SN-38 is a potent compound. It functions as an active metabolite, meaning it performs therapeutic action after a parent drug is introduced into the body. This compound is known for its remarkable effectiveness against various cancer cell types, leveraging the body’s metabolic processes to activate therapeutic agents.
SN-38’s Function in Cancer Treatment
SN-38 is not administered directly to patients. Instead, patients receive irinotecan, a precursor drug the body transforms into SN-38 through enzymatic processes, primarily by carboxylesterases. This conversion makes irinotecan a prodrug, inactive until metabolized into its active form. SN-38 is more potent than its parent compound, with cytotoxicity 100 to 2000 times greater than irinotecan itself [1, 2, 1 (search result 2)].
Irinotecan, and consequently SN-38, is commonly used in the treatment of advanced colorectal cancer [1, 1 (search result 4)]. Its application extends to other solid tumors, including pancreatic cancer, small-cell lung cancer, breast cancer, esophageal cancer, uterine cancer, ovarian cancer, and head and neck squamous cell carcinoma [1, 1 (search result 2), 4 (search result 1), 1 (search result 2)]. This highlights its broad therapeutic potential.
Cellular Mechanism Against Cancer
SN-38 exerts its cancer-killing effects by targeting topoisomerase I. This enzyme plays a role in maintaining DNA integrity, relaxing supercoiled DNA strands during replication and transcription [1 (search result 3), 2 (search result 3), 3 (search result 3)]. Topoisomerase I temporarily breaks and re-ligates a single DNA strand, allowing the helix to unwind. This action prevents tangles that would obstruct DNA replication.
SN-38 interferes by stabilizing the temporary complex formed between topoisomerase I and DNA after the DNA strand is broken [1 (search result 3), 2 (search result 3), 4 (search result 3)]. This prevents the enzyme from rejoining the broken strand, trapping topoisomerase I on the DNA molecule [1 (search result 3), 2 (search result 3)]. As the cell attempts to replicate, the machinery collides with these trapped complexes, leading to irreversible double-strand DNA breaks [1 (search result 3), 2 (search result 3), 4 (search result 3)]. These severe lesions trigger cellular checkpoints, arresting the cell cycle in S and G2 phases [5 (search result 3)]. This irreparable DNA damage activates programmed cell death, known as apoptosis, often through caspase-3 activation [2 (search result 3), 5 (search result 3)].
Metabolism and Patient Side Effects
Once SN-38 has performed its cytotoxic action, the body must neutralize and eliminate it to prevent harm to healthy cells. This detoxification primarily involves the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) [1 (search result 4), 2 (search result 4), 3 (search result 4)]. UGT1A1 modifies SN-38 by attaching a glucuronic acid molecule, converting it into an inactive, water-soluble form called SN-38 glucuronide (SN-38G). This allows for easier excretion from the body, primarily through bile and feces [1 (search result 4), 3 (search result 3)].
However, UGT1A1 enzyme activity varies among individuals due to genetic differences, or polymorphisms, in the UGT1A1 gene [1 (search result 4), 2 (search result 4)]. For instance, the UGT1A1\28 allele has seven TA repeats in the gene’s promoter region, instead of six, which significantly lowers enzyme expression and activity [1 (search result 4), 2 (search result 4)]. Another variant, UGT1A1\6, is also associated with decreased enzyme activity, particularly in East Asian populations [1 (search result 4), 3 (search result 4)].
Patients with these genetic variations, especially those homozygous for UGT1A1\28 (inheriting two copies), have an impaired ability to metabolize SN-38 [1 (search result 4), 2 (search result 4)]. This leads to higher, prolonged exposure to active SN-38 in the bloodstream and intestines [1 (search result 4), 3 (search result 4)]. Consequently, these individuals face an increased risk of severe side effects, notably severe diarrhea and neutropenia (a dangerously low count of neutrophils) [1 (search result 4), 2 (search result 4), 3 (search result 4)]. Studies show severe diarrhea occurs in approximately 70% of patients homozygous for UGT1A1\28, compared to about 17% in those with the wild-type gene [2 (search result 4)]. The FDA recommends considering a reduced starting dose of irinotecan for homozygous UGT1A1\28 patients to mitigate these toxicities [3 (search result 4)].
Innovations in SN-38 Delivery
SN-38’s poor water solubility and instability at physiological pH have presented challenges for its direct use as a therapeutic agent [3 (search result 5), 2 (search result 1), 1 (search result 1)]. Its solubility is low, ranging from approximately 11 to 38 micrograms per milliliter. These properties make it difficult to formulate SN-38 into a stable, effective injectable solution. Overcoming these limitations has spurred advancements in drug delivery technologies.
Scientists are developing drug delivery systems to enhance SN-38’s solubility, improve its stability, and direct it more precisely to tumor sites, potentially increasing effectiveness and reducing systemic side effects. One innovation involves liposomal encapsulation, where SN-38 or irinotecan is enclosed within lipid spheres [1 (search result 5), 2 (search result 5), 3 (search result 5)]. Onivyde, a liposomal formulation of irinotecan approved for certain metastatic cancers like pancreatic cancer, is an example [1 (search result 5)].
Liposomal carriers protect the encapsulated drug from premature degradation and release, extending its circulation time [1 (search result 5), 3 (search result 5)]. These liposomes accumulate preferentially in tumors due to the enhanced permeability and retention (EPR) effect, where tumor vasculature is often leaky, allowing larger particles to get trapped within the tumor microenvironment [5 (search result 5)]. Once inside tumor cells, encapsulated irinotecan converts into active SN-38 [1 (search result 5)]. Other approaches include nanoparticle-based carriers and antibody-drug conjugates, such as sacituzumab govitecan, which directly links SN-38 to an antibody targeting specific cancer cells, offering more targeted delivery [2 (search result 1), 3 (search result 5)].