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| Clinical data | |
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| Trade names | Zanosar |
| MedlinePlus | a684053 |
| Routes of administration | Intravenous |
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| Pharmacokinetic data | |
| Bioavailability | 17–25% (100% if IV) |
| Metabolism | Liver,kidney |
| Eliminationhalf-life | 35–40 minutes |
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| Chemical and physical data | |
| Formula | C8H15N3O7 |
| Molar mass | 265.222 g·mol−1 |
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Streptozotocin orstreptozocin (INN,USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producingbeta cells of thepancreas in mammals. It is used inmedicine for treating certaincancers of the islets of Langerhans and used in medical research to produce ananimal model forhyperglycemia andAlzheimer's in a large dose, as well astype 2 diabetes ortype 1 diabetes with multiple low doses.
Streptozotocin is approved by the U.S.Food and Drug Administration (FDA) for treatingmetastatic cancer of thepancreatic islet cells. Since it carries a substantial risk of toxicity and rarely cures the cancer, its use is generally limited to patients whose cancer cannot be removed by surgery. In these patients, streptozotocin can reduce the tumor size and reduce symptoms (especiallyhypoglycemia due to excessiveinsulin secretion byinsulinomas).[1] A typical dose is 500 mg/m2/day by intravenous injection, for 5 days, repeated every 4–6 weeks.
Due to its high toxicity to beta cells, in scientific research, streptozotocin has also been long used for inducinginsulitis and diabetes onexperimental animals.[2] Streptozotocin has also been used for modeling Alzheimer's disease through memory loss in mice.[3]
Streptozotocin is aglucosamine-nitrosourea compound. As with otheralkylating agents in the nitrosourea class, it is toxic to cells by causing damage to theDNA, though other mechanisms may also contribute. DNA damage induces activation ofPARP which is likely more important for diabetes induction than the DNA damage itself.[4] Streptozotocin is similar enough to glucose to be transported into the cell by the glucose transport proteinGLUT2, but is not recognized by the other glucose transporters. This explains its relative toxicity to beta cells, since these cells have relatively high levels of GLUT2.[5][6]
Streptozotocin was originally identified in the late 1950s as anantibiotic.[7] The drug was discovered in a strain of the soil microbeStreptomyces achromogenes by scientists at the drug company Upjohn (now part ofPfizer) inKalamazoo, Michigan. The soil sample in which the microbe turned up had been taken fromBlue Rapids, Kansas, which can therefore be considered the birthplace of streptozotocin. Upjohn filed for patent protection for the drug in August 1958 andU.S. patent 3,027,300 was granted in March 1962.
In the mid-1960s, streptozotocin was found to be selectively toxic to the beta cells of the pancreatic islets, the cells that normally regulate blood glucose levels by producing thehormone insulin. This suggested the drug's use as an animal model of diabetes,[8][9] and as a medical treatment for cancers of the beta cells.[10] In the 1960s and 1970s, theNational Cancer Institute investigated streptozotocin's use in cancerchemotherapy.Upjohn filed for FDA approval of streptozotocin as a treatment for pancreatic islet cell cancer in November 1976, and approval was granted in July 1982. The drug was subsequently marketed as Zanosar.
More recently, a growing body of studies has provided evidence that derangement of insulin signaling underlying type-2 diabetes significantly increase the risk of cognitive impairment and Alzheimer's disease (AD) progression.[11] On this ground, the direct administration of STZ in the brain (i.e., by intracerebroventricular (ICV) infusion) has been used to develop an animal model of brain insulin resistance to mimic in rodents the pathophysiology of sporadic AD, which represents the most common form of AD in humans. STZ infusion in the brain induced accumulation of Amyloid beta (Aβ) protein,[12]oxidative stress and cognitive impairment.[13] Notably, there is now evidence that STZ infusion within the brain produced up-regulation of amyloid precursor protein (APP), tau hyperphosphorylation and neuroinflammation.[11] Treatment with the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) can relieve APP upregulation, neuroinflammation and reduce cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations, as well as induce a nearly complete recovery of cognitive impairment in the STZ-induced SAD mouse model.[11]
Streptozotocin is now long off patent and many generic formulations are available.
Recent advancements in understanding thebiosynthesis of thisnatural product have been made by Balskuset al.[14] In short, the authors found thegene cluster responsible for production of Streptozotocin inStreptomyces achromogenes and identified novel function of a non-heme iron enzyme, SznF, which forms the N-N bond in the N-nitrosoureapharmacophore by oxidative rearrangement.
