Download Etiology of Cancer

What is Cancer?
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Disorder of cell growth and behavior
Proliferate in the absence of normal growth regulatory
signals
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Malignancies arise in populations of immature or
undifferentiated cells
– Loss of tumor suppressor gene products (p53, Rb)
– Activation of proto-oncogenesis (ras, c-myc)
– Somatic mutations
• DNA translocations
• Gene amplification
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Cells can multiply at a rate of about 2 divisions each day.
Single cell can give rise to a detectable mass of 1g (109
cells) in just 15days.
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Tumors are “altered self” cells that maintain similarities to
“normal cells” making it difficult to target cancer cells
specifically
2007 Estimated US Cancer Cases*
Children 0-14years, 15-100,000 cases, 2.5-100,000 deaths
*Source: American Cancer Society, 2007.
Lifetime Probability of Developing Cancer, Men,
2002-2004*
Site
Risk
All sites†
Prostate
1 in 2
1 in 6
Lung and bronchus
1 in 13
Colon and rectum
1 in 18
Urinary bladder‡
1 in 27
Melanoma
1 in 41
Non-Hodgkin lymphoma
1 in 46
Kidney
1 in 59
Leukemia
1 in 67
Oral Cavity
1 in 71
Stomach
1 in 88
Lifetime Probability of Developing
Cancer, Women, US, 2002-2004*
Site
Risk
All sites†
Breast
1 in 3
1 in 8
Lung & bronchus
1 in 16
Colon & rectum
1 in 19
Uterine corpus
1 in 41
Non-Hodgkin lymphoma
1 in 53
Melanoma
1 in 61
Ovary
1 in 71
Pancreas
1 in 76
Urinary bladder‡
1 in 85
Uterine cervix
1 in 142
Trends in Five-year Relative Survival (%)* Rates, US, 1975-2003
Site
1975-1977
1984-1986
1996-2003
• All sites
50
54
66
• Breast (female)
75
79
89
• Colon
51
59
65
• Leukemia
35
42
50
• Lung and bronchus
13
13
16
• Melanoma
82
87
92
• Non-Hodgkin lymphoma
48
53
64
• Ovary
37
40
45
• Pancreas
2
3
5
• Prostate
69
76
99
• Rectum
49
57
66
• Urinary bladder
74
78
81
Estimated Cancer Deaths
5000
100
4500
90
4000
80
3500
70
Per capita cigarette
consumption
3000
60
2500
50
Male lung cancer
death rate
2000
40
1500
30
1000
20
Female lung cancer
death rate
500
2000
1995
1990
1985
1980
1975
1970
1965
1960
1950
1955
1945
1940
1935
1930
1925
1920
1915
1910
1905
0
1900
0
10
Age-Adjusted Lung Cancer Death
Rates*
Per Capita Cigarette Consumption
Tobacco Use in the US, 1900-2004
Year
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Data, 1960-2004, US Mortality Volumes, 1930-1959, National Center for Health
Statistics, Centers for Disease Control and Prevention, 2006. Cigarette consumption: US Department of
Agriculture, 1900-2004.
Basic terminology/nomenclature
• Cancer
– Disorder of cell growth and dysregulation
• Neoplasia
– “New growth”
– Depends on the host for nutrition and blood supply
– Aka “tumor”
• Benign
• Malignant
Cancer Therapy
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Surgery
– Most effective form of treatment for cancer
– Most aggressive.
– Confined to particular anatomical site (if identifiable)
– Can be used in together with other treatments
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Radiation
– Used for local treatment
– Can be used as sole treatment or in conjunction with another form of
treatment
– Mechanism:
• High energy radiation kills cells by damaging the DNA of the cancer
cells and blocking their ability to divide and proliferate.
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Chemotherapy
– Typically used together with surgery
• Post-surgery = to eliminate undetectable disease
– Called adjuvant therapy
• Pre-surgery
– Called neoadjuvant
– Requires multiple cycles of treatment
R
Cell decides whether
to continue
Categories of Chemotherapeutic Agents
1. antimetabolites
a. non-base analogs: methotrexate, hydroxyurea
b. pyrimidine analogs: 5-flurouracil, cytarabin
c. purine analogs: 6-mercaptopurine (6-MP), 6-thioguanine
2. topoisomerase Inhibitors: etoposide, teniposide
3. microtubule inhibitors: vincristine, vinblastine, paclitaxel
4. antitumor antibiotics: doxorubicin, bleomycin, dactinomycin
5. alkylating agents: mechlorethamine, cyclophosphamide, cisplatin
6. hormones: prednisone, tamoxifen
7. other: procarbazine, endostatin, angiostatin, Campath®
Antimetabolites
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false substrates, structurally related to normal cellular components
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S phase specific, DNA synthesis
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many are nucleic acid base analogs and can get incorporated into DNA
or RNA
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others inhibit enzymes involved in nucleotide biosynthesis & metabolism
Types of Antimetabolites:
a.
b.
c.
Folic acid analogues: methotrexate, hydroxyurea
Pyrimidine analogues: 5-flurouracil, cytarabin
Purine analogues: 6-mercaptopurine, 6-thioguanine
Folic Acid Analogues
1. Methotrexate (MTX)
methotrexate
folic acid
FH2 ----------------->FH4
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In clinical use to treat cancer since 1948.
An antagonist of Dihydrofolate reductase (DHFR) –similar in structure to folic acid
Inhibits DHFR to cease production of tetrahydrofolate (FH4) – an active cofactor
required for thymidylate synthetase and purine synthesis
large doses of MTX are toxic to normal cells – deprives the cells of the various
folate coenzymes
normal cells can be rescued by administering relatively low levels of folinic acid
which is converted to FH4 independent of DHFR
Due to interference with folic acid, also used in treatment of types of arthritis.
S-phase specific drug
Pyrimidine Analogues
1.
5’ Flurouracil (5-FU)
dUMP ------------------------------->dTMP (2’-deoxythymidylate) ---------->DNA Synthesis
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2.
Inhibits DNA synthesis
Principally used as a thymidylate (dTMP) synthase inhibitor.
Interrupts action of an enzyme which is critical in synthesis of pyrimidine
(thymine) which is important in DNA replication.
It is a S-phase specific drug
5-FdUMP can also get incorporated into DNA and lead to strand breakage
primarily used in treatment of slowly growing, solid tumors (breast, ovarian,
pancreatic)
Cytarabine (Ara-C)
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incorporated into DNA and causes chain termination
It is a S-phase specific drug
clinical use in acute nonlymphocytic (myelogenous) leukemia
Purine Analogues
1. 6-mercaptopurine (6-MP)
(aka Purinethol)
6-MP --------------------------- 6-MPRP (6-mercaptopurine ribose phosphate, thiol analog
Hypoxanthine-guanine
of hypoxanthine)
Phosphoribosyl Transferase
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unnatural nucleotide inhibits purine ring biosynthesis
dysfunctional RNA and DNA result from incorporation of guanylate
analogs
6-MP is metabolized by xanthine oxidase, the dose of 6-MP must be
reduced when allopurinol is given
When used with allopurinol:
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Allopurinol inhibits xanthine oxidase which prevents oxidation of 6-MP
Inhibits inactivation of 6-MP
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Toxicity of 6-MP are potentiated!
6-MP is used in the maintenance of remission in acute lymphoblastic
leukemia (ALL)
Topoisomerase Inhibitors
• Topoisomerase
– Enzyme involved in replication and segregation of bacterial DNA.
– Topoisomerase enzymes (I and II) control changes in DNA structure
• Topoisomerase Inhibitors:
– Interferes with action of topoisomerase enzymes (topoisomerase I and
II)
• Blocks ligation step of cell cycle
• Therefore interferes with transcription and replication of DNA
• Examples of Topoisomerase Inhibitors:
– Etoposide
– Teniposide
Etoposide and Teniposide
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Etoposide Phosphate
– Brand name: Eposin, Etophphos, VP-16
– Inhibits topoisomerase II
– Typically given to patients diagnosed with lung cancer, testicular cancer,
leukemia
– Administered: orally, intravenously
– Often given in combination with drugs that damage DNA directly (bleomycin or
cisplatin)
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Teniposide
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Brand name Vumon ,VM-26
Typically given to treat childhood acute lymphocytic leukemia
Slows growth of cancer cells in body
Administered through injection
Major side effect:
• Lowers WBC
• Lowers platelet count
• Bone marrow suppression
Microtubule Inhibitors
1. Vinca alkaloids
a. Vinblastine
b. Vincristine
vinca alkaloids
•isolated from the periwinkle plant Catharantus roseus
•All vinca alkaloids bind to -tubulin on the molecule that overlaps with the GTPbinding domain
•Inhibits tubulin polymerization... depolimerization and
• vincristine and vinblastine
•M-phase cell cycle
•binds to the microtubular protein, tubulin
•blocks microtubule assembly
•prevents chromosomal segregation and cell proliferation
•Bone marrow suppression severe, marked nausea and vomiting.
•Peripheral neuropathy
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Taxanes
a. Paclitaxel (taxol)
• isolated from the bark of the western yew tree
• Taxanes
•binds to -tubulin subunit inside the microtubules at distinct site
from vinca alkaloids
•Promotes microtubule polymerization and inhibit depolymerization
•Irreversibly stabilizes cells in Mitosis leading to apoptosis.
•Paclitaxel
•Interferes with normal microtubule growth by hyperstabilizing
microtubule function--overly stable microtubules are dyfunctional
•Binds to  tubulin and promotes polymerization and stabilization of the
polymer rather than disassembly
•Irreversibly stabilizes cells in mitosis leading to apoptosis.
Antitumor Antibiotics
1. Daunorubicin and
Doxorubicin
• first isolated as red substances from microorganisms in 1939
• members of the Anthracycline antitumor antibiotic family
•G2 phase specific
•despite their severe cardiotoxicity, these drugs have been widely used as
chemotherapeutic agents for the treatment of cancers such as leukemia
since their discovery in the early 1960's
• the cytotoxicity arises from an intercalation of the drug between the base
pairs of the DNA using non-covalent interactions and interfering with DNA
replication
• also, hydroxyl radicals (OH·) can be generated, which can damage
proteins, membranes and DNA and stop cell growth
Cartoon diagram of
two doxorubicin
molecules intercalating
DNA
From protein data bank
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, as
evidenced by several
crystal structures.
2.
Bleomycin
•Discovered in 1962 from Japanese scientist Hamao Umezawa
•Gained FDA approval in 1973
•Bristol Myers Squibb
•Brand name Blenoxane
•Stops replication by inducing DNA strand breaks
•Inhibits incorporation of thymidine into DNA strands
•DNA cleavage by bleomycin depends on O2 and metal ions
•metal-chelating glycopeptides that causes scission of DNA by an
oxidative stress
•Mechanism:
•a DNA-bleomycin-Fe(II) complex undergoes oxidation (loss of
electrons) and the liberated electrons react with oxygen to form
superoxide (O2-) or hydroxide radicals (OH·) which, in turn,
attack the phosphodiester bonds of the DNA, resulting in strand
breakage and chromosomal damage
Side-Effects
Can cause pulmonary toxicity
Alkylating Agents
•most important step is the formation of a carbonium ion (a carbon atom with only
six electrons in its outer shell) which reacts instantaneously with an electron donor
such as amine, hydroxyl or sulfhydryl groups
• most alkylating agents are bi-functional, i.e. they have two alkylating groups
capable of reacting with two groups on the DNA and causing intra- or interchain
cross-linking
• cross-linking DNA strands and interferes with transcription and DNA replication
•leads to excision of the guanine base and pairing of the alkylated guanine with
thymine instead of cytosine
•Cells cannot separate and divide
•Nonspecific cell cycle phase
• although alkylating agents may be used for most types of cancer, they are
generally of greatest value in treating slow-growing cancers
• these chemotherapy drugs not only affect the cancer cells but also disrupt normal
cell growth in progress--in the lining of the gastrointestinal tract, blood cells, hair,
1. Cyclophosphamide
• Generic name = Cytoxan, Neosar
• Is classified as a nitrogen mustard alkylating agent
• Used to treat lymphomas and some solid tumors
• Slows/stops cell growth
• Also, works by decreasing the immune system’s response to various
diseases
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Mechanism:
– first needs to be activated by biotransformation with P450 mixed function oxidase
to hydroxylated intermediates which, in turn, undergoes breakdown to form the
active compounds, phosphoramide mustard and acrolein
– inserts foreign molecules into the genetic material of dividing cancer cells which
kills cells by disrupting their normal function and by preventing their further
growth and multiplication
2. Mechlorethamine
(aka nitrogen mustard)
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Mustard gas derived from chemical warfare in 1943
– Exposed civilians and soldiers had decreased WBC suggesting
possibility as a chemotherapy
– Used in treatment of Hodgkin’s disease or non-Hodgkin’s lymphoma
– Stops cell growth by facilitating DNA strand breaks
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Mechanism:
– Drug loses a chloride ion and forms a reactive intermediate that alkylates the N7
nitrogen of a guanine residue in one or both strands of a DNA molecule
– alkylation leads to cross-linkages between guanine residues and/or depurination
that facilitates DNA strand breakage
• 3. Cisplatin (diaminedichloroplatinum (DDP))
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first synthesized by M.Peyrone in 1844 and called Peyrone’s chloride
in 1960’s, B.Rosenberg at the Michigan State University designed and
experiment to measure the effects of electrical current on cell growth yielding
E.coli that were 300 times the normal length
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the effect was found to be due to a chemical agent formed in the reaction
between the supposedly inert Pt electrode and components of the solution
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Prevents cell division without retarding cell growth, leading to elongation
Kills cancer cells by binding to basic site of DNA and interfering with its
repair mechanism
DNA repair enzymes are recruited to the site and become irreversibly
bound, preventing repair
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Hormones
• Tamoxifen
• tamoxifen blocks the action of estrogen in breast tissue by binding to
the estrogen receptors of breast cells, thereby preventing estrogen
molecules from binding to these receptors
• unlike estrogen, binding of tamoxifen to the receptor does not cause
the receptor molecule to acquire the changed shape needed for
binding to coactivators and cell proliferation cannot be activated
• unlike normal breast cells, cancer cells arising in the breast do not
always have receptors for estrogen
• the growth of estrogen receptor-negative cancer cells is not
governed by estrogen and cannot be treated with tamoxifen
Tamoxifen
while tamoxifen acts as an
antiestrogen that blocks the effects
of estrogen on breast cells, it mimics
the actions of estrogen in other
tissues such as the uterus
its estrogen-like effects on the
uterus stimulate proliferation of the
uterine endometrium and increases
the risk of uterine cancer
Cell Cycle specificity of antineoplastic drug
classes
• some agents are "cell cycle" active i.e.
predominantly cytotoxic to actively cycling cells
1. Antimetabolites: S phase
2. Microtubule Inhibitors: M phase
• others can be cytotoxic at any phase of cell
cycle
1. prednisone
2. alkylating agents
Combination Chemotherapy
• Multi-therapy regimen:
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Reduces toxicity to the host
Reduces resistance to drug
To enhance activity (efficacy) of drug therapy against infection
To treat multiple simultaneous infections (aka polymicrobial infections)
– Introduces potential for multiple adverse effects and drug interactions
• Goal
– To efficiently remove offending pathogen or tumor without incurring
unacceptable toxicity in host.
Synergy, Additivity, Antagonism
• Synergy
= to enhance efficacy of the combination
• Antagonism= diminish efficacy of the combination
• Additivity
= sum of the effects of each drug used individually
Examples of antineoplastic combination
chemotherapy pp730
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Stage of disease determines treatment
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Hodgkin’s Disease
– Prior to 1960s, single drug chemotherapy resulted in median survival of 1 year
– MOPP (mechlorethamine, vincristine, procarbazine, prednisone)
• From this combination, 50% of these patients were cured
• Significant toxicity
– ABVP (doxorubicin, bleomycin,vinblastine, dacarbazine)
• Just as effective as MOPP
• Less toxic
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Testicular Cancer:
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PVB (cisplatin, vinblastine and bleomycin)
More examples of Combination therapy
• Leucovotin (5-FU/folinic acid)
– 5-FU (Fluorouracil)
• Pyrimidine analog
• Inhibits thymidylate synthesis
– Folinic acid (leukovorin)
• Enhances effect if 5-FU on inhibiting thymidylate synthase by
increasing MTHF.
– First line of treatment for colon cancer
Promising new approach in treating breast
cancer
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PARP (Poly [ADP-ribose] polymerase)
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Enzyme involved in repairing DNA damage and programmed cell death
Assists in repairing single-stranded DNA nicks
PARP inhibitors
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Potential in effectively killing tumor cells in women with variation in BRCA1 and BRCA2 genes.
Less toxic to healthy cells
How does this work:
• New class of drugs, PARP inhibitors are designed to exploit specific genetic make-up of
some tumor cells
• Repairs damaged DNA
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Studies:
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PARP1 deficient mice
-human cells in culture are treated with PARP1 inhibitors
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Normal human cells undergo/capable of normal cell division
human cells deficient in BRCA1 or BRCA2 are killed in response to PARP1 inhibitors.
Human aspartyl (asparaginyl) beta-hydroxylase (HAAH)
• HAAH is a cancer molecular marker that has been
detected by immunohistochemical staining in a broad
range of cancers; this marker was originally discovered
at the Rhode Island Hospital / Brown University
• HAAH gene is up-regulated in human malignancies such
as breast, colon, liver, and bile duct tumor.
high-level HAAH
expression is linked to
malignant transformation
HAAH is found on the
cell surface
HAAH immunoreactivity in a cholangiocarcinoma as detected
with the FB-50 mAb. B, negative control immunohistochemical
staining reaction in the cholangiocarcinoma shown in A
Copyright ©2000 American Association for Cancer Research
Ince, N. et al. Cancer Res 2000;60:1261-1266
HAAH antibody staining in lung cancer
Tumor formation in nude mice that received injections of
transfected clones overexpressing murine AAH
high-level HAAH expression is linked to the malignant progression and
invasiveness of multiple cancers.
Copyright ©2000 American Association for Cancer Research
Ince, N. et al. Cancer Res 2000;60:1261-1266
Three weekly IP injections of anti-HAAH antibody decrease tumor
growth in a xenograft model of primary human liver cancer
Panacea Pharmaceutics
• PAN-622, is an all-human sequence anti-HAAH
monoclonal antibody being developed as a cancer
therapeutic antibody drug and the start of Phase 1
clinical trials are anticipated in early 2009
• PAN-622 inhibited tumor growth in 90 percent of
animals, with 40 percent showing no visible tumor.
Tumors did not re-grow beyond the period of drug
administration.
• Prevents tumor growth.
– Chronic treatment
– Linkage to toxin
Summary
• Tumors are “altered self” cells that maintain similarities to “normal
cells” making it difficult to target cancer cells specifically
• Cancer therapies include:
– Surgery
– Radiation
– Chemotherapy
• Multi therapies
• Multi-drug regimen