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What is cancer?
Cancer is a group of diseases that are characterized by the loss of control of the growth, division, and spread of a group of cells leading to a primary tumor that invades and destroys adjacent tissues Become rogue cells and frequently lose their differentiation Two types: benign and malignant Spread through metastasis
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Cell cycle
Common Treatments
Surgery
Direct removal of tumor
Radiotherapy
Using ionizing radiation to control malignant cells
Chemotherapy
Using chemicals to kill actively dividing cells
Chemotherapy
Injection - Intrathecal, Intramuscular, Intravenous, Intraarterial Orally Topically
Drug targets
Enzymes - Antimetabolites Hormones - Androgens, Oestrogens, Progestins, LHRH agonists, Antioestrogens, Antiandrogens Nucleic Acids - Intercalating agents, alkylating agents, chain cutters Structural proteins Signaling pathways
Intercalating Agents
The reversible inclusion of a molecule between two other groups, most commonly seen in DNA Inhibits DNA replication in rapidly growing cells
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Anthracyclines
First anthracycline antibiotics were isolated from Streptomyces peucetius in 1958 Interact with DNA by intercalcation and inhibit topsoimerase Some of the most effective cancer drugs available
Very wide spectrum
Common Anthracyclines
Daunorubicin (Cerubidine) Doxorubicin (Adriamycin, Rubex) Epirubicin (Ellence, Pharmorubicin) Idarubicin (Idamycin)
Anthracycline structures
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Mechanisms of action
Disrupt DNA
Intercalate into the base pairs in DNA minor grooves Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA, thus blocking DNA transcription and replication Cause free radical damage of ribose in the DNA
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Intercalating Mechanism
The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the sixmembered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site Prevents Topoisomerase II and stabilizes the complex, preventing the DNA helix from resealing
Negative Effects
Causes cardiotoxicity
Interference with ryanodine receptors of the sarcoplasmic reticulum in the heart muscle cells Free-radical formation in the heart Leads to forms of congestive heart failure, often years after treatment
Bleomycins (BLM)
Natural glycopeptidic antibiotics produced by Streptomyces verticillus Efficacy against tumors Mainly used in therapy in a combination with radiotherapy or chemotherapy Commonly administered as Blenoxane, a drug that includes both bleomycin A2 and B2.
History of Bleomycins
First discovered in 1966 by Hamao Umerzawa from Japan when screening cultures of S. verticullus Launched in Japan by Nippon kayaku in 1969 Initially marketed by Bristol-Myers Squibb under brand name Blenoxance
Structure
Mechanism
Induction of DNA strand breaks Medicate DNA strand scission of single and double strand breaks dependent on metal ions and oxygen Bleomycin Action 2:10, 3:13
Side effects
Pulmonary fibrosis and impaired lung function
Age and dose related Capillary changes, atypical epithelial cells
Reading Assignment
Patrick, Graham L. An Introduction to Medicinal Chemistry. 3rd ed. Oxford: Oxford University Print, 2005. p.489-504 Hurley, Laurence H. DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer (2002), 2(3), 188-200.
Homework Questions
What are some cellular defects that are associated with cancer? Describe the mechanism of DNA intercalation and how it is used to treat cancer. Draw the two main structures of Anthracyclines and label the areas involved in the mechanism of action. How does doxorubicin interfere with topoisomerase II?
References
Avenda, Carmen, and J. Carlos Menedez. Medicinal Chemistry of Anticancer Drugs. Amsterdam: Elsevier, 2008 http://www.scribd.com/doc/11639473/Medicinal-Chemistry-ofAnticancer-Drugs Chang, Jingyang, and JoAnne Stubbe. "Bleomycins: New Methods Will Allow Reinvestigation of Old Issues." Current Opinion in Chemical Biology 8.2 (2004): 175-81. Claussen, Craig A., and Eric C. Long "Nucleic Acid Recognition by Metal Complexes of Bleomycin." Chemical Reviews 99 (1999): 2797-816. Hortobyi, G. N. "Anthracyclines in the Treatment of Cancer: An Overview." Drugs 54 (1997): 1-7. Hurley, Laurence H. "DNA And Its Associated Processes as Targets For Cancer Therapy." Nature 2 (2002): 188-200. EBSCOhost. Web. 28 Mar. 2010. <http://web.ebscohost.com/ehost/pdf?vid=2&hid=107&sid=c129efcf-31ba-47d2-960ddfb68ea0e0bd%40sessionmgr104>. Papac, Rose J. "Origins of Cancer Therapy." Yale Journal of Biology and Medicine 74 (2002): 391-98. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588755/?page=1 Patrick, Graham L. An Introduction to Medicinal Chemistry. 3rd ed. Oxford: Oxford University Print, 2005. Pratt, William B. The Anticancer Drugs. New York: Oxford UP, 1994. http://www.cancerquest.org/index.cfm?page=2225 http://knol.google.com/k/history-of-cancertreatment#History_of_Cancer_Treatmenthttp://www.drugs.com/sfx/bleomycin-sideeffects.html