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 Become rogue cells and frequently lose their differentiation Two types: benign and malignant Spread through metastasis
QuickTime and a decompressor are neede d to see this picture.

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
QuickTime an d a decompressor are need ed to see this picture .

Cell cycle

QuickTime an d a decompressor are need ed to see this p icture .

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

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

QuickTime and a decompressor are needed to se e this picture.

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
QuickTime and a decompressor are neede d to see this picture.

QuickTime and a decompressor are neede d to see this picture.

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)

QuickTime an d a decompressor are need ed to see this picture .

QuickTime an d a decompressor are need ed to see this picture .

QuickTime an d a decompressor are need ed to see this picture .

QuickTime an d a decompressor are need ed to see this picture .

Anthracycline structures
QuickTime and a decompressor are neede d to see this picture.
QuickTime and a decompressor are need ed to see this picture.

QuickTime and a decompressor are need ed to see this picture.

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.ni

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

QuickTime and a decompressor are neede d to see this picture.

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
QuickTime an d a decompressor are need ed to see this p icture .

QuickTime and a decompressor are neede d to see this picture.

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

QuickTime and a decompressor are need ed to see this picture.

Free Radical Formation

Adds to the cardiotoxicity of anthracyclines
QuickTime and a decompressor are neede d to see this picture.

QuickTime an d a decompressor are need ed to see this p icture.

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

QuickTime and a decompressor are neede d to see this picture.

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

QuickTime an d a decompressor are need ed to see this picture .

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

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

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