
This metabolite is used in the treatment of several specific types of cancer. It is a component in regimens for metastatic colorectal cancer, which is cancer that has spread from the colon or rectum to other parts of the body. Irinotecan, and by extension SN-38, is also used to treat other malignancies, including pancreatic cancer and small-cell lung cancer.
Cellular Mechanism of Action
Once formed, SN-38 works by interfering with the mechanics of DNA inside cancer cells. Its target is a nuclear enzyme called topoisomerase I. As a cell prepares to replicate, its tightly coiled DNA must be unwound so the genetic code can be accurately copied. Topoisomerase I relieves this structural tension by creating temporary, single-strand breaks in the DNA, allowing it to unwind before the enzyme reseals the break.
SN-38 traps the topoisomerase I enzyme after it has cut a DNA strand but before it can repair it. The compound stabilizes the complex formed between the enzyme and the DNA, preventing the broken strand from being reconnected. This action creates a roadblock on the DNA molecule. When the cell’s replication machinery, known as the replication fork, collides with this roadblock, the single-strand break is converted into a permanent double-strand break.
These irreversible double-strand breaks cause extensive damage that cannot be repaired, which triggers a process of programmed cell death called apoptosis. Because cancer cells are defined by their rapid and uncontrolled division, they are constantly activating their DNA replication machinery. This makes them particularly vulnerable to SN-38, as the drug selectively targets cells that are in the process of dividing.
Bodily Metabolism and Clearance
After SN-38 has disrupted DNA in cancer cells, the body must neutralize and eliminate it to prevent excessive damage to healthy tissues. This detoxification process primarily takes place in the liver. A specific enzyme, UDP-glucuronosyltransferase 1A1 (UGT1A1), is responsible for deactivating the compound.
The mechanism of detoxification is a chemical reaction called glucuronidation. During this process, the UGT1A1 enzyme attaches a glucuronic acid molecule to SN-38. This addition makes the compound significantly more water-soluble, transforming it into an inactive form known as SN-38 glucuronide (SN-38G), which is easier for the body to excrete.
Once converted to its inactive SN-38G form, the compound is transported out of the liver and into the bile. From there, it travels into the intestines and is eliminated from the body primarily through feces. This metabolic pathway is the body’s primary defense against the prolonged toxic effects of SN-38.
Genetic Influence on Side Effects
The efficiency of the body’s system for clearing SN-38 is not the same for everyone, and this variability is rooted in genetics. The gene that provides the instructions for making the UGT1A1 enzyme can have natural variations, or polymorphisms, that lead to an enzyme with reduced function. One of the most well-studied variations is known as UGT1A128. Individuals who inherit two copies of this variant gene produce a less efficient form of the UGT1A1 enzyme.
This reduced enzyme activity directly impacts the body’s ability to perform glucuronidation. With a less effective UGT1A1 enzyme, the process of attaching glucuronic acid to SN-38 slows down. As a result, the active form of the drug is not neutralized as quickly and remains in the bloodstream at higher concentrations for longer periods. This accumulation is the direct cause of the toxicities sometimes associated with irinotecan therapy.
The buildup of SN-38 affects tissues with rapidly dividing cells, including healthy cells in the bone marrow and the lining of the gastrointestinal tract. This leads to two major side effects: severe neutropenia, a drop in the number of white blood cells that fight infection, and significant diarrhea. Because of this known genetic link, patients may undergo UGT1A1 genetic testing before starting treatment. Knowing a patient’s UGT1A128 status allows oncologists to adjust the irinotecan dose to mitigate the risk of toxicity.