Streptozotocin

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Streptozotocin
Streptozocin (Haworth).svg
Clinical data
Trade names Zanosar
MedlinePlus a684053
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 17–25% (100% if IV)
Metabolism Liver, kidney
Elimination half-life 35–40 minutes
Identifiers
  • 2-Deoxy-2-({[methyl(nitroso)amino]carbonyl}amino)-β-D-glucopyranose
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C8H15N3O7
Molar mass 265.222 g·mol−1
3D model (JSmol)
  • CN(C(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@@H]1O)CO)O)O)N=O
  • InChI=1S/C8H15N3O7/c1-11(10-17)8(16)9-4-6(14)5(13)3(2-12)18-7(4)15/h3-7,12-15H,2H2,1H3,(H,9,16)/t3-,4-,5-,6-,7+/m1/s1 Yes check.svgY
  • Key:ZSJLQEPLLKMAKR-GKHCUFPYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Streptozotocin or streptozocin (INN, USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the islets of Langerhans and used in medical research to produce an animal model for hyperglycemia and Alzheimer's in a large dose, as well as type 2 diabetes or type 1 diabetes with multiple low doses.

Contents

Usage

Streptozotocin is approved by the U.S. Food and Drug Administration (FDA) for treating metastatic cancer of the pancreatic 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 (especially hypoglycemia due to excessive insulin secretion by insulinomas). [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 inducing insulitis and diabetes on experimental animals. [2] Streptozotocin has also been used for modeling Alzheimer's disease through memory loss in mice. [3]

Mechanism

Streptozotocin is a glucosamine-nitrosourea compound. As with other alkylating agents in the nitrosourea class, it is toxic to cells by causing damage to the DNA, though other mechanisms may also contribute. DNA damage induces activation of PARP 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 protein GLUT2, 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]

History

Streptozotocin was originally identified in the late 1950s as an antibiotic. [7] The drug was discovered in a strain of the soil microbe Streptomyces achromogenes by scientists at the drug company Upjohn (now part of Pfizer) in Kalamazoo, Michigan. The soil sample in which the microbe turned up had been taken from Blue Rapids, Kansas, which can therefore be considered the birthplace of streptozotocin. Upjohn filed for patent protection for the drug in August 1958 and U.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 the hormone 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, the National Cancer Institute investigated streptozotocin's use in cancer chemotherapy. 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.

Biosynthesis

Recent advancements in understanding the biosynthesis of this natural product have been made by Balskus et al. [14] In short, the authors found the gene cluster responsible for production of Streptozotocin in Streptomyces achromogenes and identified novel function of a non-heme iron enzyme, SznF, which forms the N-N bond in the N-nitrosourea pharmacophore by oxidative rearrangement.

See also

Related Research Articles

<span class="mw-page-title-main">Insulin</span> Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats, and protein by promoting the absorption of glucose from the blood into cells of the liver, fat, and skeletal muscles. In these tissues the absorbed glucose is converted into either glycogen, via glycogenesis, or fats (triglycerides), via lipogenesis; in the liver, glucose is converted into both. Glucose production and secretion by the liver are strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is thus an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules in the cells. Low insulin in the blood has the opposite effect, promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e., it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins and fats in food entering the duodenum from the stomach.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Pancreatic islets</span> Regions of the pancreas

The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Alpha cell</span> Glucagon secreting cell

Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.

<span class="mw-page-title-main">Insulinoma</span> Medical condition

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group. In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma".

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Alloxan</span> Chemical compound

Alloxan, sometimes referred to as alloxan hydrate, is an organic compound with the formula OC(N(H)CO)2C(OH)2. It is classified as a derivative of pyrimidine. The anhydrous derivative OC(N(H)CO)2CO is also known, as well as a dimeric derivative. These are some of the earliest known organic compounds. They exhibit a variety of biological activities.

<span class="mw-page-title-main">GLUT2</span> Transmembrane carrier protein

Glucose transporter 2 (GLUT2) also known as solute carrier family 2, member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood Unlike GLUT4, it does not rely on insulin for facilitated diffusion.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

<span class="mw-page-title-main">Islet cell transplantation</span> Transference of pancreatic islets

Islet transplantation is the transplantation of isolated islets from a donor pancreas into another person. It is a treatment for type 1 diabetes. Once transplanted, the islets begin to produce insulin, actively regulating the level of glucose in the blood.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">PDX1</span> A protein involved in the pancreas and duodenum differentiation

PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.

<span class="mw-page-title-main">Free fatty acid receptor 1</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded by the FFAR1 gene. This gene is located on the short arm of chromosome 19 at position 13.12. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2, FFAR3, and FFAR4. FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">Free fatty acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 2 (FFAR2), also termed G-protein coupled receptor 43 (GPR43), is a rhodopsin-like G-protein coupled receptor. It is coded by the FFAR2 gene. In humans, the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12. Like other GPCRs, FFAR2s reside on the surface membrane of cells and when bond to one of their activating ligands regulate the function of their parent cells. FFAR2 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes three other receptors which, like FFAR2, are activated by certain fatty acids: FFAR1, FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids whereas FFAR1 and FFAR4 are activated by long-chain fatty acids.

<span class="mw-page-title-main">Type 3 diabetes</span> Medical condition

Type 3 diabetes is a proposed pathological linkage between Alzheimer's disease and certain features of type 1 and type 2 diabetes. Specifically, the term refers to a set of common biochemical and metabolic features seen in the brain in Alzheimer's disease, and in other tissues in diabetes; it may thus be considered a "brain-specific type of diabetes." It was recognized at least as early as 2005 that some features of brain function in Alzheimer's disease mimic those that underlie diabetes. However, the concept of type 3 diabetes is controversial, and as of 2021 it was not an officially recognized diagnosis.

<span class="mw-page-title-main">Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A</span> Protein-coding gene in the species Homo sapiens

Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A is a type II membrane protein and an enzyme – particularly a glycosyltransferase – that, in addition to the related isoenzyme B (MGAT4B), takes part in the transfer of N-acetylglucosamine (GlcNAc) to the core mannose residues of N-linked glycans in Golgi apparatus. Therefore, it is essential for the formation of tri- and tetra-antennary sugar chains. Furthermore, it is involved in glucose transport by mediating SLC2A2/GLUT2 glycosylation with controlling cell-surface expression of SLC2A2 in pancreatic beta cells and, as it is suggested, in regulating the availability of serum glycoproteins, oncogenesis, and differentiation.

References

  1. ↑ Brentjens R, Saltz L (June 2001). "Islet cell tumors of the pancreas: the medical oncologist's perspective". The Surgical Clinics of North America. 81 (3): 527–542. doi:10.1016/S0039-6109(05)70141-9. PMID   11459269.
  2. ↑ Rossini AA, Like AA, Chick WL, Appel MC, Cahill GF (June 1977). "Studies of streptozotocin-induced insulitis and diabetes". Proceedings of the National Academy of Sciences of the United States of America. 74 (6): 2485–2489. Bibcode:1977PNAS...74.2485R. doi: 10.1073/pnas.74.6.2485 . PMC   432197 . PMID   142253.
  3. ↑ Costa M, Bernardi J, Fiuza T, Costa L, Brandão R, Pereira ME (June 2016). "N-acetylcysteine protects memory decline induced by streptozotocin in mice". Chemico-Biological Interactions. 253: 10–17. doi: 10.1016/j.cbi.2016.04.026 . PMID   27087133.
  4. ↑ Szkudelski T (2001). "The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas". Physiological Research. 50 (6): 537–546. PMID   11829314.
  5. ↑ Wang Z, Gleichmann H (January 1998). "GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice". Diabetes. 47 (1): 50–56. doi:10.2337/diabetes.47.1.50. PMID   9421374.
  6. ↑ Schnedl WJ, Ferber S, Johnson JH, Newgard CB (November 1994). "STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells". Diabetes. 43 (11): 1326–1333. doi:10.2337/diabetes.43.11.1326. PMID   7926307.
  7. ↑ Vavra JJ, Deboer C, Dietz A, Hanka LJ, Sokolski WT (1959). "Streptozotocin, a new antibacterial antibiotic". Antibiotics Annual. 7: 230–235. PMID   13841501.
  8. ↑ Mansford KR, Opie L (March 1968). "Comparison of metabolic abnormalities in diabetes mellitus induced by streptozotocin or by alloxan". Lancet. 1 (7544): 670–671. doi:10.1016/S0140-6736(68)92103-X. PMID   4170654.
  9. ↑ Rerup CC (December 1970). "Drugs producing diabetes through damage of the insulin secreting cells". Pharmacological Reviews. 22 (4): 485–518. PMID   4921840. Archived from the original on 2012-07-12.
  10. ↑ Murray-Lyon IM, Eddleston AL, Williams R, Brown M, Hogbin BM, Bennett A, et al. (October 1968). "Treatment of multiple-hormone-producing malignant islet-cell tumour with streptozotocin". Lancet. 2 (7574): 895–898. doi:10.1016/S0140-6736(68)91058-1. PMID   4176152.
  11. 1 2 3 Velayudhan L, Poppe M, Archer N, Proitsi P, Brown RG, Lovestone S (January 2010). "Risk of developing dementia in people with diabetes and mild cognitive impairment". The British Journal of Psychiatry: The Journal of Mental Science. 196 (1): 36–40. doi: 10.1192/bjp.bp.109.067942 . PMID   20044657. S2CID   1794324.
  12. ↑ Knezovic A, Osmanovic-Barilar J, Curlin M, Hof PR, Simic G, Riederer P, Salkovic-Petrisic M (April 2015). "Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer's disease" (PDF). Journal of Neural Transmission. 122 (4): 577–592. doi:10.1007/s00702-015-1394-4. PMID   25808906. S2CID   16417856.
  13. ↑ Sharma M, Gupta YK (January 2001). "Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment". Life Sciences. 68 (9): 1021–1029. doi:10.1016/s0024-3205(00)01005-5. PMID   11212865.
  14. ↑ Ng TL, Rohac R, Mitchell AJ, Boal AK, Balskus EP (February 2019). "An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin". Nature. 566 (7742): 94–99. Bibcode:2019Natur.566...94N. doi:10.1038/s41586-019-0894-z. PMC   6369591 . PMID   30728519.
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