Doxorubicin



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
Chemical data
O11 
mol
Pharmacokinetic data
Bioavailability 5% (Oral)
CYP3A4
Half life 12-18.5 hours[1]
Excretion Biliary and fecal
Therapeutic considerations
Pregnancy cat.

D(AU) D(US)

Legal status

℞-only(US)

Routes Intravenous

Doxorubicin (trade name Adriamycin) or hydroxyldaunorubicin is a intercalates DNA. It is commonly used in the treatment of a wide range of cancers.

The drug is administered by injection. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex.[2] Doxil is a liposome-encapsulated dosage form of doxorubicin made by Ben Venue Laboratories for Johnson & Johnson. The main benefits of this form are a reduction in cardiotoxicity.

History

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 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 relatively 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 fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.  

Mechanism of action

The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with 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 platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma.[18]

Experimental therapy

Combination therapy experiments with Akt-positive lymphomas in mice.[19]

Recent animal research coupling a murine antiretroviral therapy (ART) still leaves pockets of HIV within the host. The immunoconjugate could potentially provide a complimentary treatment to ART to eradicate antigen-expressing T cells.[20]

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 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." [21]

See also

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. 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. PMID 10455495.
  13. ^ Lown JW (1993). "Anthracycline and anthraquinone anticancer agents: current status and recent developments". Pharmacol. Ther. 60 (2): 185-214. 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. 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. PMID 16988511.
  21. ^ Bloch, Richard; Bloch, Annette. 25 Most Asked Questions. Fighting Cancer. R. A. Bloch Cancer Foundation. Retrieved on 2007-06-28.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Doxorubicin". A list of authors is available in Wikipedia.