Transcript Anticancer Antibiotics

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
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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
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
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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
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
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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 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
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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.
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
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
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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