Anticancer Agents

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Anticancer Agents

• By
• Cristina Sanders

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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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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

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Cell cycle
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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

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Common Treatments

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

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Chemotherapy

• Injection - Intrathecal, Intramuscular,
  Intravenous, Intra-arterial
• Orally
• Topically

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Drug targets

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

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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

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Common Anthracyclines

• Daunorubicin (Cerubidine)
• Doxorubicin (Adriamycin, Rubex)
• Epirubicin (Ellence, Pharmorubicin)
• Idarubicin (Idamycin)

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Anthracycline structures
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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

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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 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

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Free Radical Formation

• Adds to the cardiotoxicity of anthracyclines

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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

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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.

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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

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Structure
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Mechanism

• Induction of DNA strand breaks
• Medicate DNA strand scission of single and double
  strand breaks dependent on metal ions and oxygen
• Bleomycin Action 210, 313

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Side effects

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

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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

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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.

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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?

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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.
  lthttp//web.ebscohost.com/ehost/pdf?vid2hid107
  sidc129efcf-31ba-47d2-960d-dfb68ea0e0bd40session
  mgr104gt.
• 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/P
  MC2588755/?page1
• 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?page2225
• http//knol.google.com/k/history-of-cancer-treatme
  ntHistory_of_Cancer_Treatmenthttp//www.drugs.com
  /sfx/bleomycin-side-effects.html