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Streptozotocin or streptozocin (INN, USP) (STZ) 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 2 diabetes or 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

^ Brentjens R, Saltz L (2001). "Islet cell tumors of the pancreas: the medical oncologist's perspective". Surg Clin North Am. 81 (3): 527–42. PMID 11459269. doi:10.1016/S0039-6109(05)70141-9.
^ 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. PMC 432197 . PMID 142253. doi:10.1073/pnas.74.6.2485.
^ 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.
^ 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. PMID 9421374. doi:10.2337/diabetes.47.1.50.
^ Schnedl WJ, Ferber S, Johnson JH, Newgard CB (1994). "STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells". Diabetes. 43 (11): 1326–33. PMID 7926307. doi:10.2337/diabetes.43.11.1326.
^ Vavra JJ, Deboer C, Dietz A, Hanka LJ, Sokolski WT (1959). "Streptozotocin, a new antibacterial antibiotic". Antibiot Annu. 7: 230–5. PMID 13841501.
^ Mansford KR, Opie L (1968). "Comparison of metabolic abnormalities in diabetes mellitus induced by streptozotocin or by alloxan". Lancet. 1 (7544): 670–1. PMID 4170654. doi:10.1016/S0140-6736(68)92103-X.
^ Rerup CC (1970). "Drugs producing diabetes through damage of the insulin secreting cells". Pharmacol Rev. 22 (4): 485–518. PMID 4921840.
^ 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. PMID 4176152. doi:10.1016/S0140-6736(68)91058-1.

External links

U.S. Patent 3,027,300
FDA drug details

UpToDate Contents

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1. 転移性の高分化型膵管系神経内分泌（カルチノイド）腫瘍：腫瘍増殖およびホルモン過剰分泌による症状を管理するための全身治療の選択肢 metastatic well differentiated pancreatic neuroendocrine tumors systemic therapy options to control tumor growth and symptoms of hormone hypersecretion
2. 転移性の高分化型胃腸系神経内分泌（カルチノイド）腫瘍：腫瘍増殖およびホルモン過剰分泌による症状を管理するための全身治療の選択肢 metastatic well differentiated gastrointestinal neuroendocrine carcinoid tumors systemic therapy options to control tumor growth and symptoms of hormone hypersecretion
3. Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents
4. 肝疾患を有する患者における化学療法による肝毒性および用量調整 chemotherapy hepatotoxicity and dose modification in patients with liver disease
5. グルカゴン産生腫瘍およびグルカゴノーマ症候群 glucagonoma and the glucagonoma syndrome

English Journal

Inhibition of NF-kappaB activation by Pyrrolidine dithiocarbamate partially attenuates hippocampal MMP-9 activation and improves cognitive deficits in streptozotocin-induced diabetic rats.

Zhao Z, Huang G, Wang B, Zhong Y.SourceDepartment of Gerontology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China.
Behavioural brain research.Behav Brain Res.2013 Feb 1;238:44-7. doi: 10.1016/j.bbr.2012.10.018. Epub 2012 Oct 23.
Matrix metalloproteinase-9 (MMP-9) has been found at significantly increased activity and also contributes to blood-brain barrier degradation in diabetes. Activation of NF-κB pathway is associated with diabetes-induced cognitive impairment, and MMP-9 gene promoter contains a highly conserved motif
PMID 23089644

Hypoglycemic dipeptide cyclo (His-Pro) significantly altered plasma proteome in streptozocin-induced diabetic rats and genetically-diabetic (ob/ob) mice.

Choi SA, Yun JW, Park HS, Choi JW.SourceDepartment of Bioindustry, Daegu University, Gyeongsan, Gyeongbuk, 712-714, Republic of Korea.
Molecular biology reports.Mol Biol Rep.2013 Feb;40(2):1753-65. doi: 10.1007/s11033-012-2229-0. Epub 2012 Oct 20.
The proteins in plasma perform many important functions in the body, and the protein profiles of the plasma vary under different physiological and pathological conditions. In an attempt to identify novel marker proteins for diabetes prognosis, we examined the effect of hypoglycemic dipeptide cyclo (
PMID 23086277

Cardiac-derived adiponectin induced by long-term insulin treatment ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic mice via AMPK signaling.

Pei H, Qu Y, Lu X, Yu Q, Lian K, Liu P, Yan W, Liu J, Ma Y, Liu Y, Li C, Li W, Lau WB, Zhang H, Tao L.SourceDepartment of Cardiology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China.
Basic research in cardiology.Basic Res Cardiol.2013 Jan;108(1):322. doi: 10.1007/s00395-012-0322-0. Epub 2012 Dec 22.
Type 1 diabetes (T1DM) portends poor prognosis concerning ischemic heart disease. Adiponectin (APN), an adipocytokine possessing insulin sensitizing and metabolic regulatory effects, has been recognized as a potent cardioprotective molecule. However, the relationship between APN and T1DM remains con
PMID 23262803

Japanese Journal

膵神経内分泌腫瘍に対する薬物療法 (特集膵がん・膵内分泌腫瘍の最近の動向)

五十嵐久人,伊藤鉄英,大野隆真 [他]
腫瘍内科 7(2), 198-204, 2011-02-00
NAID 40018767492

Combination Therapy With Olmesartan and Azelnidipine Improves EDHF-Mediated Responses in Diabetic Apolipoprotein E-Deficient Mice

HOSOYA Maki,OHASHI Junko,SAWADA Ayuko,TAKAKI Aya,SHIMOKAWA Hiroaki
Circulation journal : official journal of the Japanese Circulation Society 74(4), 798-806, 2010-03-25
… We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE<sup>-/-</sup> …
NAID 10026472808

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★リンクテーブル★

リンク元	「ストレプトゾトシン」「STZ」「ストレプトゾシン」
拡張検索	「streptozocin diabetes」

「ストレプトゾトシン」

Streptozotocin
Clinical data
Trade names	Zanosar
MedlinePlus	a684053
Pregnancy; category	US: D (Evidence of risk); ;
Routes of; administration	Intravenous
ATC code	L01AD04 (WHO);
Legal status
Legal status	In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	17–25% (100% if IV)
Metabolism	Liver, kidney
Biological half-life	35–40 minutes
Identifiers
	IUPAC name 2-Deoxy-2-({[methyl(nitroso)amino]carbonyl}amino)-β-D-glucopyranose;
CAS Number	18883-66-4 ;
PubChem CID	29327;
DrugBank	DB00428 ;
ChemSpider	27273 ;
UNII	5W494URQ81;
KEGG	C07313 ;
ChEBI	CHEBI:9288 ;
ChEMBL	CHEMBL450214 ;
ECHA InfoCard	100.038.754
Chemical and physical data
Formula	C8H15N3O7
Molar mass	265.221 g/mol
3D model (JSmol)	Interactive image;
	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 ; Key:ZSJLQEPLLKMAKR-GKHCUFPYSA-N ;
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