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Pharmacology II Chemotherapy of Hematological Malignancies Pharmacology III Targeted Therapies

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Title: Pharmacology II Chemotherapy of Hematological Malignancies Pharmacology III Targeted Therapies


1
Pharmacology II Chemotherapy of Hematological
MalignanciesPharmacology IIITargeted Therapies
  • John S. Lazo
  • January 11, 2006
  • BST-3 1036
  • Department of Pharmacology
  • lazo_at_pitt.edu

2
References
  • Craig and Stitzel, Modern Pharmacology, 6th Ed.,
    Chapters 57 and 58, pp. 630-656, 2004. Sound and
    clear.
  • Goodman and Gilman, The Pharmacological Basis of
    Therapeutics, Brunton, Lazo Parker, Eds. 11th
    Ed. pp. 1315-1403, 2006. Comprehensive.
  • Katzung, Basic Clinical Pharmacology, 9th Ed.
    pp 896-958, 2004. Considerable information about
    clinical usage.
  • Lippincotts Illustrated Reviews Pharmacology
    3rd Edition. R. D. Howland M.J. Mycek Ed. pp.
    453-484, 2006.
  • A useful site http//www.fda.gov/cder/cancer/app
    roved.htm This lists all of the FDA approved
    anticancer drugs with indications

3
Objectives
  • To provide a broad overview of how drugs used
    for hematological malignancies are classified.
  • To describe the mechanism of action and the
    toxicities of a few prototype cytotoxic agents
    used for hematological malignancies.
  • To describe the mechanism of action of prototype
    targeted agents used for hematological
    malignancies.

 
4
Cancer victims
5
Five-Year Relative Survival Rates
Source Surveillance, Epidemiology and End
Results (SEER) Program. National Cancer Institute
2004
6
Sites of Inhibition by Anticancer Agents.
7
Alkylating Agents
Chemistry. They have at least one CH2R
group. i. Nitrogen mustards Melphalan,
cyclophosphamide, chlorambucil, melphalan ii.
Alkyl sulfonates busulfan iii. Nitrosoureas iv.
Miscellaneous. Temozoloamide Mechanism of
Action These contain reactive groups that bind
covalently with biologically important cell
constituents, e.g. DNA. Usually there are two
reactive moieties and they cross link DNA.
8
1949
1959
9
Figure 5. Mechanism of alkylation.
 
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11
Alkylating Agents (cont)
  • Absorption, Distribution and Metabolism
  • Melphalan, chlorambucil, CCNU, BCNU and busulfan
    are orally active.
  • The nitrosoureas are highly lipid soluble and
    cross the blood brain barrier. They are rapidly
    metabolized to form carbonium ions (CI-CH2 CH
    2). The nitrosoureas also can add carbamoyl
    groups (RNCO), mainly to the e-NH2 of lysine.The
    R-group of cyclophosphamide undergoes hepatic
    metabolism to give the active alkylating agent,
    phosphoramide mustard. Cyclophosphamide itself
    is not active.
  • Uses of cyclophosphamide (Cytoxan) Acute
    lymphoid leukemia (ALL), acute myeloblastic
    leukemia (AML), Hodgkin's disease, malignant
    lymphoma, multiple myeloma (MM).
    Mechlorethamine Chronic lymphoid leukemia (CLL),
    chronic myeloid leukemia (CML) Hodgkins
    disease.
  • Melphalan MM non-Hodgkins disease.
  • Chlorambucil CLL, Hodgkins disease lymphoma.

12
Cyclophosphamide metabolism
13
Antimetabolites
Antimetabolites are compounds that bear a
structural similarity to normally occurring
substances, such as vitamin, nucleoside, or amino
acid. They compete with the natural substrate
for the active site on an essential enzyme and/or
substitute for the natural compound in DNA. Most
antimetabolites inhibit DNA synthesis they kill
cells in S-phase. Although bone marrow
depression occurs with all the drugs in this
group, oral and GI ulceration can be dose
limiting for some (e.g., methotrexate). The
antimetabolites require biotransformation to
produce their cytotoxic effects conversion to
the active form takes place intracellularily and
is referred to as lethal synthesis.
14
Pteridines AntifolatesChemical Mimicry
15
Folate dependent biosynthesis. Cycle of reactions
in the synthesis of thymidylate (dTMP) from dUMP.
Thymidylate synthase catalyzes the first reaction
of this cycle producing dTMP. The other product
of the reaction, dihydrofolate, must be reduced
by NADPH in a reaction catalyzed by dihydrofolate
reductase before a methylene group can be added
to regenerate 5,10-methylene-tetrahydrofolate.
Methylenetetrahydrofolate is regenerated in a
reaction catalyzed by serine hydroxymethyltransfer
ase.
16
Folate dependent biosynthesis (cont)
17
5.
18
Methotrexate
  R1 R2 Folic acid OH H Aminopterin NH2 H Meth
otrexate NH2 CH3
Chemistry and Mechanism of Action.
Methotrexate (1953) is a folic acid analog that
competitively inhibits dihydrofolate reductase
(DHFR). The inhibition of tetrahydrofolate
synthesis interrupts one carbon transfer
reaction the synthesis of thymidylate, purine
nucleotides and the amino acids glycine and
methionine. Methotrexate kills cells in S-phase.
Because methotrexate also inhibits RNA and
protein synthesis, it can block cellular entry
into S-phase thus, it is self-limiting.   b.     
19
Methotrexate
  • Absorption, Distribution and Metabolism. It is
    well absorbed orally. It is a weak acid,
    secreted, and eliminated primarily by the kidney.
    It is plasma bound (50). It does not penetrate
    the blood-brain barrier well. It has been
    administrated intrathecally. Methotrexate is
    metabolized intracellularily to polyglutamate
    derivatives these are retained by cells better
    and are better inhibitors of DHFR than the parent
    compound.
  • Therapeutic uses include ALL.
  • The toxic effects of methotrexate are bone
    marrow, oral and GI mucosa.

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21
Mechanism of MTX inhibition
NADPH H NADP
Serine Glycine
Folic Acid/ MTX
Tetrahydrofolate (THF) N5,
N10-Methylene-THF
22
Pteridines
Pemetrexed Methotrexate
23
Pemetrexed - Alimta
  • This is a unique antifolate in that it has been
    shown to inhibit at least five of the major
    folate-dependent enzymes.
  • Thymidylate synthase
  • Dihydrofolate reducatase
  • Glycinamide ribonucelotide formyltransferase
  • 5-aminoimidazole-4-carboxamide ribonucleotide
    formyltransferase
  • C-1 tetrahydrofolate synthetase
  • Premetrexed was approved in February 2004 for
    malignant plural mesothelioma
  • This is an example of a dirty drug or a
    multi-targeted drug.

24
Pyrimidines Cytarabine (AraC)
Chemistry. Cytarabine (also known as Ara-C or
Cytosar-U) (1969) is 1-ß-D-arabinofuranosylcytosi
ne. Absorption, Distribution and Metabolism.
Only poor bioavailability after oral dose (20)
because of cytidine deaminase in the GI and
liver. Must be given iv by continuous infusion
because of short half life (10 min). Less than
10 of the injected drug is excreted unchanged.
Like other antimetabolites, Ara-C must be
anabolized to Ara-CTP.

Cytosine Cytarabine
25
Pyrimidines Cytarabine (cont)
  • Mechanism of Action. The most important cause of
    cell death is incorporation into DNA with
    subsequent inhibition of DNA polymerase. Ara-C
    also induces terminal differentiation of cells.
  • Toxicity. Ara-C is a potent myelosuppressive
    agent capable of causing acute, severe
    leucopenia, thrombocytopenia and anemia with
    striking megaloblastic changes. It can also cause
    GI toxicity, stomatitis and noncardiogenic
    pulmonary edema.

26
Pyrimidines Cytarabine (AraC)
  • Acute nonlymphocytic leukemia
  • Acute lymphoid leukemia
  • Acute myeloid leukemia
  • Chronic myeloid leukemia
  • Non-Hodgkins lymphoma

27
Purines Mercaptopurine and Thioguanine
Chemistry. Mercaptopurine and thioguanine
(1966) are analogs of hypoxanthine and
guanine.   Mechanism of Action. Both of
these drugs must be converted intracellularily to
the nucleotide forms by hypoxanthine-guanine
phophoribosyl transferase (HGPRT). Cytotoxicity
occurs by several mechanisms including feedback
inhibition of the first and rate-limiting step in
purine biosynthesis and inhibition of purine
interconversions. In addition, the purine
analogs have effects on DNA and RNA synthesis,
glycoprotein synthesis and chromosomal
replication.  
28
Purines Mercaptopurine and Thioguanine
  • Administration, Distribution and Metabolism.
    Mercaptopurine and thioguanine are routinely
    given orally. They are metabolized extensively
    and the metabolites are excreted in the urine
    50 of the administered drug is found in the
    urine after 24 hr. Xanthine oxidase, which
    catalyzes the first step in mercaptopurine
    breakdown, is inhibited by allopurinol.
    Allopurinol is often used with anticancer drugs
    to prevent the hyperuricemia and uricosuria that
    follows marked cell kill. The cytotoxic effect
    and toxicity of mercaptopurine is increased in
    the presence of allopurinol you must reduce the
    dosage of mercaptopurine by ¼ or 1/3 of the usual
    dose. Thioguanine is not extensively metabolized
    by xanthine oxidase it can be used in
    combination with allopurinol without the dosage
    being reduced.
  • Toxicity. Myelosuppression is a common side
    effect with both purine analogs. Hepatotoxicity
    is less common with 6-thioguanine than with
    6-mercaptopurine. Approximately 1/3 of patients
    develop jaundice after 6-mercaptopurine this is
    associated with bile stasis and hepatic necrosis.
  •  

29
Purine Metabolism
30
Natural Products
Unlike the other classes of antitumor
agents, membership in this group is determined by
the source of the drug. They are obtained from
lower organisms, such as plants and Streptomyces.
With the exception of the vincas and bleomycin
the natural products are phase nonspecific. The
chemical structures are often complex and,
therefore, not always presented.  
31
Anthracyclines
Chemistry. There are two
anthracyclines doxorubicin (Adriamycin) (1974)
and daunorubicin.   Absorption,
Distribution and Metabolism. Both doxorubicin
and daunorubicin are rapidly taken up by all
tissues except the brain. They are extensively
bound to cellular components, which is
responsible partially for their long plasma
half-life. They are cleared mainly by hepatic
metabolism severe clinical toxicity may result
if there is impaired hepatic function.
Mechanism of Action. Inhibition of topoisomerase
II enzyme catalyzes the breaking and rejoining of
DNA strands. Stabilization of the enzyme-DNA
complex leads to inhibition of DNA synthesis and
cell death.
a.  
32
Doxorubicin Toxicity
  • Toxicity. Bone marrow depression and alopecia.
    The most serious toxicity (irreversible) is
    cardiomyopathy. There are two types acute and
    chronic. The acute form is characterized by
    abnormal ECG changes it is reversible and is not
    a predictor of chronic cardiomyopathy. The
    second form is a chronic cumulative does-related
    toxicity, manifested by congestive heart failure
    that is unresponsive to digitalis. For this
    reason the total dose of doxorubicin is kept
    below 500 mg/sq. m. The mechanism of cardiac
    toxicity is unknown but may be due to the
    excessive local production of free radicals in
    the myocardium.

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34
Bleomycin
Chemistry. Bleomycin (1973) is a mixture of
several different complex glycopeptides extracted
from Streptomyces.   Absorption, Distribution and
Metabolism. Bleomycin is a peptide and cannot be
administered orally. More than ½ of drug is
excreted in the urine unchanged within 24 hr.
Bleomycin is inactivated in most tissues by
bleomycin hydrolase the sensitivity of lungs and
skin to the toxicity of bleomycin is believed to
be due to low levels of bleomycin hydrolase.    
Mechanism of Action. Bleomycin forms a complex
with iron and molecular oxygen and then binds to
double strand DNA and causes both single and
double strand breaks the double strand breaks
are believed to cause cell death. The DNA damage
is nucleotide-sequence specific. For most cells
the G2 phase is the most sensitive.     
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37
Bleomycin
Toxicity. The most serious adverse effect is
pulmonary toxicity. This manifestation begins
with decreasing pulmonary function, fine rales
and cough and it progresses to severe and
sometimes fatal pulmonary fibrosis. An unusual
toxicity is a lethal anaphylactoid reaction that
occurs in patients with lymphoma small test
doses are commonly given. It is important that
bleomycin does not have significant
myelosuppressive effects and, thus, it is a
popular agent for combination chemotherapy.
38
Vinca Alkaloids
Chemistry. The two members of this
group are vincristine and vinblastine both are
derived from the periwinkle plant. They have
complex chemical structures.   Absorption,
Distribution and Metabolism. Both agents are
given i.v. and they bind extensively to tissue
components therefore long half-life. They do
not pass the blood-brain barrier. Both are
metabolized by the liver and excreted in the
bile, although vinblastine is cleared 7x more
slowly than vincristine.
39
Vincas
Paclitaxel
Mechanism of action. Both vincristine and
vinblastine bind specifically to the microtubule
proteins and blocks polymerization. The
dissolution of the mitotic spindle interferes
with chromosome segregation and leads of mitotic
arrest.
40
Etoposide
41
Etoposide
Chemistry. Etoposide (1996) and teniposide are
analogs of the alkaloid, podophyllotoxin, which
is obtained from the Mandrake (may-apple) plant
(used by American Indians and early colonists).
Absorption, Distribution and Metabolism.
Etoposide is available for iv use or oral
administration, although absorption is variable
and ranges 50. After iv injection the terminal
half-life is 6-8 h. Approximately 40 of the drug
is excreed in the urine unchanged so in patients
with compromised renal function the dose must be
reduced.
42
Etoposide
Mechanism of Action. Both etoposide and
teniposide form a ternary complex with
topoisomerase II and DNA, preventing resealing of
the topoisomerase II-induced DNA break. The
enzyme remains bound to the free end of the
broken DNA strand, leading to an accumulation of
DNA strand breaks and cell death. Thus, they
poison the enzyme. Cell in S and G2 are most
sensitive. Both drugs are affected by
p-glycoprotein. Uses Etoposide Acute
nonlymphocytic leukemia and Non-Hodgkins
lymphoma Teniposide ALL and Non-hodgkins
lymphoma.
43
Etoposide
44
Pharmacology IIITargeted Therapies
John S. Lazo January 11, 2006 BST-3
1036 Department of Pharmacology lazo_at_pitt.edu
45
Gleevec
FDA and Novartis, the drug's manufacturer, should
be commended for the rapid development and review
that will make this product available soon for
the leukemia patients who desperately need it,"
said Health and Human Services Secretary Tommy G.
Thompson. "It is also important to recognize that
today's approval is also a culmination of years
of work and years of investment, by many people
in many different institutions, and even in
different fields of medicine. It's a testament to
the groundbreaking scientific research taking
place in labs throughout America." FDA News May
10, 2001
46
Anti-signaling agents Imatinib mesylate
(Gleevec)
  Chemistry. Gleevec was discovered by
screening many thousands of compounds (so called
high throughput screening) and it is an analog of
ATP and binds to the ATP binding pocket of the
Bcr-Abl tyrosine kinase. Absorption,
Distribution and Metabolism. Imatinib is well
absorbed after oral administration with a mean
absolute bioavailability of 98. CYP3A4 is the
major enzyme responsible for metabolism of
imatinib.
47
Imatinib
Mechanism of Action. Imatinib is a
protein-tyrosine kinase inhibitor that inhibits
the Bcr-Abl tyrosine kinase, the constitutive
abnormal tyrosine kinase created by the
Philadelphia chromosome abnormality in CML.
Imatinib is also an inhibitor of the receptor
tyrosine kinases for platelet-derived growth
factor (PDGF) and stem cell factor (SCF), c-kit,
inhibits PDGF- and SCF-mediated cellular
events. In vitro, imatinib inhibits proliferation
and induces apoptosis in gastrointestinal stromal
tumor (GIST) cells, which express an activating
c-kit mutation.
48
Imatinib Mechanism of Action
49
Gleevec binding to Bcr-Abl
50
Anti-signaling agents Trastuzumab (Herceptin)
Chemistry. Herceptin is a recombinant
DNA-derived humanized monoclonal antibody.  
Absorption, Distribution and Metabolism.
Trastuzumab is admistered i.v. The half-life
averaged 1.7 and 12 days at the 10 and 500 mg
dose levels, respectively. Trastuzumab's volume
of distribution was approximately that of serum
volume (44 ml/kg) and its mean half-life is 6
days.
51
Bortezomib
Chemistry. Bortezomib (2003) is an unique
boronic acid containing small molecule.Absorptio
n, Distribution and Metabolism. Bortezomib is
administered iv. It has a half-life of 6 h and is
metabolized with the loss of the broronic acid by
CYP3A4 and CYP2D6.
52
Bortezomib
Mechanism of Action. Bortezomib binds to the 20S
core of the 26S proteosome and is a reversible
inhibitor of its chymotrypsin-like activity.
Inhibition of the proteosome blocks multiple
signaling cascades most importantly it decreases
NK-?B. This occurs because Bortezomib inhibits
the degradation of I?B so NF-?B activities are
blocked. Toxicity. Thrombocytopenia
peripheral neuropathy
53
Bortezomib
Cytokine activation of receptors
Cytokines
NF-?B
Activation of NK-?B by I?B degradation
NF-?B activates transcription
Proteasome
Decreased cell adhesions molecules
Decreased inflammatory molecules
Degraded I?B
Decreased antiapoptotic factors
p50 P65 I?B
54
Rituximab (Rituxan)
Chemistry. Rituximab is a genetically
engineered, chimeric monoclonal antibody (the
first monoclonal antibody to be approved by the
FDA for the treatment of cancer (1997)) directed
against the CD20 antigen on the surface of normal
and malignant B lymphocytes. CD20 participates in
the activation process for cell cycle initiation
and differentiation. The CD20 antigen is found on
cells from the pre-B-cell stage through terminal
differentiation to plasma cells ad is expressed
on 90 of B-cell neoplasm. The biological
functions of CD20 are unknown. Absorption,
Distribution and Metabolism. Because it is an
antibody, Rituximab must be given iv. It has a
serum half-life of 75 h with a rather large
range in values.
55
Rituximab
Mechanism of Action. Monoclonal antibody binding
to CD20 generates transmembrane signals that
produce autophosphorylation and activation of
serine/tyrosine protein kinases. This leads to
antibody dependent cellular cytotoxicity and
cells death. Toxicity. Rituximab toxicities are
mostly related to infusion reactions
56
Trastuzumab
Chemistry. Trastuzumab is a recombinant
DNA-derived humanized monoclonal antibody.
Absorption, Distribution and Metabolism.
Trastuzumab is administered i.v. The half-life
averaged 2 and 12 days at the 10 and 500 mg dose
levels, respectively. Trastuzumab's volume of
distribution was approximately that of serum
volume (44 ml/kg) and its mean half-life is 6
days.
57
Trastuzumab
Mechanism of Action. Trastuzumab selectively
binds with high affinity in a cell-based assay
(Kd 5 nM) to the extracellular domain of the
human epidermal growth factor receptor 2 protein,
HER2. Toxicity. Congestive heart failure is the
most noteworthy.
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59
Miscellaneous/Mysterious Agents Thalidomide
  • Chemical structure. An old drug (developed in the
    1950s as a sedative) with a very simple
    structure.
  • Absorption, Distribution, and Metabolism.
  • Slow and highly variable oral absorption. Wide
    tissue distribution including in semen. Rapid
    spontaneous nonenzymatic hydrolysis leads to gt50
    metabolites.
  • Toxicity. Most common side effects are sedation
    and constipation. Is a notorious teratogen
    causing dysmyleia (stunted limb growth).
  • Mechanism(s) of action. Complex including direct
    apoptosis, reduced tumor adhesion to matrix,
    inhibition of angiogenesis, inhibition of
    cytokine release, and enhanced natural killer
    cell functionality

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61
Schematic overview of proposed mechanism of
antimyeloma activity of thalidomide
62
Miscellaneous Hydroxyurea
Chemical structure. A simple chemical.
a.        Absorption, Distribution and
Metabolism. Excellent oral bioavailability and
crosses the blood-brain barrier. Mechanism of
action. Inhibits ribonucleotide reductase and
blocks cells in at the G1/S interphase and kills
in S-phase.
63
Arsenic Trioxide
  • Chemistry. Arsenic was used gt2,400 years ago in
    Greece and Rome. Arsenic trioxide was used a
    century ago for syphilis and parasitic diseases.
    It was FDA approved in 2000.
  • Absorption, Distribution and Metabolism. It is
    administered as a 2 h iv infusion. The primary
    mechanism is through enzymatic methylation but no
    dose reduction is recommended in patients with
    hepatic or renal dysfunction.
  • Mechanism of Action. The mechanism of action
    remains uncertain. I causes cellular
    differentiation and promotes apoptosis. It is
    highly reactive to sulfhydryls and it generates
    this may be important
  • Toxicity. Well tolerated with sine reversible
    hyperglycemia and fatigue. Can length QT
    interval.
  • Use. CML

64
Summary
  • Remember the major classes.
  • Remember the irreversible toxicities.
  • Targeted therapies are emerging as exciting new
    agents and will grow in numbers.

65
The Future of Cancer Chemotherapy
2025 future Cocktails of novel antisignaling
agents become mainstay. Diagnostics combined with
individual therapy is standard. Cytotoxics phased
out. Small molecules replace biologics. Cancer is
viewed as a chronic disease.
2005-2015 Cytotoxics and hormonals remain
foundation. Emergence of targeted antisignaling
compounds. Increasing use of biologics. Novel
combinations of cytotoxics along with other
modalities. Tailored, individualized
chemotherapies.
1992-2005 Cytotoxic hormonal agents are
mainstays
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