doxorubicin

[D(E)OX(Y)- + Latin ruber, red; see rubric + -(MY)CIN.]

Definition

Doxorubicin, which kills cancer cells, is among the most widely used chemotherapy drugs. It is also known by its trade name, Adriamycin.

Purpose

This anticancer drug may be used to fight several different cancers: breast cancer, ovarian cancer, gastric (stomach) cancer, thyroid cancer, lung cancer, testicular cancer, and endometrial cancer. In addition it may be used against Hodgkin's and non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), sarcomas of the soft tissue, sarcomas of the bone (osteosarcomas), neuroblastoma, Wilms' tumor, small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC).

Because doxorubicin is used to treat so many different cancers, a complete description of how it may be combined with other medications in the treatment of each of the cancers cannot be given here. A few examples follow: In the treatment of Hodgkin's disease, for instance, one widely used chemotherapy regimen is the so-called ABVD, which consists of doxorubicin, bleomycin, vinblastine, and dacarbazine. Another is the so-called MOPP/ABV, which consists of mechloretha-mine, vincristine (Oncovin), prednisone, procarbazine, doxorubicin, bleomycin, and vinblastine. Yet another is the so-called EVA: etoposide, vinblastine, and doxorubicin. Still another is the so-called EPOCH, which consists of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone.

Doctors may treat stage III and IV non-Hodgkin's lymphoma with the so-called m-BACOD chemotherapy regimen, which consists of methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone. Yet another regimen called the ProMACECytaBOM, which consists of cyclophosphamide, doxorubicin, etoposide, prednisone, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin.

Complete remission (CR) is the total elimination of all diseased cells detectable following therapy. Continuous complete remission is CR that continues indefinitely. In the treatment of acute lymphocytic leukemia (ALL), it has been found that the likelihood that continuous complete remission will be achieved is increased if the patient receives at least three drugs. Two of these are usually prednisone and vincristine. The third may be doxorubicin.

Description

Doxorubicin is a DNA-binding anticancer drug and belongs to an anthracycline antibiotic, although doctors do not use this drug to attack microbial infections.

Recommended Dosage

Between 60 and 90 milligrams per square meter of doxorubicin are administered via a single intravenous (IV) injection every 21 days. Alternately, between 20 and 30 milligrams per square meter per day may be given via IV for three days every three to four weeks. Alternately, 20 milligrams per square meter may be given via IV weekly. The dose of doxorubicin used depends upon which regimen for cancer is being followed.

For example, in the treatment of acute myelocytic leukemia (AML), 30 milligrams per square meter may be given over a period of three days. When the medication is used in the treatment of breast cancer, one chemotherapy regimen is the so-called AC, which consists of doxorubicin plus cyclophosphamide. A total of 60 milligrams of doxorubicin per square meter are given per day. AC is then repeated every 21 days.

Another chemotherapy regimen used for breast cancer is known as either FAC or CAF: fluorouracil, doxorubicin, and cyclophosphamide. In this regimen, 50 milligrams of doxorubicin are given per square meter per day.

Doxorubicin is not given by mouth, as an insufficient amount of the medication would be transported through the stomach wall if this were done. Rather this medication is usually administered through an intravenous (IV) procedure. Patients with liver problems may be given a reduced dose of doxorubicin.

Precautions

Doxorubicin may cause serious heart problems. To prevent these, doctors may limit the amount of doxorubicin given to each patient so that the total amount of doxorubicin a patient receives over her or his entire lifetime is 550 milligrams per square meter, or less. An encouraging recent development is that medication is now available that appears to help protect the patient's heat from the effects of doxorubicin. This new medication is called dexrazoxane (Zinecard).

Side Effects

Patients may develop problems with heart rhythms while doxorubicin is being taken. In addition, a serious heart illness known as heart failure may develop later. Some patients develop heart failure more than 20 after having received doxorubicin.

Studies have shown that the use of the new medication dexrazoxane (Zinecard) helps protect the patient's heart from the harmful effects of doxorubicin. However, dexrazoxane itself has side effects. For example, it may intensify the reduction of blood cells that may occur with doxorubicin therapy. In addition, it may make doxorubicin less effective in attacking cancer. Dexrazoxane is used only in patients being treated for breast cancer and only in patients who have already been given more than half of the total lifetime amount of doxorubicin they should ever receive.

The activity of the bone marrow in producing blood cells may be harmed by doxorubicin. Side effects affecting the heart and bone marrow may cause doctors to lower the dose of doxorubicin. Other side effects associated with doxorubicin are nausea and vomiting, stomach problems, eye problems, loss of appetite (anorexia), and hair loss (alopecia). Blistering may result if bleeding occurs. In addition, the medication has a harmless side effect about which patients should be forewarned: the urine and tears may have a red color.

Patients receiving doxorubicin in conjunction with certain other anticancer drugs may, very rarely, develop a type of leukemia.

—Bob Kirsch

Brand names: Adriamycin PFS®Adriamycin RDF®Adriamycin®Rubex®

Chemical formula:

Drug Forms:
• Doxorubicin injection (below)
• Doxorubicin Hydrochloride Solution for injection

Español:
• Inyección de doxorrubicina
• Clorhidrato de doxorrubicina, Solución para inyección

Doxorubicin injection

What is doxorubicin injection?

DOXORUBICIN (Adriamycin®, Rubex®) is a type of cancer chemotherapy for treating a number of cancers, including bone, breast, stomach, lung, bladder, thyroid, ovarian, and leukemia, Wilms's tumor and lymphoma. Doxorubicin interferes with the growth of rapidly growing cells, like cancer cells, and eventually causes cell death. Doxorubicin is used alone or in combination with other cancer chemotherapy agents. Generic doxorubicin injections are available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• angina
• bleeding problems
• blood disorders
• hypertension
• heart disease
• infection (bacterial, viral or fungal)
• liver disease
• previous chemotherapy with daunorubicin, epirubicin, idarubicin, or mitoxantrone
• previous radiation therapy
• an unusual or allergic reaction to doxorubicin, other chemotherapy agents, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

Doxorubicin is for infusion into a vein. It is usually given in a hospital or clinic setting by a trained health-care professional. If you notice pain, swelling, burning or any unusual feeling around the site of your injection, tell your health care professional immediately. There may be several weeks between doses.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What drug(s) may interact with doxorubicin?

Ask your prescriber or health care professional about other medicines that may increase the effect of doxorubicin.
• certain antibiotics (clarithromycin, erythromycin, sparfloxacin)
• cisapride
• chloroquine
• dolasetron
• droperidol
• foscarnet
• levomethadyl
• medicines used to control the heart rhythm (examples: amiodarone, bepridil, disopyramide, flecainide, probucol, procainamide, propafenone, quinidine, sotalol)
• medicines used for mental problems, psychosis, or depression (examples: amitriptyline, chlorpromazine, fluphenazine, haloperidol, mesoridazine, perfenazine, pimozide, prochlorperzine, risperidone, thioridazine, ziprasidone)
• methadone
• other chemotherapy agents may increase the side effects seen with doxorubicin
• palonosetron
• pentamidine
• phenobarbital
• phenytoin
• prochlorperazine
• vaccines
• zidovudine

Talk to your prescriber or health care professional before taking any of these medicines:
• aspirin
• acetaminophen
• ibuprofen
• ketoprofen
• naproxen

Tell your prescriber or health care professional about all other medicines you are taking, including nonprescription medicines, nutritional supplements, or herbal products. Also, tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking doxorubicin?

Visit your prescriber or health care professional for regular checks on your progress. You will need to have regular blood checks.

After treatment with doxorubicin your urine may be a red color. This is different from blood in the urine and will disappear within a few days, with no cause for alarm. If you think you may have blood in the urine call your prescriber or health care professional for advice.

Doxorubicin may make you feel generally unwell. This is not uncommon because doxorubicin affects good cells as well as cancer cells. Report any side effects as above, but continue your course of medicine even though you feel ill, unless your prescriber or health care professional tells you to stop.

Doxorubicin will decrease your body's ability to fight infections. Call your prescriber or health care professional if you have a fever, chills, sore throat or other symptoms of a cold or flu. Do not treat these symptoms yourself. Try to avoid being around people who are sick. Doxorubicin may increase your risk to bruise or bleed. Call your prescriber or health care professional if you notice any unusual bleeding. Be careful not to cut, bruise or injure yourself because you may get an infection and bleed more than usual.

Avoid taking aspirin, acetaminophen (Tylenol®), ibuprofen (Advil®), naproxen (Aleve®), or ketoprofen (Orudis® KT) products as these may hide a fever, unless instructed to by your prescriber or health care professional.

Call your prescriber or health care professional if you get diarrhea. Do not treat yourself. Some diarrhea medicine will make the diarrhea worse.

Be careful brushing and flossing your teeth or using a toothpick while receiving doxorubicin because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you have received doxorubicin.

Men and women of childbearing age should use effective birth control methods during doxorubicin treatment. There is a risk of birth defects if a woman becomes pregnant and is being treated with doxorubicin. Women should not become pregnant while being treated with doxorubicin or if their partner is being treated with doxorubicin.

Caregivers of patients receiving doxorubicin should take care to prevent contact with the patient's urine and other body fluids by wearing latex gloves for at least 5 days after each treatment.

What side effects may I notice from receiving doxorubicin?

The side effects you may experience with doxorubicin therapy depend upon the dose, other types of chemotherapy or radiation therapy given, and the disease being treated. Not all of these effects occur in all patients. Discuss any concerns or questions with your prescriber or health care professional.

Side effects that you should report to your prescriber or health care professional as soon as possible:
Rare or uncommon:
• chest pain
• difficulty breathing, wheezing
• irregular heart beat
• swelling of ankles or feet
More common:
• low blood counts - doxorubicin may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
• signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
• signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine
• signs of decreased red blood cells - unusual weakness or tiredness, fainting spells, lightheadedness
• irregular heartbeat, palpitations, chest pain
• mouth or throat sores or ulcers
• pain, redness, swelling or irritation at the injection site
• skin rash, itching, peeling skin

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• diarrhea
• facial flushing
• hair loss
• heartburn
• nail discoloration or damage
• nausea
• red color in urine (may appear for 1 to 2 days after treatment)
• red or watery eyes

Where can I keep my medicine?

This medicine is given through your vein at a clinic or hospital. You will not have to take this medicine at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

An antineoplastic antibiotic, which binds to DNA and inhibits synthesis of nucleic acids and cell division. It is used intravenously to produce regression in various neoplastic conditions. The side-effects include bone marrow depression, alopecia and cardiac toxicity. Called also adriamycin. See also anthracycline antibiotic.

Doxorubicin
Systematic (IUPAC) name
(8S,10S)-10-(4-amino-5-hydroxy-6-methyl- tetrahydro-2H-pyran-2-yloxy) -6,8,11-trihydroxy-8-(2-hydroxyacetyl) -1-methoxy-7,8,9,10-tetrahydrotetracene -5,12-dione
Identifiers
CAS number	23214-92-8
ATC code	L01DB01
PubChem	31703
DrugBank	APRD00185
ChemSpider	29400
Chemical data
Formula	C27H29NO11
Mol. mass	543.52 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	5% (Oral)
Metabolism	CYP3A4
Half life	12–18.5 hours when released from liposomes [1]
Excretion	Biliary and fecal
Therapeutic considerations
Pregnancy cat.	D(AU) D(US)
Legal status	POM(UK) ℞-only(US)
Routes	Intravenous
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Doxorubicin (INN, pronounced /ˌdɒksəˈruːbəsɪn/; trade name Adriamycin; also known as hydroxydaunorubicin) is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines it intercalates DNA. It is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas.

The drug is administered in the form of hydrochloride salt intravenously. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex.^[2] It is photosensitive and it is often covered by an aluminum bag to prevent light from affecting it.

Contents 1 History 2 Biosynthesis 3 Mechanism of action 4 Clinical use 4.1 Experimental therapy 5 Liposomal formulations 6 Side effects 7 See also 8 References 9 External links

History

See also: History of cancer chemotherapy

The history of doxorubicin can be traced back to the 1950s, when an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th century castle. A new strain of Streptomyces peucetius which produced a red pigment was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against murine tumors. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color.^[3] Clinical trials began in the 1960s, and the drug saw success in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity.^[4]

Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-N-methyl urethane and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention.^[5] Doxorubicin showed better activity than daunorubicin against murine tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.^[6]

Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research by many investigators throughout the world has led to many other anthracycline antibiotics, or analogs, and today, it is estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them have been evaluated in the screening program at the National Cancer Institute (NCI).^[3]

Biosynthesis

Main article: Biosynthesis of doxorubicin

Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of streptomyces. In contrast, only one known non-wild type species, streptomyces peucetius subspecies cesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin.^[7] This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities.^[8] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of streptomyces can produce doxorubicin.^[9] His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR.^[10] By 1999, they produced recombinant Dox A, a Cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin.^[11] This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing Dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides.^[7] Some triple mutants, that also over-expressed Dox A, were able to double the yield of DXR. This is of more than academic interest because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum.^[12] More efficient production techniques have brought the price down to $1.1 million per kg for the non-liposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps and the yield is poor.^[13] Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.

Cartoon diagram of two doxorubicin molecules intercalating DNA, from PDB 1D12.

Mechanism of action

The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation.^[14] Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis.^[15] This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.

The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.^[16][17]

Clinical use

Doxorubicin is commonly used to treat some leukemias, Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others.^[2] Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (Taxotere, CA), ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), BEACOPP, CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Doxil is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma.^[18]

Experimental therapy

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.^[19]

Recent animal research coupling a murine monoclonal antibody with doxorubicin has created an immunoconjugate that was able to eliminate HIV-1 infection in mice. Current treatment with antiretroviral therapy (ART) still leaves pockets of HIV within the host. The immunoconjugate could potentially provide a complementary treatment to ART to eradicate antigen-expressing T cells.^[20]

Liposomal formulations

Doxil is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin made by Ben Venue Laboratories for Johnson & Johnson in the United States. It was developed to treat Kaposi's sarcoma, an AIDS-related cancer that causes lesions to grow under the skin, in the lining of the mouth, nose and throat, or in other organs. The polyethylene glycol coating results in preferential concentration of Doxil in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome. Following administration of Doxil, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50mg/m2 dosing every 4 weeks, 50.6% of patients treated with Doxil developed Hand-Foot Syndrome. The prevalence of this side effect limits the Doxil dose that can be given as compared with doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. Doxil is also approved by the FDA for treatment of ovarian cancer and multiple myeloma. Outside the United States, Doxil is known as Caelyx and is marketed by Schering-Plough.

Myocet is a non-pegylated liposomal doxorubicin made by Enzon Pharmaceuticals for Cephalon in Europe and for Sopherion Therapeutics in the United States and Canada. Myocet is approved in Europe and Canada for treatment of metastatic breast cancer in combination with cyclophosphamide, but is not yet approved by the FDA for use in the United States. It is currently being studied by Sopherion Therapeutics in a pivotal phase III global registrational trial in concurrent combination with Herceptin (trastuzumab) and Taxol (paclitaxel) for treatment of HER2-positive metastatic breast cancer. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating and therefore does not result in the same prevalence of hand-foot Syndrome. The minimization of this side effect may allow for 1 for 1 substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as Herceptin. There is an FDA black box warning that Herceptin cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of Herceptin and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as CHF. Published phase II study results have shown that Myocet, Herceptin, and Taxol can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for the on-going phase III trial for FDA approval.

^[21][22]

Side effects

Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause neutropenia (a decrease in white blood cells), as well as complete alopecia (hair loss). When the cumulative dose of doxorubicin reaches 550 mg/m², the risks of developing cardiac side effects, including congestive heart failure, dilated cardiomyopathy, and death, dramatically increase. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes (heart cells), causing myofibrillar loss and cytoplasmic vacuolization. Additionally, some patients may develop palmar plantar erythrodysesthesia, or, "hand-foot syndrome," characterized by skin eruptions on the palms of the hand or soles of the feet, characterized by swelling, pain and erythema ^[18].

Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"^[23] or "red death."^[24]

Doxorubucin can also cause reactivation of hepatitis B.^{[citation needed]}

See also

Pharmacy and Pharmacology portal

• Anthracycline
• Chemotherapy regimen
  • ABVD
  • BEACOPP
  • CHOP

References

1. ^ Laginha, K.M. "Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors." Clinical Cancer Research. October 1, 2005. Vol. 11 (19). Retrieved on April 19, 2007.
2. ^ ^{a b} "Doxorubicin (Systemic)." Mayo Clinic. Last updated on: June 15, 1999. Retrieved on April 19, 2007.
3. ^ ^{a b} Weiss, Raymond B. "The Anthracyclines: Will We Ever Find a Better Doxorubicin?" Seminars in Oncology. Vol. 19, No. 6. December 1992. pp. 670–686. PMID 1462166.
4. ^ Tan, C.; Tasaka, H.; Kou-Ping, Y.; et al. Daunomycin, An Antitumor Antibiotic, In the Treatment of Neoplastic Disease. Clinical Evaluation with Special Reference to Childhood Leukemia. 1967, Cancer, 20, 333 – 353. PMID 4290058.
5. ^ Arcamone, F.; Cassinelli, G.; Fantini, G.; et al. Adriamycin, 14-hydroxydaunomycin, A New Antitumor Antibiotic from S. peucetius var. caesius. 1969, Biotechnol. Bioeng., 11, 1101 – 1110. PMID 5365804.
6. ^ Di Marco, A.; Gaetani, M.; Scarpinato, B. Adriamycin (NSC-123,127): A New Antibiotic with Antitumor Activity. 1969, Cancer Chemotherapy Reports, 53, 33 – 37. PMID 5772652.
7. ^ ^{a b} Lomovskaya N, Otten SL, Doi-Katayama Y, et al. (1999). "Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene". J. Bacteriol. 181 (1): 305–18. PMID 9864344. 
8. ^ Arcamone F, Cassinelli G, Fantini G, et al. (1969). "Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius". Biotechnol. Bioeng. 11 (6): 1101–10. doi:10.1002/bit.260110607. PMID 5365804. 
9. ^ Grimm A, Madduri K, Ali A, Hutchinson CR (1994). "Characterization of the Streptomyces peucetius ATCC 29050 genes encoding doxorubicin polyketide synthase". Gene 151 (1–2): 1–10. doi:10.1016/0378-1119(94)90625-4. PMID 7828855. 
10. ^ Dickens ML, Strohl WR (1996). "Isolation and characterization of a gene from Streptomyces sp. strain C5 that confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans TK24". J. Bacteriol. 178 (11): 3389–95. PMID 8655530. 
11. ^ Walczak RJ, Dickens ML, Priestley ND, Strohl WR (1999). "Purification, properties, and characterization of recombinant Streptomyces sp. strain C5 DoxA, a cytochrome P-450 catalyzing multiple steps in doxorubicin biosynthesis". J. Bacteriol. 181 (1): 298–304. PMID 9864343. 
12. ^ Hutchinson CR, Colombo AL (1999). "Genetic engineering of doxorubicin production in Streptomyces peucetius: a review". J. Ind. Microbiol. Biotechnol. 23 (1): 647–52. doi:10.1038/sj.jim.2900673. PMID 10455495. 
13. ^ Lown JW (1993). "Anthracycline and anthraquinone anticancer agents: current status and recent developments". Pharmacol. Ther. 60 (2): 185–214. doi:10.1016/0163-7258(93)90006-Y. PMID 8022857. 
14. ^ Fornari, F.A.; Randolph, J.K.; Yalowich, J.C.; Ritke, M.K.; Gewirtz, D.A. Interference by Doxorubicin with DNA Unwinding in MCF-7 Breast Tumor Cells. 1994, Molecular Pharmacology, 45, 649 – 656. PMID 8183243.
15. ^ Momparler, R.L.; Karon, M.; Siegel, S.E.; Avila, F. Effect of Adriamycin on DNA, RNA and Protein Synthesis in Cell-Free Systems and Intact Cells. 1976, Cancer Research, 36, 2891 – 2895. PMID 1277199. Free full text
16. ^ Frederick, C.A.; Williams, L.D.; Ughetto, G.; van der Marel, G.A.; van Boom, J.H.; Rich, A.; Wang, A.H. Structural Comparison of Anticancer Drug-DNA Complexes: Adriamycin and Daunomycin. 1990, Biochemistry, 29, 2538 – 2549. PMID 2334681. Crystal structure is available for download as a PDB file.
17. ^ Pigram, W.J.; Fuller, W.; Hamilton, L.D. Stereochemistry of Intercalation: Interaction of Daunomycin with DNA. 1972, Nature New Biology, 235, 17 – 19. PMID 4502404.
18. ^ ^{a b} "DOXIL Product Information." Ortho Biotech Products, L.P. Retrieved on April 19, 2007.
19. ^ Wendel H, De Stanchina E, Fridman J, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe S (2004). "Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy". Nature 428 (6980): 332–7. doi:10.1038/nature02369. PMID 15029198. 
20. ^ Johansson S, Goldenberg D, Griffiths G, Wahren B, Hinkula J (2006). "Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody". AIDS 20 (15): 1911–1915. doi:10.1097/01.aids.0000247111.58961.60. PMID 16988511. 
21. ^ Cancerbackup: Liposomal doxorubicin (Caelyx, Myocet)
22. ^ Chemocare: Doxorubicin liposomal
23. ^ Bloch, Richard; Bloch, Annette. "25 Most Asked Questions". Fighting Cancer. R. A. Bloch Cancer Foundation. http://www.blochcancer.org/fighting/chap13.html. Retrieved 2007-06-28. 
24. ^ Groopman, Jerome E. (2007). How Doctors Think. Boston: Houghton Mifflin. p. 49. ISBN 0-618-61003-0. 

External links

• MedlinePlus DrugInfo medmaster-a682221
• Overview at BC Cancer Agency
• Doxil Site
• Adriamycin Solution / Doxorubicin hydrochloride Virtual Cancer Centre

v • d • e Intracellular chemotherapeutic agents/antineoplastic agents (L01) SPs/MIs (M phase) Block microtubule assembly Vinca alkaloids (Vinblastine, Vincristine, Vinflunine, Vindesine, Vinorelbine) Block microtubule disassembly Taxanes (Docetaxel, Larotaxel, Ortataxel, Paclitaxel, Tesetaxel) · Epothilones (Ixabepilone) DNA replication inhibitor DNA precursors/ antimetabolites (S phase) Folic acid dihydrofolate reductase inhibitor (Aminopterin, Methotrexate, Pemetrexed) · thymidylate synthase inhibitor (Raltitrexed, Pemetrexed) Purine adenosine deaminase inhibitor (Pentostatin) halogenated/ribonucleotide reductase inhibitors (Cladribine, Clofarabine, Fludarabine) thiopurine (Thioguanine, Mercaptopurine) Pyrimidine thymidylate synthase inhibitor (Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine) DNA polymerase inhibitor (Cytarabine) ribonucleotide reductase inhibitor (Gemcitabine) hypomethylating agent (Azacitidine, Decitabine) Deoxyribonucleotide ribonucleotide reductase inhibitor (Hydroxyurea) Topoisomerase inhibitors (S phase) I Camptotheca (Camptothecin, Topotecan, Irinotecan, Rubitecan, Belotecan) II Podophyllum (Etoposide, Teniposide) II+Intercalation Anthracyclines (Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin) · Anthracenediones (Mitoxantrone, Pixantrone) Crosslinking of DNA (CCNS) Alkylating Nitrogen mustards: Mechlorethamine · Cyclophosphamide (Ifosfamide, Trofosfamide) · Chlorambucil (Melphalan, Prednimustine) · Bendamustine · Uramustine · Estramustine Nitrosoureas: Carmustine · Lomustine (Semustine) · Fotemustine · Nimustine · Ranimustine · Streptozocin Alkyl sulfonates: Busulfan (Mannosulfan, Treosulfan) Aziridines: Carboquone · ThioTEPA · Triaziquone · Triethylenemelamine Alkylating-like Platinum (Carboplatin, Cisplatin, Nedaplatin, Oxaliplatin, Triplatin tetranitrate, Satraplatin) Nonclassical Hydrazines (Procarbazine) · Triazenes (Dacarbazine, Temozolomide) · Altretamine · Mitobronitol Intercalation Streptomyces (Actinomycin, Bleomycin, Mitomycin, Plicamycin) Photosensitizers/PDT Aminolevulinic acid/Methyl aminolevulinate · Efaproxiral · Porphyrin derivatives (Porfimer sodium, Talaporfin, Temoporfin, Verteporfin) Other Enzyme inhibitors FI (Tipifarnib)  · CDK inhibitors (Alvocidib, Seliciclib) · PrI (Bortezomib) · PhI (Anagrelide) · IMPDI (Tiazofurine) · LI (Masoprocol) · PARP inhibitor (Olaparib) · HDAC (Vorinostat, Romidepsin) Receptor antagonists ERA (Atrasentan) · retinoid X receptor (Bexarotene) · sex steroid (Testolactone) Other/ungrouped Amsacrine · Trabectedin · retinoids (Alitretinoin, Tretinoin) · Arsenic trioxide · asparagine depleter (Asparaginase/Pegaspargase) · Celecoxib · Demecolcine · Elesclomol · Elsamitrucin · Etoglucid · Lonidamine · Lucanthone · Mitoguazone · Mitotane · Oblimersen · Temsirolimus

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