Mitomycin C

description

Mitomycin C (MMC), an antineoplastic antibiotic derived from Streptomyces caespitosus or Streptomyces lavendulae, is a cell cycle-specific alkylating agent, inhibits DNA synthesis through covalent mitomycin C-DNA adduct with EC50 values of 0.14μM in PC3 cells. Therefore, it was served as a chemotherapeutic agent that has demonstrated its antitumor activity and has been used widely in treatment of various cancers.
Although it is active against a wide variety of tumors, newer agents have largely replaced MMC except in anal cancer; outside of the United States, MMC is infrequently used for treatment of advanced non-small cell lung cancer (NSCLC), and breast cancer.

Chemical properties

It is a crystalline powder or a powder with blue-purple shiny crystal. Its solid state is stable, while easily deactivated in acidic and alkaline solution. Mp> 360 ℃; the maximum absorption wavelength in methanol is 216nm, 360nm and 560nm.The maximum absorption wavelength in aqueous solution is 365nm ± 2nm. This product is soluble in water, methanol, acetone and ethyl acetate and other organic solvents, slightly soluble in benzene, ether and carbon tetrachloride, insoluble in petroleum ether. Highly toxic chemical, LD50 (rat, oral) 14mg/kg. Tests show that this product has potential carcinogenic effects on experimental animals.

Side effects

As with many other chemotherapeutic agents, most of the side effects of Mitomycin C (MMC)  are dose-related, including myelosuppression (which is typically delayed in onset), nausea, vomiting, diarrhea, stomatitis, dementia, and alopecia. Pulmonary toxicity associated with MMC is unpredictable, but more likely to occur at higher doses.
The following side effects are common (occurring in greater than 30%) for patients taking Mitomycin C:
Low blood counts.  Your white and red blood cells and platelets may temporarily decrease.  This can put you at increased risk for infection, anemia and/or bleeding.  The nadir counts are delayed with this drug.
Nadir: Meaning low point, nadir is the point in time between chemotherapy cycles in which you experience low blood counts.
Onset: 3 weeks
Nadir: 4-6 weeks
Recovery: 6-8 weeks
Mouth sores
Poor appetite
Fatigue
These side effects are less common side effects (occurring in about 10-29%) of patients receiving Mitomycin C:
Nausea and vomiting, usually mild
Diarrhea
Hair loss
Bladder inflammation (urinary frequency, burning, cramping, pain)-seen with intravesical (into the bladder) therapy.

Uses

(1) It is a cell division inhibitors, nucleic acid inhibitors and phage inducer; an anti-tumor drugs in clinical use.
(2) This drug has a broad anti-tumor spectrum, and effective for gastric cancer, breast cancer. It has a certain effect on lung cancer, liver cancer, malignant lymphoma, Hodgkin's disease, reticular cell sarcoma, uterine cancer, leukemia, intestinal cancer and pancreatic cancer, but with a short remission. Combination with urokinase can improve the efficacy. The goods exert its function quickly, but the number of operators is not high, and it has a high toxicity. The goods and bleomycin as well as its derivatives ——doxorubicin are anti-cancer drugs of antibiotic which can disrupt DNA. It can depolymerize DNA in the cell, inhibit DNA replication in proliferating cell. The LD50 of intravenous injection of mice is 5ml/kg. It acts as an anticancer drugs, commonly used in the treatment of digestive system cancers.

Description

Mitomycin C is naturally produced by Streptomyces caespitosus, an Actinobacteria found in soil. Mitomycin C has antibiotic and antitumor activities and has been studied extensively since the 1950s. A unique feature of this drug is strong bioreductive alkylation under hypoxic conditions. Oxygen-poor cells internal to solid tumors provide an environment in which this drug is highly activated. As an antitumor agent, it has shown efficacy in a wide variety of cancers, including gastric cancer, pancreatic cancer, breast cancer, non-small-cell lung cancer, cervical cancer, prostate cancer, and bladder cancer. The sideeffect profile is large, which prohibits its widespread use. Mitomycin C is antibacterial to gram-positive, gram-negative, and acid-fast bacilli.

Chemical Properties

Mitomycin is a blue-violet crystalline solid.

Chemical Properties

Blue-violet crystals or crystalline powder.

Originator

Mitomycin,Medac,W. Germany,1960

Uses

Mitomycin C USP (Mutamycin) is used to treat chronic myelogenous leukemia; reticulum cell sarcoma; Hodgkin.s disease; non-Hodgkin.s lymphomas; cancer of stomach, pancreas, lung; epithelial tumors.

Uses

An antitumor antibiotic. It is used as antineoplastic.

Uses

Mitomycin C is the most studied of a family of highly distinctive blue/purple metabolites produced by several Streptomyces species. Mitomyin C exhibits potent antibacterial and antitumour activity and inhibits DNA synthesis by intercalation, blocking nuclear division with the induction of apoptosis in cancer cells.

Definition

Antibiotic derivedfrom Streptomyces, stated to be effective againsttumors.

Indications

Mitomycin (mitomycin C, Mitocin-C, Mutamycin) is an antibiotic that is derived from a species of Streptomyces. It is sometimes classified as an alkylating agent because it can covalently bind to and cross-link DNA. Mitomycin is thought to inhibit DNA synthesis through its ability to alkylate double-strand DNA and bring about interstrand cross-linking. There is evidence that enzymatic reduction by a reduced nicotinamide– adenine dinucleotide phosphate (NADPH) dependent reductase is necessary to activate the drug.
The drug is rapidly cleared from serum after intravenous injection but is not distributed to the brain.

Manufacturing Process

The commercial production of mitomycin involves the preparation of mitomycin-containing broths by culturing a mitomycin-producing organism, e.g. Streptomyces caespitosus, in suitable media as described at length in the literature. At the end of the fermentation cycle the whole broth is usually centrifuged, filtered or otherwise treated to separate the solids (mycelia) from the supernatant which contains substantially all of the antibiotic activity.
In commercial processes there is usually a period of time intervening between the end of the fermentation cycle and the time at which the mycelia is actually removed from the broth; such a period may range from several minutes to several hours in length and may be due to a number of factors, e.g., the time necessary to conduct the actual centrifugation or filtration of large quantities of broth, or the time involved in waiting for equipment to become available for use. In the commercial preparation of mitomycin, the mitomycin-containing whole broths decrease rapidly in potency during the time following the completion of the fermentation cycle and prior to the removal of the mycelia. It has been observed that a whole broth will lose substantially all of its mitomycin activity within about 6 hours at room temperature and within about 24 hours at 10°C. It has, however, been discovered, as described in US Patent 3,042,582, that in the process for the recovery of mitomycin C from mitomycin C-containing whole broth, the step of adding about 0.1 wt % with whole broth of sodium lauryl sulfate to the whole broth at the completion of the fermentation cycle substantially eliminates such destruction of mitomycin C by mitase.

brand name

Mutamycin (Bristol-Myers Squibb);Mytozytrex (SuperGen).

Therapeutic Function

Cancer chemotherapy

General Description

Blue-violet crystals. Used as an anti-tumor antibiotic complex.

General Description

Mitomycin C was isolated from Streptomyces caespitosus in 1958 by Japanese workers and is considered the prototype of the bioreductive alkylating agents. Mitomycin is sometimes included as an alkylating agent but is included here because. It was reasoned that selective activation could be achieved in a reductive environment such as that found in an area of low oxygen content. This is known to occur in tumors where the fast-growing cells often grow beyond the blood supply that would normally provide oxygen. Mitomycin C is capable of being activated and alkylating DNA in an anaerobic environment. The drug contains what would appear to be reactive functionalities, including the quinone and aziridine functionalities, both or which would be thought to be susceptible to nucleophilic attack; however, the reactivity of these functionalities is reduced because of steric and electronic effects in the parent molecule. It was reasoned that selective activation could be achieved in a reductive environment such as that found in an area of low oxygen content. This is known to occur in tumors where the fast-growing cells often grow beyond the blood supply that would normally provide oxygen.A normal cell would undergo apoptosis under these conditions, but because cancer cells often have their apoptotic mechanisms inhibited they continue to survive with little or no oxygen available. Mitomycin C is capable of being activated and alkylating DNA in an anaerobic environment, but there is actually little selectivity for hypoxic cells. Activation can occur enzymatically by both one- and twoelectron processes. Reductive enzymes such as NADPHCYP reductase and DT-diaphorase have been implicated in these processes.Involvement of one-electron processes such as those seen for the anthracylines result in redox cycling and the production of ROS that may result in DNA damage, but the cytotoxicity of mitomycin C is primarily associated with its ability to alkylate DNA.

General Description

administration in the treatment of cancers of the stomachand pancreas when other treatments have failed. Other useshave included breast, NSCLC, cervical, bladder, and headand neck cancers. Mechanisms of resistance include increasedsynthesis of nucleophilic detoxifying compoundssuch as glutathione, decreased expression of activating enzymessuch as DT-diaphorase, and increased efflux by Pgp.The drug is rapidly cleared from the plasma after administrationand widely distributed but does not cross the bloodbrainbarrier. The parent and metabolites are excretedmainly in the feces with an elimination half-life of 50 minutes.Adverse effects include dose-limiting myelosuppression,mild nausea and vomiting,.

Air & Water Reactions

Water soluble.

Reactivity Profile

Mitomycin C is sensitive to prolonged exposure to light. Mitomycin C may be sensitive to prolonged exposure to air. Mitomycin C is incompatible with strong oxidizing agents, strong acids and strong bases. Calcium salts may cause decomposition.

Hazard

Possible carcinogen.

Health Hazard

Toxic doses as low as 750 mg/kg have been reported in humans. The major toxic effect is myelosuppression, characterized by marked leukopenia and thrombocytopenia; this may be delayed and cumulative. Interstitial pneumonia and glomerular damage resulting in kidney failure are unusual but well documented complications. Lung conditions -- administration of mitomycin has been recognized as causing pneumonitis, alveolitis and pulmonary fibrosis. Kidney conditions -- administration of Mitomycin Can cause kidney damage. Kidney toxicity was observed in 1-5 percent of patients. Depressed immune conditions.

Fire Hazard

Flash point data for Mitomycin C are not available; however, Mitomycin C is probably combustible.

Biological Activity

Antibiotic and antitumor agent. Covalently binds DNA forming intra- and interstrand crosslinks. Inhibits DNA synthesis.

Clinical Use

Mitomycin has limited palliative effects in carcinomas of the stomach, pancreas, colon, breast, and cervix.

Side effects

The major toxicity associated with mitomycin therapy is unpredictably long and cumulative myelosuppression that affects both white blood cells and platelets. A syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure also has been described. Renal, hepatic, and pulmonary toxicity may occur. The drug is teratogenic and carcinogenic, and it can cause local blistering.

Potential Exposure

This compound is an antitumor antibiotic complex. This drug is usually injected intravenously.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Live vaccines: risk of generalised infections - avoid.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit. Keepvictim quiet and maintain normal body temperature.

Environmental Fate

Mitomycin C is naturally produced by S. caespitosus, a microorganism found in soil and decaying vegetation. As a compound potentially released in commercial solid waste or in spill or container residue, mitomycin C is not thought to persist in soil and water. Calculations based on its hydrolysis rate in water at 25 ℃ show a half-life of 12.9 days. It is readily soluble in water, so mobility in groundwater is high. Mitomycin persistence in air is low and bioaccumulation is low.

Metabolism

Mitomycin is administered IV in the treatment of disseminated adenocarcinoma of the stomach or pancreas, and it has been used intravesically in superficial bladder cancer. Biotransformation pathways are saturable, and approximately 10% of an administered dose is eliminated unchanged via the kidneys.

storage

+4°C

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Purification Methods

Mitomycin C forms blue-violet crystals from *C6H6/pet ether. It is soluble in Me2CO, MeOH and H2O, moderately soluble in *C6H6, CCl4 and Et2O but insoluble in pet ether. It has UV max at 216, 360 and a weak peak at 560nm in MeOH. [Stevens et al. J Med Chem 8 1 1965, Shirahata & Hirayama J Am Chem Soc 105 7199 1983, Beilstein 25 III/IV 516.]

Toxicity evaluation

Mitomycin C inhibits DNA synthesis and cross-links DNA at the N6 position of adenine and at the O6 and N2 positions of guanine. In addition, single-strand breakage of DNA is caused by reduced mitomycin C (this can be prevented by free radical scavengers). Its action is most prominent during the late G1 and early S phases of the cell cycle. Mitomycin C can inhibit RNA and protein synthesis at high concentrations. Mytomycin C is an aneuploidy-inducing agent. Oxygen and radiation therapy have been shown to enhance the development of toxicity.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides, heat, strong light, calcium salts.

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform to EPA regulations governing storage, transportation, treatment, and waste disposal. It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

References

1) Tee and Proud (2000), DNA-damaging agents cause inactivation of translational regulators linked to mTOR signaling; Oncogene, 30 21 2) Park et al. (2000), Mitomycin C induces apoptosis in a caspases-dependent and Fas/CD95- independent manner in human gastric adenocarcinoma cells; Cancer Lett., 158 125 3) Merck Index 14:6215

Raw materials

Preparation Products