Introduction:
Below is the structure of Doxorubicin:
Space fill Ball and Stick Sticks Spin on Doxorubicin is an anthracyline (a three aromatic ring based molecule) that has proven to be an effective chemotherapy drug.. Traditionally, doxorubicin has been prescribed to patients afflicted with breast cancer. In fact, doxorubicin is thought to be the single most active agent against breast cancer. Doxorubicin has been shown to intercalate between the bases in double stranded DNA, poison topoisomerase II, generate free radicals, and possibly disrupt the functioning of the cell membrane. It is generally believed that the poisoning of DNA topoisomerase constitutes the major antitumor action because topoisomerase II is essential for DNA replication. Topoisomerase II is the enzyme responsible for catalyzing the uncoiling and breakage of both strands of double stranded DNA, modifying the types and numbers of linkage twists. Mechanism of Action on DNA and Topoisomerase II: The covalent intercalation of doxorubicin into the DNA molecule is due to it's planar three ring structure. This complex, in some way, enhances the rate at which topoisomerase II cuts the DNA for supercoiling changes, and also decreases the rate at which these breaks are resealed. This induces a higher than normal level of transient protein breaks in the DNA. Replication and transcription enzymes readily rupture these protein bridged DNA breaks, and render the breaks permanent. So in essence, DNA intercalated doxorubicin stabilizes a covalent complex of enzyme-DNA intermediate that prevents the DNA breaks from rejoining. Despite having cellular enzymes to repair DNA, a significant amount of DNA damage leads to cell death. Rapidly proliferating cells, such as bone marrow, hair follicle, epithelial and cancer cells are most susceptible to this topoisomerase II-transcription inhibiting drug. Doxorubicin Covalently Attached To N2(G4) Via Methylene Bridge Space fill Sticks Ball and Stick Rotation Still Image Example of Doxorubicin Intercalation In a Single Strand of DNA Side Effects of Doxorubicin: Besides the typical side effects chemotherapy drugs have on proliferating cells and the body (results like hair loss, gastrointestinal irritation, anemia, etc.) long-term use of doxorubicin is associated with cardiotoxicity. The detailed mechanism is not yet fully understood, however, it is believed that Ca+ activated ATPase, cAMP, and lipid peroxidation are involved, as well as doxorubicin's facilitation of free radicals. Myocardial cells seem to have an enhanced sensitivity to these effects, producing congestive heart failure, secondary to myocardial infarction-like symptoms like decreased cardiac ventricular ejection fraction. The primary metabolite of doxorubicin, doxorubicinol, is a potent inhibitor of Na+, K+ ATPase, Mg2+ ATPase and Ca2+ ATPase. This may contribute to the serious side-effects of this otherwise highly regarded antitumor drug. Future Research Goals: The search for a chemical which maintains Doxorubicin's antitumor activity and has a reduced free radical, metabolite mediated cardiotoxicity has been underway for some time. The ketones and hydroxl groups of the anthracyline structure are the most suspicious for free radical formation, while the planar three ring system is nearly always preserved to maintain DNA intercalation. Many doxorubicin derivatives that have proven beneficial in the treatment of other types of cancers share the anthracyline structure, and have simple functional group substitutions in various positions. As of yet though, none have shown significantly lower toxicity, although they are still used in the treatments of cancers such as Leukemia and other bone marrow cancers. References Human Pharmacology : molecular to clinical (1998) edited by Brody, Larner, and Minneman - 3rd edition: pgs 606,612 Fundamentals of Biochemistry (1999) Veot, Voet and Pratt - pgs 738 Podell, E. R., Harrington, D. J., Taatjes, D. J., Koch, T. H.: Crystal Structure of Epidoxorubicin-Formaldehyde Virtual Crosslink of DNA and Evidence for its Formation in Human Breast-Cancer Cells Acta Crystallogr., Sect.D 55 pp. 1516 (1999) Cirilli, M., Bachechi, F., Ughetto, G., Colonna, F. P., Capobianco, M. L.: Interactions between morpholinyl anthracyclines and DNA. The crystal structure of a morpholino doxorubicin bound to d(CGTACG). J Mol Biol 230 pp. 878 (1993)
Doxorubicin is an anthracyline (a three aromatic ring based molecule) that has proven to be an effective chemotherapy drug.. Traditionally, doxorubicin has been prescribed to patients afflicted with breast cancer. In fact, doxorubicin is thought to be the single most active agent against breast cancer. Doxorubicin has been shown to intercalate between the bases in double stranded DNA, poison topoisomerase II, generate free radicals, and possibly disrupt the functioning of the cell membrane. It is generally believed that the poisoning of DNA topoisomerase constitutes the major antitumor action because topoisomerase II is essential for DNA replication. Topoisomerase II is the enzyme responsible for catalyzing the uncoiling and breakage of both strands of double stranded DNA, modifying the types and numbers of linkage twists.
Mechanism of Action on DNA and Topoisomerase II:
The covalent intercalation of doxorubicin into the DNA molecule is due to it's planar three ring structure. This complex, in some way, enhances the rate at which topoisomerase II cuts the DNA for supercoiling changes, and also decreases the rate at which these breaks are resealed. This induces a higher than normal level of transient protein breaks in the DNA. Replication and transcription enzymes readily rupture these protein bridged DNA breaks, and render the breaks permanent.
So in essence, DNA intercalated doxorubicin stabilizes a covalent complex of enzyme-DNA intermediate that prevents the DNA breaks from rejoining. Despite having cellular enzymes to repair DNA, a significant amount of DNA damage leads to cell death. Rapidly proliferating cells, such as bone marrow, hair follicle, epithelial and cancer cells are most susceptible to this topoisomerase II-transcription inhibiting drug.
Doxorubicin Covalently Attached To N2(G4) Via Methylene Bridge
Space fill Sticks Ball and Stick Rotation Still Image Example of Doxorubicin Intercalation In a Single Strand of DNA Side Effects of Doxorubicin: Besides the typical side effects chemotherapy drugs have on proliferating cells and the body (results like hair loss, gastrointestinal irritation, anemia, etc.) long-term use of doxorubicin is associated with cardiotoxicity. The detailed mechanism is not yet fully understood, however, it is believed that Ca+ activated ATPase, cAMP, and lipid peroxidation are involved, as well as doxorubicin's facilitation of free radicals. Myocardial cells seem to have an enhanced sensitivity to these effects, producing congestive heart failure, secondary to myocardial infarction-like symptoms like decreased cardiac ventricular ejection fraction. The primary metabolite of doxorubicin, doxorubicinol, is a potent inhibitor of Na+, K+ ATPase, Mg2+ ATPase and Ca2+ ATPase. This may contribute to the serious side-effects of this otherwise highly regarded antitumor drug. Future Research Goals: The search for a chemical which maintains Doxorubicin's antitumor activity and has a reduced free radical, metabolite mediated cardiotoxicity has been underway for some time. The ketones and hydroxl groups of the anthracyline structure are the most suspicious for free radical formation, while the planar three ring system is nearly always preserved to maintain DNA intercalation. Many doxorubicin derivatives that have proven beneficial in the treatment of other types of cancers share the anthracyline structure, and have simple functional group substitutions in various positions. As of yet though, none have shown significantly lower toxicity, although they are still used in the treatments of cancers such as Leukemia and other bone marrow cancers. References Human Pharmacology : molecular to clinical (1998) edited by Brody, Larner, and Minneman - 3rd edition: pgs 606,612 Fundamentals of Biochemistry (1999) Veot, Voet and Pratt - pgs 738 Podell, E. R., Harrington, D. J., Taatjes, D. J., Koch, T. H.: Crystal Structure of Epidoxorubicin-Formaldehyde Virtual Crosslink of DNA and Evidence for its Formation in Human Breast-Cancer Cells Acta Crystallogr., Sect.D 55 pp. 1516 (1999) Cirilli, M., Bachechi, F., Ughetto, G., Colonna, F. P., Capobianco, M. L.: Interactions between morpholinyl anthracyclines and DNA. The crystal structure of a morpholino doxorubicin bound to d(CGTACG). J Mol Biol 230 pp. 878 (1993)
Still Image Example of Doxorubicin Intercalation In a Single Strand of DNA
Side Effects of Doxorubicin:
Besides the typical side effects chemotherapy drugs have on proliferating cells and the body (results like hair loss, gastrointestinal irritation, anemia, etc.) long-term use of doxorubicin is associated with cardiotoxicity. The detailed mechanism is not yet fully understood, however, it is believed that Ca+ activated ATPase, cAMP, and lipid peroxidation are involved, as well as doxorubicin's facilitation of free radicals. Myocardial cells seem to have an enhanced sensitivity to these effects, producing congestive heart failure, secondary to myocardial infarction-like symptoms like decreased cardiac ventricular ejection fraction. The primary metabolite of doxorubicin, doxorubicinol, is a potent inhibitor of Na+, K+ ATPase, Mg2+ ATPase and Ca2+ ATPase. This may contribute to the serious side-effects of this otherwise highly regarded antitumor drug.
Future Research Goals:
The search for a chemical which maintains Doxorubicin's antitumor activity and has a reduced free radical, metabolite mediated cardiotoxicity has been underway for some time. The ketones and hydroxl groups of the anthracyline structure are the most suspicious for free radical formation, while the planar three ring system is nearly always preserved to maintain DNA intercalation. Many doxorubicin derivatives that have proven beneficial in the treatment of other types of cancers share the anthracyline structure, and have simple functional group substitutions in various positions. As of yet though, none have shown significantly lower toxicity, although they are still used in the treatments of cancers such as Leukemia and other bone marrow cancers.
References
Human Pharmacology : molecular to clinical (1998) edited by Brody, Larner, and Minneman - 3rd edition: pgs 606,612
Fundamentals of Biochemistry (1999) Veot, Voet and Pratt - pgs 738
Podell, E. R., Harrington, D. J., Taatjes, D. J., Koch, T. H.: Crystal Structure of Epidoxorubicin-Formaldehyde Virtual Crosslink of DNA and Evidence for its Formation in Human Breast-Cancer Cells Acta Crystallogr., Sect.D 55 pp. 1516 (1999)
Cirilli, M., Bachechi, F., Ughetto, G., Colonna, F. P., Capobianco, M. L.: Interactions between morpholinyl anthracyclines and DNA. The crystal structure of a morpholino doxorubicin bound to d(CGTACG). J Mol Biol 230 pp. 878 (1993)