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Anticancer Agents

Anticancer Agents. By: Cristina Sanders. 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

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Anticancer Agents

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  1. Anticancer Agents By: Cristina Sanders

  2. 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

  3. How cancer develops • Can be inherited or develop by being exposed to certain environmental factors (cigarette smoke, alcohol, certain diets) • Tumorigenesis - accumulation of mutations in oncogenes that deregulates the cell cycle • Cancer Link

  4. Cell cycle

  5. History of Cancer Treatment • Long history of treating cancer, but did not successfully begin until the invention of the microscope • Early 20th - surgery and radiation • World Wars began chemical warfare, and thus began chemotherapy - nitrogen mustards • Currently, targeted cancer therapy

  6. Common Treatments • Surgery • Direct removal of tumor • Radiotherapy • Using ionizing radiation to control malignant cells • Chemotherapy • Using chemicals to kill actively dividing cells

  7. Chemotherapy • Injection - Intrathecal, Intramuscular, Intravenous, Intra-arterial • Orally • Topically

  8. Drug targets • Enzymes - Antimetabolites • Hormones - Androgens, Oestrogens, Progestins, LHRH agonists, Antioestrogens, Antiandrogens • Nucleic Acids - Intercalating agents, alkylating agents, chain cutters • Structural proteins • Signaling pathways

  9. Intercalating Agents • The reversible inclusion of a molecule between two other groups, most commonly seen in DNA • Inhibits DNA replication in rapidly growing cells

  10. Anthracyclines • First anthracycline antibiotics were isolated from Streptomycespeucetius in 1958 • Interact with DNA by intercalcation and inhibit topsoimerase • Some of the most effective cancer drugs available • Very wide spectrum

  11. Common Anthracyclines • Daunorubicin (Cerubidine) • Doxorubicin (Adriamycin, Rubex) • Epirubicin (Ellence, Pharmorubicin) • Idarubicin (Idamycin)

  12. Anthracycline structures http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi%3Fbook%3Dcmed%26part%3DA11644%26blobname%3Dch49f5.jpg&imgrefurl=http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi%3Fbook%3Dcmed%26part%3DA11644&usg=__1ixIg12np9lq0vQwN14mBnjs5oU=&h=744&w=412&sz=53&hl=en&start=2&um=1&itbs=1&tbnid=TYigCqbnaRkjfM:&tbnh=141&tbnw=78&prev=/images%3Fq%3Dcommon%2Banthracyclines%26um%3D1%26hl%3Den%26sa%3DN%26rlz%3D1G1GGLQ_ENUS251%26tbs%3Disch:1

  13. DOX vs. DNR • Daunomycin (DNR) for acute lymphocytic and myeloid leukenmia • Doxorubicin (DOX) for chemotherapy for solid tumors including breast cancer, soft tissue sarcomes, and aggressive lymphomas

  14. 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

  15. Intercalating Mechanism • 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 • Prevents Topoisomerase II and stabilizes the complex, preventing the DNA helix from resealing

  16. Free Radical Formation • Adds to the cardiotoxicity of anthracyclines

  17. 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 • Counteract with dexrazoxane

  18. 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.

  19. 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

  20. Structure

  21. 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

  22. Side effects • Pulmonary fibrosis and impaired lung function • Age and dose related • Capillary changes, atypical epithelial cells

  23. Resistance to Anticancer Agents • Resistance mechanisms can operate to • Prevent agents from entering cells, as in loss of plasma membrane carriers for nucleoside analogs • Enhance their extrusion, as exemplified by energy-dependent pumps such as ABC transporters

  24. 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.

  25. 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?

  26. References • Avenda, Carmen, and J. Carlos Menedez. Medicinal Chemistry of Anticancer Drugs. Amsterdam: Elsevier, 2008 http://www.scribd.com/doc/11639473/Medicinal-Chemistry-of-Anticancer-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-47d2-960d-dfb68ea0e0bd%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-cancer-treatment#History_of_Cancer_Treatmenthttp://www.drugs.com/sfx/bleomycin-side-effects.html

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