Doxorubicin
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Doxorubicin
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| 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 |
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| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C27H29NO11 |
| Mol. mass | 543.52 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 5% (oral) |
| Metabolism | To 13-hydroxyl doxorubicinol |
| Half life | ? |
| Excretion | Biliary and fecal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Intravenous |
Doxorubicin (trade name Adriamycin) or hydroxyldaunorubicin is a DNA-interacting drug widely used in chemotherapy. It is an anthracycline antibiotic and structurely closely related to daunomycin, and also intercalates DNA. It is commonly used in the treatment of a wide range of cancers.
Doxil is a liposome-encapsulated dosage form of doxorubicin made by Ben Venue Laboratories for Johnson & Johnson. Its main benefits are a reduction in cardiotoxicity. It follows the similar preparation of daunorubicin in a liposomal carrier.
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[edit] 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.[1] Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis.[2] 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.[3][4]
[edit] Side effects
Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause a decrease in white blood cells and 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 adults who were treated with doxorubicin when they were children have developed dilated cardiomyopathy up to 15 years later.
[edit] Uses
[edit] Clinical use
Doxorubicin is commonly used to treat Hodgkin's disease, breast cancer, lung cancer, soft tissue sarcoma, multiple myeloma and recurring instances of ovarian cancer. Commonly used doxorubicin-containing regimens are ABVD (Adriamycin®, Bleomycin, Vinblastine, Dacarbazine), CHOP (Cyclophosphamide, Adriamycin®, Vincristine, Prednisone) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide).
[edit] Experimental
Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.[5]
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 complimentary treatment to ART to eradicate antigen-expressing T cells.[6]
[edit] See also
[edit] References
- ^ 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.
- ^ 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.
- ^ 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. Crystal structure is available for download as a PDB file.
- ^ Pigram, W.J.; Fuller, W.; Hamilton, L.D. Stereochemistry of Intercalation: Interaction of Daunomycin with DNA. 1972, Nature New Biology, 235, 17 – 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.
- ^ 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.
[edit] External links
- NIH/Medline
- BC Cancer Agency
- Doxil Site
- Adriamycin Solution / Doxorubicin hydrochloride Virtual Cancer Centre
