Uses
Doxorubicin (adriamycin) is the most extensively studied of a family of highly fluorescent anthracycline antibiotics produced by several Streptomyces species, first reported in 1967 and later approved for human therapeutic use as an antitumour agent for the treatment of a wide range of cancers. Doxorubicin also exhibits anti-HIV and antibacterial activity. The mode of action of doxorubicin is thought to be due to intercalation of DNA and inhibition of nucleic acid synthesis.
Brand name
Adriblastina (Farmitalia, Societa Farmaceutici Italia, Italy).
Potential Exposure
An antibiotic product from streptomyces, used as anticancer drug
First aid
Move victim to fresh air. Call 911 or emergency medical service. Give artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involvedand take precautions to protect themselves. Medical observation is recommended for 24 to 48 hours after breathing overexposure, as pulmonary edema may be delayed. As first aid for pulmonary edema, a doctor or authorized paramedic may consider administering a drug or other inhalation therapy.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.
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
Chemical Properties
Adriamycin is an orange to red cake-like or needle-like crystalline solid.
Waste Disposal
It is inappropriate and possibly dangerous to the environment to dispose of expired or waste 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.
Originator
Adriblastina,Farmitalia,Italy,1971
History
Adriamycin was first discovered in 1967 by Arcamone, Cassinelli, Di Marco, and Gaetani at the FI Research Laboratory. It was found in cultures of a mutant Streptomyces peucetius (Streptomyces peucetius caesius) (Arcamone, 1969). The compound's chemical structure is very similar to daunomycin, the only difference being that a hydrogen atom on the acetyl group is replaced by a hydroxyl group. The new compound is named after the view of the Adriatic Sea from Castel del Monte, where the strain that produced it was isolated. Subsequently, researchers conducted extensive preclinical, pharmacological, toxicological, and formulation studies. However, it wasn't until 1969, when Monfardini published authoritative results in a journal confirming the drug's broad activity spectrum, that it gained widespread attention from the scientific community.
Definition
ChEBI: Doxorubicin is a deoxy hexoside, an anthracycline, an anthracycline antibiotic, an aminoglycoside, a member of tetracenequinones, a member of p-quinones, a primary alpha-hydroxy ketone and a tertiary alpha-hydroxy ketone. It has a role as an Escherichia coli metabolite. It is a conjugate base of a doxorubicin(1+). It derives from a hydride of a tetracene.
Indications
Doxorubicin binds tightly to DNA by its ability to
intercalate between base pairs and therefore is preferentially
concentrated in nuclear structures. Intercalation
results in steric hindrance, hence production of
single-strand breaks in DNA and inhibition of DNA
synthesis and DNA-dependent RNA synthesis. The enzyme
topoisomerase II is thought to be involved in the
generation of DNA strand breaks by the anthracyclines.
Cells in S-phase are most sensitive to doxorubicin, although
cytotoxicity also occurs in other phases of the
cell cycle.
Manufacturing Process
Two 300 ml Erlenmeyer flasks, each containing 60 ml of the following culture
medium for the vegetative phase, were prepared: peptone 0.6%; dry yeast
0.3%; hydrated calcium carbonate 0.2%; magnesium sulfate 0.01%; the pH
after sterilization was 7.2. Sterilization has been effected by heating in
autoclave to 120°C for 20 minutes. Each flask was inoculated with a quantity
of mycelium of the mutant F.I.106 (the new strain thus obtained has been
given the code F.I.106 of the Farmitalia microbiological collection and has
been called Streptomycespeucetius var. caesius) corresponding to 1/9 of a
suspension in sterile water of the mycelium of a 10 day old culture grown in a
big test tube on the following medium: saccharose 2%; dry yeast 0.1%;
bipotassium phosphate 0.2%; sodium nitrate 0.2%; magnesium sulfate 0.2%;
agar 2%; tap water up to 100%. The flasks were then incubated at 28°C for
48 hours on a rotary shaker with a stroke of 30 mm at 220 rpm.，
2 ml of a vegetative medium thus grown were used to inoculate 300 ml
Erlenmeyer flasks with 60 ml of the following medium for the productive
phase: glucose 6%; dry yeast 2.5%; sodium chloride 0.2%; bipotassium
phosphate 0.1%; calcium carbonate 0.2%; magnesium sulfate 0.01%; ferrous
sulfate 0.001%; zinc sulfate 0.001%; copper sulfate 0.001%; tap water to
100%. The glucose was previously sterilized separately at 110°C for 20
minutes. The resulting pH was 7. This was sterilized at 120°C for 20 minutes
and incubated at 28°C under the same conditions by stirring, as for the
vegetative media.
The maximum concentration of the antibiotic was reached on the 6th day of
fermentation. The quantity of adriamycin produced at this time corresponds to
a concentration of 15 μg/ml.
Therapeutic Function
Cancer chemotherapy
Biological Activity
doxorubicin is a semi-synthesized anticancer agent derived from bacterial culture. [1] it is an anthracycline antibiotic. it is been widely used in blood cancers, solid tumors and sarcomas.doxorubicin intercalates into dna double strand and inhibits the progression of dna topoisomerase ii, stopping replication process. [2] doxorubicin also induces histone eviction from open chromatin, causing dna damage and epigenetic deregulation. [3]doxorubicin is administrated intravenously. approximately 75% of doxorubicin and its metabolites bind to plasma protein. doxorubicin does not cross blood brain barrier. 50% of the drug is eliminated unchanged from the body mainly though bile excretion. the remaining undergoes one-electron reduction, two-electron reduction, and deglycosidation. the major metabolite is a potent membrane ion pump inhibitor, which is associated with cardiomyopathy. [4]
Mechanism of action
Doxorubicin is not absorbed orally, and because of
its ability to cause tissue necrosis must not be injected
intramuscularly or subcutaneously. Distribution studies
indicate rapid uptake in all tissues except the CNS.
Extensive tissue binding, primarily intranuclear, accounts
for the prolonged elimination half-life.The drug
is extensively metabolized in the liver to hydroxylated
and conjugated metabolites and to aglycones that are
primarily excreted in the bile.
Clinical Use
Doxorubicin is one of the most effective agents used
in the treatment of carcinomas of the breast, ovary, endometrium,
bladder, and thyroid and in oat cell cancer
of the lung. It is included in several combination regimens
for diffuse lymphomas and Hodgkin’s disease.
Doxorubicin can be used as an alternative to daunorubicin
in acute leukemias and is useful in Ewing’s sarcoma,
osteogenic sarcoma, soft-tissue sarcomas, and
neuroblastoma. Some activity has been reported in
non–oat cell lung cancer, multiple myeloma, and adenocarcinomas
of the stomach, prostate, and testis.
Side effects
The most important toxicities caused by doxorubicin
involve the heart and bone marrow.Acutely, doxorubicin
may cause transient cardiac arrhythmias and
depression of myocardial function. Doxorubicin may
cause radiation recall reactions, with flare-ups of dermatitis,
stomatitis, or esophagitis that had been produced
previously by radiation therapy. Less severe toxicities
include phlebitis and sclerosis of veins used for
injection, hyperpigmentation of nail beds and skin
creases, and conjunctivitis. Because of its intense red
color, doxorubicin will impart a reddish color to the
urine for 1 or 2 days after administration.
Carcinogenicity
Adriamycin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
storage
Store at -20°C, protect from light
References
[1]brayfield, a, ed. (2013). doxorubicin. martindale: the complete drug reference. pharmaceutical press. retrieved 15 april 2014.
[2]pommier y., et al. (2010). dna topoisomerases and their poisoning by anticancer and antibacterial drugs. chemistry & biology 17 (5): 421–433.
[3]pang, b., et al. (2013). drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. nature communications 4 (5): 1908
[4]boucek rj., et al. (1987). the major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. a correlative study of cardiac muscle with isolated membrane fractions. j of biol chem 262: 15851-15856.
