Chemical Properties
off-white to pale yellow crystalline powder
Definition
ChEBI: An antibiotic that is produced by Streptomyces achromogenes. It is used as an antineoplastic agent and to induce diabetes in experimental animals.
General Description
Off-white powder. Melting point 115°C. Used as an anti-cancer drug. Carcinogenic.
Air & Water Reactions
Water soluble.
Reactivity Profile
[D-GLUCOSE, 2-DEOXY-2-[[(METHYLNITROSOAMINO)-CARBONYL]AMINO] is weakly basic. Reacts exothermically with acids. Reacts with both strong oxidizing agents and strong reducing agents.
Biological Activity
Antibiotic and antitumor agent. Alkylates DNA and induces diabetes mellitus via reduction of nicotinamide adenine dinucleotide in pancreatic β -cells in vivo .
Description
Streptozotocin (STZ) was originally identified in the late 1950s
as an antibiotic and was discovered in a strain of the soil
microbe Streptomyces achromogenes. In the mid-1960s, STZ was
found to be selectively toxic to the beta cells of the pancreatic
islets and thus it is used in animal model of diabetes and as
a medical treatment for cancers of the beta cells. STZ’s use in
cancer chemotherapy received Food and Drug Administration
approval in July 1982 and the drug was subsequently marketed
as Zanosar.
Originator
Zanosar,Upjohn,US,1982
Indications
Streptozocin (Zanosar), a water-soluble nitrosourea
produced by the fungus Streptomyces achromogenes,
acts through methylation of nucleic acids and proteins.
In addition, it produces rapid and severe depletion of
the pyridine nucleotides nicotinamide adenine dinucleotide
(NAD) and its reduced form (NADH) in liver
and pancreatic islets.
Streptozocin is not well absorbed from the gastrointestinal
tract and must be administered intravenously or
intraarterially. In preclinical studies, the plasma half-life
was 5 to 10 minutes.
Streptozocin produces remission in 50 to 60% of patients
with islet cell carcinomas of the pancreas. It is also
useful in malignant carcinoid tumors.
Almost all patients have nausea and vomiting. The
major toxicity is renal tubular damage, which may be severe
in 5 to 10% of patients taking streptozocin.
Treatment of metastatic insulinomas may result in the
release of insulin from the tumor and subsequent hypoglycemic
coma. Less severe toxicities include diarrhea,
anemia, and mild alterations in glucose tolerance or
liver function tests.
Manufacturing Process
On a sterile maltose-tryptone agar slant of the following composition: 1 g
maltose; 0.5 g tryptone; 0.05 g K2HPO4; 0.01 g FeSO4·7H2O; 1.5 g agar; and
sufficient distilled water to make 100 ml, Streptomyces achromogenes var.
streptozoticus was grown for 7 days at 28°C.
The culture thus produced was used as an inoculum for the following sterile
medium: 1 g glucose; 1 g beef extract; 0.5 g Bacto peptone (Difco); 0.5 g
NaCl; and sufficient distilled water to make 100 ml. The pH was adjusted to
7.0 before sterilization. The inoculated medium was incubated in shake flasks
for 3 days at 28°C on a reciprocating shaker and 75 ml of the resulting
growth was used to inoculate 12 l of sterile medium of the same formulation.
The medium was incubated in a 20 l stainless steel bottle, at 28°C for 2 days,
the contents being stirred continuously with sparged air at the rate of 6 l of
free air per minute. The resulting growth was used to inoculate 250 l of the
following sterile medium. 2 g Bacto peptone (Difco); 2.5 g blackstrap
molasses; 2 g glucose; 0.25 g NaCl; and sufficient distilled water to make 100
ml. The pH was adjusted to 7.0 before sterilization.
This medium was incubated in a 100 gallon stainless steel fermentor, at 24°C
with sparged air being introduced at the rate of 50 l/min and with agitation by
an impeller. After 66 hours of fermentation the beer was harvested. To 100
gallons of harvested beer was added 17 pounds of diatomite, and 35 pounds
of activated carbon. The mixture was stirred well and then filtered, the cake
was water-washed with 10 gallons of tap water, and then washed with 25
gallons of acetone followed by 30 gallons of 1:1 aqueous acetone. The
acetone solutions of streptozotocin were pooled and dried in vacuo to 3.88
pounds.
Brand name
Zanosar (Sicor).
Therapeutic Function
Antineoplastic
Biochem/physiol Actions
An N-nitroso-containing compound that acts as a nitric oxide donor in pancreatic islets; induces death of insulin-secreting cells, producing an animal model of diabetes. Potent DNA methylating agent that induces chromosomal breakage. Cytotoxic to neuroendocrine tumor cell lines that express the GLUT2 glucose transporter.
Clinical Use
The glucopyranose moiety of streptozocin confers both islet cell specificity and high water solubility to this nitrosourea-based antineoplastic. As a result, it is used exclusively in metastatic islet cell carcinoma of the pancreas and is administered IV in D5W or normal saline.
Side effects
Lacking the 2-chloroethyl substituent of carmustine and lomustine, it is much less reactive as a DNA alkylating agent, and myelotoxicity is relatively rare but not unknown. Cumulative, dose-related renal toxicity can be severe or fatal, however, and 67% of patients receiving this drug will exhibit some kidney-related pathology.
Veterinary Drugs and Treatments
At present the primary purpose for streptozocin use in veterinary
medicine is as a treatment for insulinomas in dogs, particularly
those with refractory hypoglycemia and when tumors are nonresectable
or have metastasized. Streptozocin potentially could be
used for other oncologic conditions as well.
Carcinogenicity
Streptozotocin is reasonably anticipated to be a human carcinogenbased on sufficient evidence of carcinogenicity from studies in experimental animals.
Environmental Fate
STZ is an odorless ivory-colored crystalline powder or pale
yellow crystals. Having the solubility of 5070 mg l-1 in water at
25 °C, STZ is soluble in alcohol and ketones and slightly
soluble in polar organic solvents and insoluble in nonpolar
organic solvents. STZ is produced by the soil microorganism
and therefore isolated from soil samples that assumed a source
of release to the environment. Vapor pressure and Henry’s law
constant of STZ are 1.74E-12 mm Hg and 1.08E-10 cm3 per
molecule-sec at 25 °C, respectively. No information is currently
available for partition behavior in water, sediment, and soil;
environmental persistency, long-range transport, or bioaccumulation/
biomagnification.
storage
-20°C, protect from light, stored under nitrogen,unstable in solution, ready to use.
Purification Methods
Recrystallise streptozotocin from 95% EtOH. It is soluble in H2O, MeOH and Me2CO. It has UV max at 228nm ( 6360) in EtOH. The tetraacetate has m 111-114o(dec), and [] D 25 +41o (c 0.78, 95% EtOH) after recrystallisation from EtOAc. [Herr et al. J Am Chem Soc 89 4808 1967, NMR: Wiley et al. J Org Chem 44 9 1979.] It is a potent methylating agent for DNA [Bennett & Pegg Cancer Res 41 2786 1981].
Toxicity evaluation
STZ as an antibiotic is effective against Gram-negative bacteria.
As a diabetogenic agent, STZ by its N-nitroso group acts as
a nitric oxide donor in pancreatic islets. STZ inhibits synthesis
of DNA in microorganisms and mammalian cells by alkylation
and cross-linking the strands of DNA, and also affects on all
stages of mammalian cell cycle. STZ-induced DNA damage
causes activation of poly ADP-ribosylation, which is important
in induction of diabetes rather than DNA damage. Biochemical
studies indicated that STZ inhibits pyridine nucleotides and the
key enzymes that are involved in glyconeogenesis. STZ transports
glucose into the cell by the glucose transport protein
GLUT2, but is not recognized by the other glucose transporters.
Since beta cells have relatively high levels of GLUT2, this
explains STZ’s relative toxicity in these cells.
References
1) Szkudelski?et al. (2001),?The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas.; Physiol. Res.,?50?537
2) Bennett & Pegg (1981),?Alkylation of DNA in rat tissues following administration of streptozotocin; Cancer Res.,?41?27861
3) Konrad?et al.?(2001),?The potential mechanism of the diabetogenic action of streptozotocin inhibition of pancreatic beta-cell O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase; Biochem. J.,?356 Pt 1?31
4) Gao?et al.?(2000),?Streptozotocin-induced beta-cell death is independent of its inhibition of O-GlcNAcase in pancreatic Min6 cells; Arch. Biochem. Biophys.,?383?296
5) Kroncke & Kolb-Bachofen (1996),?Streptozotocin is not a spontaneous NO donor.; Free Radic. Res.,?24?77
