Streptozotocin

Streptozotocin
Names
Trade namesZanosar
IUPAC name
  • 2-Deoxy-2-({[methyl(nitroso)amino]carbonyl}amino)-β-D-glucopyranose
Clinical data
Drug classAlkylating agent[1]
Main usesIslet cell cancer of the pancreas, carcinoid tumor, pancreatic adenocarcinoma[1]
Side effectsNausea, kidney problems, bone marrow suppression[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa684053
    Legal
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability17–25% (100% if IV)
    MetabolismLiver, kidney
    Elimination half-life35–40 minutes
    Chemical and physical data
    FormulaC8H15N3O7
    Molar mass265.222 g·mol−1
    3D model (JSmol)
    SMILES
    • CN(C(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@@H]1O)CO)O)O)N=O
    InChI
    • 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 checkY
    • Key:ZSJLQEPLLKMAKR-GKHCUFPYSA-N checkY

    Streptozotocin, also known as streptozocin (STZ), is a medication used for treating certain islet cell cancer of the pancreas, carcinoid tumor, and pancreatic adenocarcinoma.[1] It is given by injection into a vein.[1]

    Common side effects include nausea, kidney problems, and bone marrow suppression.[1] Other side effects may include liver problems, confusion, and pain at the site of injection.[1] Use during pregnancy may harm the baby.[1] It is a alkylating agent.[1]

    Streptozotocin was approved for medical use in the United States in 1982.[1] In the United Kingdom it cost the NHS about £570 per 1 gram as of 2021.[2] This amount in the United States costs about 370 USD.[3] It is sold under the brand name Zanosar among others.[1]

    Medical uses

    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).[4] 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.[5] Streptozotocin has also been used for modeling Alzheimer's disease through memory loss in mice.[6]

    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.[7] 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.[8][9]

    History

    Streptozotocin was originally identified in the late 1950s as an antibiotic.[10] 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. Recent advancements in understanding the biosynthesis of this natural product have been made by Balskus et al.[11] 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.

    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,[12][13] and as a medical treatment for cancers of the beta cells.[14] 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 long off patent and many generic formulations are available.

    Research

    It is used in 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.

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 "Streptozocin Monograph for Professionals". Drugs.com. Archived from the original on 7 September 2015. Retrieved 14 October 2021.
    2. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 949. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    3. ↑ "Zanosar Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 15 October 2021.
    4. ↑ Brentjens R, Saltz L (2001). "Islet cell tumors of the pancreas: the medical oncologist's perspective". Surg Clin North Am. 81 (3): 527–42. doi:10.1016/S0039-6109(05)70141-9. PMID 11459269.
    5. ↑ Rossini, A. A.; Like, A. A. A; Chick, W. L.; Appel, M. C.; Cahill Jr, G. F. (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.
    6. ↑ Costa, Michael; Bernardi, Jamile; Fiuza, Tiago; Costa, Lidiane; Brandão, Ricardo; Pereira, Maria E. (2016-06-25). "N-acetylcysteine protects memory decline induced by streptozotocin in mice". Chemico-Biological Interactions. 253: 10–17. doi:10.1016/j.cbi.2016.04.026. ISSN 1872-7786. PMID 27087133.
    7. ↑ Szkudelski T (2001). "The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas". Physiol Res. 50 (6): 537–46. PMID 11829314.
    8. ↑ Wang Z, Gleichmann H (1998). "GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice". Diabetes. 47 (1): 50–6. doi:10.2337/diabetes.47.1.50. PMID 9421374.
    9. ↑ Schnedl WJ, Ferber S, Johnson JH, Newgard CB (1994). "STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells". Diabetes. 43 (11): 1326–33. doi:10.2337/diabetes.43.11.1326. PMID 7926307.
    10. ↑ Vavra JJ, Deboer C, Dietz A, Hanka LJ, Sokolski WT (1959). "Streptozotocin, a new antibacterial antibiotic". Antibiot Annu. 7: 230–5. PMID 13841501.
    11. ↑ Ng, Tai L.; Rohac, Roman; Mitchell, Andrew J.; Boal, Amie K.; Balskus, Emily (2019). "An N-nitrosating metalloenzyme constructs the pharmacaphore of streptozotocin". Nature. 566 (7742): 94–99. Bibcode:2019Natur.566...94N. doi:10.1038/s41586-019-0894-z. PMC 6369591. PMID 30728519.
    12. ↑ Mansford KR, Opie L (1968). "Comparison of metabolic abnormalities in diabetes mellitus induced by streptozotocin or by alloxan". Lancet. 1 (7544): 670–1. doi:10.1016/S0140-6736(68)92103-X. PMID 4170654.
    13. ↑ Rerup CC (1970). "Drugs producing diabetes through damage of the insulin secreting cells". Pharmacol Rev. 22 (4): 485–518. PMID 4921840. Archived from the original on 2012-07-12.
    14. ↑ Murray-Lyon IM, Eddleston AL, Williams R, Brown M, Hogbin BM, Bennett A, Edwards JC, Taylor KW (1968). "Treatment of multiple-hormone-producing malignant islet-cell tumour with streptozotocin". Lancet. 2 (7574): 895–8. doi:10.1016/S0140-6736(68)91058-1. PMID 4176152.
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