Streptozotocin
Encyclopedia
Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cell
s 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 Type 1 diabetes.
(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 insulinoma
s).
A typical dose is 500 mg/m2/day by intravenous injection, for 5 days, repeated every 4-6 weeks.
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. 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.
. 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 was granted in March 1962.
In the mid-1960s streptozotocin was found to be selectively toxic to the beta cell
s 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, and as a medical treatment for cancers of the beta cells. 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
).
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
s of the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
in mammals. It is used in medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
for treating certain cancers of the Islets of Langerhans
Neuroendocrine tumors
Neuroendocrine tumors are neoplasms that arise from cells of the endocrine and nervous systems. Many are benign, while some are cancers...
and used in medical research to produce an animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
for Type 1 diabetes.
Usage
Streptozotocinine is approved by the U.S. Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) for treating metastatic cancer of the pancreatic islet cells
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
. 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
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
due to excessive insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion by insulinoma
Insulinoma
An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin.Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is...
s).
A typical dose is 500 mg/m2/day by intravenous injection, for 5 days, repeated every 4-6 weeks.
Streptozotocin is a glucosamine
Glucosamine
Glucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and...
-nitrosourea compound. As with other alkylating agents
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
in the nitrosourea class, it is toxic to cells by causing damage to the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, though other mechanisms may also contribute. Streptozotocin is similar enough to glucose to be transported into the cell by the glucose transport protein GLUT2
GLUT2
Glucose transporter 2 also known as solute carrier family 2 , member 2 is a transmembrane carrier protein that enables passive glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood, and for renal glucose reabsorption...
, 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.
History
Streptozotocin was originally identified in the late 1950s as an antibioticAntibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
. The drug was discovered in a strain of the soil microbe Streptomyces achromogenes
Streptomyces achromogenes
Streptomyces achromogenes is a species of gram-positive bacterium that belongs in the genus Streptomyces. S. achromogenes can be grown at 28°C in a medium of yeast and malt extract with glucose....
by scientists at the drug company Upjohn (now part of Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
) in Kalamazoo, Michigan
Kalamazoo, Michigan
The area on which the modern city stands was once home to Native Americans of the Hopewell culture, who migrated into the area sometime before the first millennium. Evidence of their early residency remains in the form of a small mound in downtown's Bronson Park. The Hopewell civilization began to...
. The soil sample in which the microbe turned up had been taken from Blue Rapids, Kansas
Blue Rapids, Kansas
Blue Rapids is a city in Marshall County, Kansas in the United States. As of the 2010 census, the city population was 1,019.-History:The first endeavor to establish a town below the junction of the rivers, in 1857, failed due to misfortunes of two of the three participants...
, which can therefore be considered the birthplace of streptozotocin. Upjohn filed for patent protection for the drug in August 1958 and was granted in March 1962.
In the mid-1960s streptozotocin was found to be selectively toxic to the beta cell
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
s of the pancreatic islets
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
, the cells that normally regulate blood glucose levels by producing the hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
. This suggested the drug's use as an animal model of diabetes, and as a medical treatment for cancers of the beta cells. In the 1960s and 1970s the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
investigated streptozotocin's use in cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. Upjohn
Upjohn
The Upjohn Company was a pharmaceutical manufacturing firm founded in 1886 in Kalamazoo, Michigan by Dr. William E. Upjohn, an 1875 graduate of the University of Michigan medical school. The company was originally formed to make friable pills, which were specifically designed to be easily digested...
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
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
).