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

10. 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

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

12. Anthracycline structures

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 Counteract with dexrazoxane
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 :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, p
Hurley, Laurence H. DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer (2002), 2(3),

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,
Chang, Jingyang, and JoAnne Stubbe. "Bleomycins: New Methods Will Allow Reinvestigation of Old Issues." Current Opinion in Chemical Biology 8.2 (2004):
Claussen, Craig A., and Eric C. Long "Nucleic Acid Recognition by Metal Complexes of Bleomycin." Chemical Reviews 99 (1999):
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): EBSCOhost. Web. 28 Mar <
Papac, Rose J. "Origins of Cancer Therapy." Yale Journal of Biology and Medicine 74 (2002):
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.