Streptozotocin

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Streptozotocin
Streptozocin.svg
Systematic (IUPAC) name
2-Deoxy-2-({[methyl(nitroso)amino]carbonyl}amino)-β-D-glucopyranose
Clinical data
Trade names Zanosar
MedlinePlus a684053
Pregnancy
category
  • US: D (Evidence of risk)
Legal status
  • ℞ (Prescription only)
Routes of
administration
Intravenous
Pharmacokinetic data
Bioavailability 17-25%
Metabolism liver, kidney
Biological half-life 35-40 minutes
Identifiers
CAS Number 18883-66-4 YesY
ATC code L01AD04 (WHO)
PubChem CID: 29327
DrugBank DB00428 YesY
ChemSpider 27273 YesY
UNII 5W494URQ81
KEGG C07313 N
ChEBI CHEBI:9288 YesY
ChEMBL CHEMBL450214 N
Chemical data
Formula C8H15N3O7
Molecular mass 265.221 g/mol
  • 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 YesY
  • Key:ZSJLQEPLLKMAKR-GKHCUFPYSA-N YesY
 NYesY (what is this?)  (verify)

Streptozotocin (Streptozocin, STZ, Zanosar®) is a naturally occurring chemical 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 in a large dose as well as Type 1 diabetes with multiple low doses.

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 researches, streptozotocin has also been long used for inducing insulitis and diabetes on experimental animals.[2]

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 poly ADP-ribosylation, which is likely more important for diabetes induction than DNA damage itself.[3] 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.[4][5]

History

Streptozotocin was originally identified in the late 1950s as an antibiotic.[6] 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,[7][8] and as a medical treatment for cancers of the beta cells.[9] 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.

Streptozotocin is now marketed by the generic drug company Sicor (Teva).

References

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External links