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Chapter 54
Cancer Chemotherapy
Background

It is the second most common cause of death in the
developed nations

One in three people will be diagnosed with cancer
during their lifetime

The

Both benign and malignant tumours manifest
uncontrolled proliferation, but the latter are
distinguished by their capacity for dedifferentiation,
their invasiveness and their ability to metastasise
(spread to other parts of the body
cancer, malignant
malignant tumour are synonymous
terms
neoplasm
and
Background

Cancer:
is a disease in which there is
uncontrolled multiplication & spread within the
body of abnormal forms of body’s own cells

Cancer cells manifest, to varying degrees, four
characteristics that distinguish them from normal
cells:
1)
2)
3)
4)
Uncontrolled proliferation
Dedifferentiation & loss of function
Invasiveness
Metastasis
Causes

A normal cell turns into a cancer cell b/c of one or
more mutation in its DNA, which can be inherited or
acquired , which can be inherited or acquired, usually
through exposure to viruses or carcinogens (e.g.
tobacco products, asbestos)

2 main categories of genetic changes:
– Induce of oncogenic transformation
– Inactivation of tumour suppressor genes
About 30 tumour suppressor genes and
dominant oncogenes have been identified

100
Causes

Incidence, geographical distribution, & behaviour of
specific types of cancer are related to: age, sex, race,
genetic predisposition, & exposure to environmental
carcinogens
Principles of cancer chemotherapy
•


Drug therapy is used in patients with cancer
to:
1. Eradicate the disease
2. Induce a remission
3. Control symptoms
Ideal anticancer drugs would eradicate cancer cells
without harming normal tissues
Unfortunately, most currently available agents do not
specifically recognize neoplastic cells but affect all
kind of proliferating cells
Principles of cancer chemotherapy

The treatment of cancer patients requires a skillful
interdigitation of pharmacotherapy with other
modalities of treatment (e.g., surgery and irradiation)

In biochemical terms, cancer cells and normal cells
are so similar in most respects that it is more difficult
to find general, exploitable, biochemical differences
between them
Principles of cancer chemotherapy

Individual patient characteristics
choice of modalities
determine
the

Not all patients can tolerate drugs, and not all drug
regimens are appropriate for a given patient

Renal and hepatic function, bone marrow reserve,
general performance status, and concurrent medical
problems all come into consideration in making a
therapeutic plan
Principles of Drug Treatment

The log cell kill hypothesis: cytotoxic effect of
anticancer drugs follow log-cell kinetics: a given dose
would
be
predicted
to
kill
a
constant
proportion/fraction of cells

For example: if an individual drug leads to a 3 log kill
of cancer cells and reduces the tumor burden from
1010 to 107 cells, the same dose used at a tumor
burden of 105 cells reduces the tumor mass to 102
cells

Cell kill is, therefore, proportional, regardless of
tumor burden
Benefits of combination therapy

Combination-drug chemotherapy is more successful
than single-drug treatment in most of the cancers
for which chemotherapy is effective b/c:
1)
It provides maximal cell kill within the range of
toxicity tolerated by the host for each drug
It provides a broader range of interaction between
drugs and tumor cells with different genetic
abnormalities in a heterogeneous tumor population
It may prevent or slow the subsequent development
of cellular drug resistance
2)
3)
Benefits of combination therapy




Certain principles have been used in designing such
treatments
Efficacy: each drug should have some individual
therapeutic activity against the particular tumor
being treated
Toxicity: Drugs with different dose-limiting toxicities
should be used to avoid overlapping toxicities
Optimum scheduling: Intensive intermittent
schedules should allow time for recovery from the
acute toxic effects, primarily bone marrow toxicity
Benefits of combination therapy

Drugs that act by different mechanisms may have
additive
or
synergistic
therapeutic
effects.
Combination therapy will thus increase log cell kill
and diminish the probability of emergence of
resistant clones of tumor cells

Several cycles of treatment should be given, since
one or two cycles of therapy are rarely sufficient to
eradicate a tumor. Most curable tumors require at
least six to eight cycles of therapy
Benefits of combination therapy

Example of combination therapy of advanced
Hodgkin’s disease:
– MOPP (mechlorethamine, Oncovin [vincristine
sulfate], procarbazine, prednisone)
– ABVD (Adriamycin [doxorubicin hydrochloride],
bleomycin,vinblastine, dacarbazine), has resulted
in cure rates of 50 to 60%
Cell-cycle specificity of drugs



Both normal cells & tumor cells go through growth
cycle
The number of cells that are in various stages of the
cycle may differ in the normal & neoplastic tissues
The normal cell cycle consists of a definable
sequence of events that characterize the growth and
division of cells
Cell-cycle specificity of drugs


Cell cycle specific (CCS) drugs: effective only
against replicating cells (most effective against
hematological malignancies & in solid tumors in
which large proportion of the cells are proliferating)
Cell-cycle nonspecific (CCNS) drugs: many bind
to cellular DNA. Useful against low growth and high
growth tumors (e.g., carcinomas of the colon or
non–small cell lung cancer)
Resistance


Primary
resistance
(inherent
drug
resistance): melanoma, renal cell cancer, &
brain cancer
Acquired
resistance:
genetic
mutation
particularly after prolonged administration of
suboptimal doses (minimized by short term,
intensive, intermittent therapy administration or
by drug combinations)
Possible mechanisms of Anticancer Drug
Resistance
Mechanism
Chemotherapy Agents
Improved proficiency in repair of DNA
Cisplatin, cyclophosphamide, melphalan,
mitomycin, mechlorethamine
 In drug activation
Cytarabine, doxorubicin, fluorouracil,
mercaptopurine, methotrexate, thioguanine
in drug inactivation
Cytarabine, mercaptopurine
 In cellular uptake of drug
Methotrexate, melphalan
 In efflux of drug (multidrug
resistance)
Doxorubicin, daunorubicin, etoposide,
vincristine, vinblastine, teniposide,
docetaxel, paclitaxel, vinorelbine
Alternative biochemical pathways
Cytarabine, fluorouracil, methotrexate
Alterations in target enzymes (DHFR,
topoisomerase II)
Fluorouracil, hyroxyurea, mercaptopurine,
methotrexate, thioguanine, teniopside,
doxorubicin, daunoruricin, idarubicin
Multidrug resistance



Tumor cells may become generally resistant to a
variety of cytotoxic drugs on the basis of decreased
uptake or retention of the drugs
It is the major form of resistance to a broad range of
structurally unrelated anticancer agents, including the
anthracyclines,
vinca
alkaloids,
taxanes,
camptothecins, epipodophyllotoxins
It is associated with increased expression of the
MDR1 gene, which encodes a cell surface transporter
glycoprotein (P-glycoprotein)
Multidrug resistance

Associated with increased expression of a normal
gene (the MDR1 gene) for a cell surface glycoprotein
(P-glycoprotein) involved in drug efflux

Multidrug resistance can be reversed experimentally
by calcium channel blockers, such as verapamil, and
a variety of other drugs, which inhibit the transporter
The multidrug resistance gene MDR1, which encodes the cell-surface molecule P-glycoprotein
(PGP), can confer resistance to a wide variety of drugs. PGP transports drugs out of the cell, which is
a process that requires the presence of two ATP-binding domains. These domains are a defining
characteristic of this family of ATP-binding cassette (ABC) transporters. The exact mechanism of drug
efflux is not well understood, but might involve either direct transport out of the cytoplasm or
redistribution of the drug as it transverses the plasma membrane. Some cytotoxic drugs that are
known substrates for PGP include etoposide, daunomycin, taxol, vinblastine and doxorubicin. PGP is
modified by sugar moieties (black) on the external surface of the protein
Toxicity of cancer chemotherapy


Most anticancer s have a narrow therapeutic
index
Therapy aimed at killing rapidly dividing
cancer cells also affects normal cells
undergoing rapid proliferation (for example,
cells of the buccal mucosa, bone marrow,
gastrointestinal (GI) mucosa, and hair),
contributing to the toxic manifestations of
chemotherapy
Common ADEs
1)
2)
Bone marrow suppression that
predisposes to infections
GIT:
– N & V: phenothiazines and other centrally acting
– Damage to the the GIT muycosa: stomatitis,
dysphagia, and diarrhea
3)
4)
5)
Alopecia
Sterility
Hyperuricemia (tumor lysis syndrome)
Drugs used in cancer chemotherapy
1)
2)
3)
4)
5)
6)
Alkylating agents and related compounds
Antimetabolites
Cytotoxic antibiotics
Plant derivatives (vinca alkaloids, taxanes,
campothecins)
Hormones
Miscellaneous agents
ALKYLATING AGENTS
The alkylating agents are the largest class of
anticancer agents
1) Nitrogen
mustards:
chlorambucil,
cyclophosphamide, mechlorethamine
2) Nitrosureas: carmistine, lomustine
3) Alkylsulfonates: busulfan
4) Platinum analogs: cisplatin, carboplatin, and
oxaliplatin
5) Other
Alkylating Agents: dacarbazine,
procarbazine,
&
bendamustine

Mechanism of actions




Form reactive molecular species/ intermediate that
transfer of their alkyl groups to various cellular
constituents
The macromolecular sites of alkylation damage
include DNA, RNA, proteins, and various enzymes
Alkylations of DNA within the nucleus represent the
major interactions that lead to cell death
The major site of alkylation within DNA is the N7
position of guanine
Most major alkylating agents are bifunctional,
with two reactive groups
ALKYLATING AGENTS

Are cell cycle-nonspecific, but cells are most
susceptible to alkylation in late G1 & S phases

Used in combination with other agents to treat a
wide variety of lymphatic and solid cancer

Mutagenic & carcinogenic and can lead to
secondary malignancies, such as acute leukemia
Drug resistance
1)
2)
3)
Increase capability to repair DNA lesions
Decrease permeability of the cell to the alkylating
agents
Increase production/activity of glutathione of
glutathione S-transferase, which can conjugate with
and detoxify electrophilic intermediates
A. Cyclophosphamide

Pro-drug that needs hepatic activation by CYP450 (4hydroxy cyclophosphamide):The active compounds,
are phosphoramide mustard and acrolein

Clinical uses:
Cyclophosphamide has a wide spectrum of
antitumor activity: Breast cancer, ovarian cancer,
non-Hodgkin's lymphoma, CLL, soft tissue sarcoma,
neuroblastoma, Wilms' tumor, rhabdomyosarcoma
Alternative
to
azathioprine
in
suppressing
immunological rejection of transplant organs
1)
2)
A. Cyclophosphamide

Specific ADE:

Hemorrhagic cystitis: Dysuria and decreased urinary
frequency
Due to acrolein in the urine
Can be minimized by vigorous hydration & by use of
sodium 2-mercaptoethane sulfonate (MESNA) which
“traps” acrolein



Other common ADEs:

Alopecia
NVD
Bone marrow suppression


B. Mechlorethamine



Originally developed as a vesicant (nitrogen
mustard) during world war I
IV administered
The major indication for mechlorethamine is
Hodgkin’s disease; the drug is given in the MOPP
regimen
B. Mechlorethamine

Specific ADEs:

Marked vesicant action (blistering agent): care should be
taken to avoid extravasation into Sc tissues or even
spillage onto the skin
Reproductive toxicity includes amenorrhea and inhibition
of oogenesis and spermatogenesis


Common ADEs:

Bone marrow suppression
Immunosuppression (herpes zoster infections, especially
in patients with lymphomas)
Alopecia
NVD



C. Nitrosureas: Carmustine (IV) &
Lomustine (orally)

Are highly lipid-soluble and are able to cross the
BBB, making them effective in the treatment of
brain tumors

Both alkylation and carbamoylation contribute to
the therapeutic and toxic effects of the
nitrosoureas
C. Nitrosureas: Carmustine (IV) &
Lomustine (orally)

ADEs:
– Bone marrow depression: 4 to 5 weeks
– Severe nausea and vomiting
– Pulmonary toxicity, manifested by cough,
dyspnea, and interstitial fibrosis (long term)
– Less frequent: alopecia, stomatitis, and mild
abnormalities of liver function
– Potentially, mutagenic, teratogenic, and
carcinogenic
Streptozocin (STZ)

Sugar-containing nitrosourea

It has a high affinity for cells of the islets of
Langerhans & is transported into the cell by the
glucose transport protein GLUT2

Clinical use: insulin-secreting islet cell carcinoma of
the pancreas
ADEs:

– Abnormal glucose tolerance (hypoglycemic coma)
– Renal tubular damage in 5 to 10% of patients
D. Platinum analogs (cisplatin, carboplatin, &
oxaliplatin)
1)


First generation: Cisplatin
Clinical uses: solid tumors (non-small cell and small
cell lung cancer, esophageal and gastric cancer, head
and neck cancer, and genitourinary cancers,
particularly testicular, ovarian, and bladder cancer)
ADEs:
– Renal toxicity (major)
– N and V
– Anemia: require transfusions of RBCs
– Hearing loss (10 to 30% of patients)
D. Platinum analogs (cisplatin, carboplatin, &
oxaliplatin)
2)



3)


Second generation: Carboplatin
MOA, mechanisms of resistance, and clinical uses
are identical to cisplatin
it exhibits significantly less renal toxicity and IT
toxicity, peripheral nerves, and hearing loss
It is more myelosuppressive than cisplatin
Third generation: oxaliplatin
Similar to cisplatin and carboplatin, but with
significant activity against colorectal cancer
ADEs: Neurotoxicity manifested by a peripheral
sensory neuropathy
Other Alkylating Agents

Procarbazine:

Activated by hepatic CYPs to highly reactive
alkylating species that methylate DNA
Oxidative metabolism of this drug by microsomal
enzymes generates azoprocarbazine and H2O2, which
may be responsible for DNA strand scission
It is commonly used in combination regimens for
Hodgkin's and non-Hodgkin's lymphoma and brain
tumors


Other Alkylating Agents
1.
Procarbazine:

Procarbazine is a weak MAOI: hypertensive reactions
may result from its use concurrently with
sympathomimetic agents, TCA, or ingestion of foods
with high tyramine content

CNS toxicity with neuropathy, ataxia, lethargy, and
confusion

The carcinogenic potential of procarbazine is thought
to be higher than that of most other alkylating agents
Other Alkylating Agents
2.


Dacarbazine
It is used in the treatment of malignant melanoma
It is a potent vesicant, and care must be taken to
avoid extravasation
Other alkylating agents
1.
2.
3.
4.
5.
6.
7.
8.
Dacarbazine
Temzolomide (brain tumor)
Melphalan
Chlorambucil
Busulfan
Bendamustine
Thiotepa
Altretamine
ANTIMETABOLITES (Structural Analogs)

Are structurally similar to endogenous
compounds, such as vitamins, amino
acids,and nucleotides

These drugs can compete for binding sites on
enzymes or can themselves become
incorporated into DNA or RNA and thus
interfere with cell growth and proliferation
ANTIMETABOLITES (Structural Analogs)

The antimetabolites in clinical use include:
- Folic acid analogues: methotrexate
- Purine
analogues:
mercaptopurine,
thioguanine
- Pyrimidine
analogues:
fluorouracil,
cytarabine

CCS drugs acting primarily in S phase
Are also used as immunosuppressants

Folate antagonist
Methotrexate (MTX)

Folic acid is an essential dietary factor that is
converted by enzymatic reduction to a series of
tetrahydrofolate (FH4) cofactors that provide
methyl groups for the synthesis of precursors of
DNA (thymidylate and purines) and RNA (purines)

Interference with FH4 metabolism reduces the
cellular capacity for one-carbon transfer and the
necessary methylation reactions in the synthesis of
purine
ribonucleotides
and
thymidine
monophosphate (TMP), thereby inhibiting DNA
replication
Folate antagonist
Methotrexate (MTX)

MoA:

Cellular uptake of the drug is by carrier-mediated
active transport

MXT competitively inhibits the binding of folic acid
to the enzyme dihydrofolate reductase (DHFR),
interfering with the synthesis of tetrahydrofolate
(FH4), which serves as the key one-carbon carrier
for enzymatic processes involved in de novo
synthesis of thymidylate, purine nucleotides, and
the amino acids serine and methionine
Folate (Diet)
Methotrexate
DHFR
FH2
dTMP
DHFR
FH4
N5, N10- Ch2FH4
Purine biosynthesis
Folate antagonist
Methotrexate (MTX)

MTX is metavolized to polyglutamte derivatives
which are retained in the cell and are also potent
inhibitors DHFR

Clearance depends on renal function

Drugs such as aspirin, penicillin, cephalosporins,
and NSAIDs inhibit the renal excretion of MTX
Folate antagonist
Methotrexate (MTX)

Resistance:
(1) Decrease drug transport
(2) Decrease formation of cytotoxic MTX
polyglutamates
(3) Increase levels of DHFR
(4) Alter DHFR protein with reduced affinity for
MTX
Folate antagonist
Methotrexate (MTX)

Clinical uses
– Cancer: Breast cancer, head and neck
cancer, osteogenic sarcoma, primary
central nervous system lymphoma, nonHodgkin's lymphoma, bladder cancer,
choriocarcinoma
– Immunosuppressive agent in severe
rheumatoid arthritis
Folate antagonist
Methotrexate (MTX)

Specific Toxicity
1.
Common toxicities
- GIT (NVD & ulcerative mucositis), stomatitis,
melosuppression, alopecia, and dermatitis
- Prevented or reveresed by administration of folinic
acid (leucovorin) “leucovorin rescue”
2.
Renal damage:
– High doses of MTX and its 7-OH metabolite, which
can ppt in the renal tubules
– Alkalinization of the urine and adequate hydration
can help
Folate (Diet)
Methotrexate
DHFR
FH2
dTMP
DHFR
FH4
N5, N10- Ch2FH4
Purine biosynthesis
Leucovorin
Folate antagonist
Methotrexate (MTX)

Specific Toxicity
3.
Hepatotoxicity: long term use may lead to
cirrhosis
4.
Pulmonary toxicity (cough, dyspnea, fever, &
cyanosis
5.
Neurologic
toxicities
(intrathecal
adminiosrtation): stiff neck, headach, meningeal
irritation
Folate antagonist
Pemetrexed

A new antifolate therapeutic agent that inhibits
enzymes within the pyrimidine and purine cycle

It works by inhibiting DHFR & thymidylate
synthase

It also inhibits glycinamide ribo-nucleotide formyl
transferase (GARFT), an enzyme that is involved
in purine synthesis and therefore reduces purine
production
Sites of Action of Pemetrexed. Actions of pemetrexed
on purine and pyrimidine pathways in DNA synthesis.
dUMP, Deoxyuridine Monophosphate; TMP, Thymidine
Monophosphate; CH2FH2, Methylenetetrahydrofolate;
CHOFH4,
10-Formyltetrahydrofolate;
FH2,
Dihydrofolate;
FH4,
Tetrahydrofolate;
DHFR,
Dihydrofolate
Reductase;
GARFT,
Glycinamide
Ribonucleotide Formyl Transferase.
Folate antagonist
Pemetrexed

Clinical uses: in combination with cisplatin in
the treatment of mesothelioma & as first-line
treatment of non-small cell lung cancer, as a
single agent in the second-line therapy of nonsmall cell lung cancer

ADEs: myelosuppression, skin rash, mucositis,
diarrhea, fatigue, & hand-foot syndrome

Toxicity is reduced by the coadministration of
folic acid, vitamin B12 and dexamethasone
Purine analoges
6-thiopurine: 6- Mercaptopurine (6-MP) & 6thioguanine (6-TG)
a.
6-MP
Analogue of hypoxanthine
 Inactive and is activated intracellularly by hypoxanthineguanine phosphoribosyltransferases (HGPRT) to to form
the monophosphate nucleotide 6-thioinosinic acid (TIMP)
 TIMP:
– Inhibits several enzymes of de novo purine nucleotide
synthesis
– Incorporation into nucleic acids: the monophosphate
form is eventually metabolized to the triphosphate
form, which can then get incorporated into both RNA
and DNA

Purine analoges
6-thiopurine: 6- Mercaptopurine (6-MP) & 6thioguanine (6-TG)
a.




6-MP
Clinical use: acute myelogenous leukemia
Potential D-D interaction with xanthine oxidase
inhibitor (allopurinol): the dose of mercaptopurine
must be reduced by 50–75%
Specific toxicity: hepatic dysfunction (cholestasis
jaundice, necrosis)
Bone marrow is the principle toxicity
Purine analoges
6-thiopurine: 6- Mercaptopurine (6-MP) & 6thioguanine (6-TG)
b.



6-TG
Analogue of the natural purine guanine
6-TG is converted intracellularly by the enzyme
hypoxanthine
guanine–phosphoribosyltransferase
(HGPRTase) to 6-TGMP
TGMP is further converted to the di- and
triphosphates, thioguanosine diphosphate and
thioguanosine triphosphate, which then inhibit the
biosynthesis of purines
Purine analoges
6-thiopurine: 6- Mercaptopurine (6-MP) & 6thioguanine (6-TG)
b.




6-TG
Clinical use: with cytarabine in the treatment of
adult acute leukemia
Interaction does not occur with allopurinol
Specific toxicity: hepatic dysfunction (cholestasis
jaundice, necrosis) less common than with
mercaptopurine
Bone marrow is the principle toxicity
Pyrimidine analoges
1-Fluorouracil (5-FU)

1)
2)
Halogenated pyrimidine analogue that must be
activated metabolically:
5-fluoro-2’-deoxyuridine-5’-monophosphate (5FdUMP): forms a covalently ternary complex
with the enzyme thymidylate synthase and the
5,10-methylenetetrahydrofolate
5-fluorouridine-5'-triphosphate
(FUTP):incorporate into RNA, where it interferes
with RNA processing and mRNA translation
Pyrimidine analoges
1-Fluorouracil (5-FU)

Clinical uses: Colorectal cancer, anal cancer,
breast cancer, gastroesophageal cancer, head and
neck cancer, hepatocellular cancer
IV administered b/c of its severe toxicity to the GIT

Resistance:







Depletion of enzymes (especially uridine kinase) that
activate 5-fluorouracil to nucleotides
Increased thymidylate synthase level
Altered affinity of thymidylate synthetase for FdUMP
Increase in the pool of the normal
metabolite deoxyuridylic acid (dUMP)
Increase in the rate of catabolism of 5-fluorouracil
Pyrimidine analoges
1-Fluorouracil (5-FU)

1.
2.
3.
4.
ADEs
Myelosuppression
GIT (mucositis and diarrhea)
Skin toxicity manifested by the hand-foot
syndrome
Neurotoxicity
Hand-foot syndrome is a side effect of some types of chemotherapy that
causes redness, swelling, and pain on the palms of the hands and/or the
soles of the feet. Hand-foot syndrome occurs when small amounts of
chemotherapy leak out of the capillaries (small blood vessels) in the hands
and feet. Once out of the blood vessels, the chemotherapy damages the
surrounding tissues
http://www.cancer.net
Pyrimidine analoges
2-Capecitabine




Prodrug that is enzymatically converted to 5-FU in
the tumor
Adv: orally administered
Clinical use: metastatic breast cancer that is
resistant to first line drugs & colorectal cancer
ADEs:
– Main: diarrhea and the hand-foot syndrome
– Myelosuppression, NV, and mucositis: the
incidence is significantly less than that seen with
IV 5-FU
Pyrimidine analoges
3-Cytarabine (cytosine arabinoside, Ara-C)






It is a CCS (S-phase)
MOA:
Is an analogue of the pyrimidine nucleosides cytidine
and deoxycytidine
Is activated by kinases to AraCTP: an inhibitor of
DNA polymerases which will incorporate into DNA
and can retard chain elongation
This agent has absolutely no activity in solid tumors
Its activity is limited exclusively to hematologic
malignancies (e.g. acute myelogenous leukemia and
non-Hodgkin's lymphoma)
Pyrimidine analoges
3-Cytarabine (cytosine arabinoside, Ara-C)

Resistance
 Defect in the transport process
 Changes in the kinase enzymes activity
 Increased deamination of the drug

Specific Toxicity
 Leukoenphalopathy: high doses with intrathecal
administration
Pyrimidine analoges
4-Gemcitabine

MOA:
Activated
to
2',2'-difluorodeoxycytidine
triphosphate which will inhibit DNA synthesis by
being incorporated into sites in the growing
strand that ordinarily would contain cytosine
Pyrimidine analoges
4-Gemcitabine


Resistance:
Alteration in the deoxycytidine kinase
Increase tumor production of endogenous
deoxycytidine
Clinical use:
 First-line treatment of locally advanced or metastatic
adenocarcinoma of the pancreas
 Non-small cell lung cancer, bladder cancer, ovarian
cancer, soft tissue sarcoma, and non-Hodgkin's
lymphoma
PLANT ALKALOIDS


These classes differ in their structures and MOA but
share the multidrug resistance mechanism, since they
are all substrates for the multidrug transporter Pglycoprotein
Cell cycle specific agents
Vinca alkaloids (vinblastine, vincristine)
Podophyllotoxins (etoposide, teniposide)
Camptothecins (Topotecan & Irinotecan)
Taxanes (paclitaxel, docetaxel)
A.




Vinca alkaloids: Vinblastine,
Vincristrine, & vinorelbine
Structurally related compounds derived from Vinca
rosea (Vinblastine & vincristrine)
Vinorelbine is a semi-synthetic derivative
Despite their structural similarity, there are significant
differences between them in regard to clinical
usefulness and toxicity
MOA: The vinca alkaloids bind avidly to tubulin &
inhibition tubulin polymerization, which disrupts
assembly of microtubules. This inhibitory effect
results in mitotic arrest in metaphase (M) prevent,
and cell division cannot be completed
A. Vinca alkaloids: Vinblastine,
Vincristrine, & vinorelbine

Resistance:
– Decreased rate of drug uptake
– Increased drug efflux : multidrug resistance &
cross-resistance usually occurs with
anthracyclines, dactinomycin, and
podophyllotoxins
A. Vinca alkaloids: Vinblastine,
Vincristrine, & vinorelbine
 ADRs
Vinblastine:
 NV, bone marrow suppression, alopecia, &
vesicant
Vincristine:
 Neurotoxicity: peripheral sensory neuropathy
 Syndrome of inappropriate secretion of antidiuretic
hormone (SIADH)
Vinorelbine:
 Bone marrow suppression with neutropenia
B. Taxanes: Paclitaxel, Docetaxel, &
Ixabepilone


Cell cycle specific (G2/M phase of the cell
cycle)
MoA: They bind reversibly to the β-tubulin subunit
promoting polymerization and stabilization of the
polymer rather than disassembly. Thus, they shift the
depolymerization-polymerization
process
to
accumulation of microtubules. The overly stable
microtubules formed are nonfunctional, and
chromosome desegregation does not occur. This
results in death of the cell
Figure 1 Mechanism of action of docetaxel
Mackler NJ and Pienta KJ (2005) Drug Insight: use of docetaxel in prostate and urothelial cancers. Nat Clin
Pract Urol 2: 92–100 doi:10.1038/ncpuro0099
B. Taxanes: Paclitaxel, Docetaxel, &
Ixabepilone

Resistance:
 Multidrug resistant P-glycoprotein
 Mutation in the tubulin structure

Clinical uses: advanced ovarian cancer and
metastatic breast cancer. Non-small cell in
combination with cisplatin
B. Taxanes: Paclitaxel, Docetaxel, &
Ixabepilone

ADEs:
 Neutropenia: treatment with colony stimulating
factor (Filgrastim) can help
 Peripheral neuropathy
 Transient,
asymptomatic
bradycardia:
Paclitaxel
 Fluid retention: Docetaxel
 Serious hypersensitivty: patients are pretreated with dexamethazone, diphenylhydramine,
and an H2 blocker
C. podophyllotoxins: Etoposide &
Teniposide



Cell cycle specific (most active in the late S
to G2 phase of the cell cycle)
MoA: Both drugs bind to the topoisomerase II
-DNA complex and prevent resealing of the
break that normally follows topoisomerase
binding to DNA
The enzyme remains bound to the free end of
the broken DNA strand, leading to an
accumulation of DNA breaks and cell death
Mechanism of action of etoposide
D. Camptothecins: Topotecan &
Irinotecan


Cell
cycle specific (most active in the S
phase)
MoA:
 Interfere with activity of topoisomerase I,
the enzyme responsible for cutting &
religating single DNA strands. Inhibition
of the enzyme results in DNA damage
DNA
CPT
Topoisomerase I
Binding of CPT to topo I and DNA
http://en.wikipedia.org/wiki/Camptothecin
Action of Type I DNA topoisomerases
ANTITUMOR ANTIBIOTICS


Antitumor antibiotics produce their effect
mainly by direct action on DNA, leading to
disruption of the DNA function
All the anticancer antibiotics now being
used in clinical practice are products of
various strains of the soil microbe
Stremptomyces

Cell cycle non-specific
A. Anthracyclin antibiotics

Agents: Doxorubicin, daunorubicin, idarubcin,
epirubicin , & mitoxantrone

MoA:
a.
b.
c.
d.
Inhibitoin of topoisomerase II
Intercalation in the DNA: block the synthesis of
DNA and RNA, and DNA strand scission
Binding to cellular membranes to alter fluidity and
ion transport
Generation of semiquinone free radicals and
oxygen free radicals through an iron-dependent,
enzyme-mediated reductive process
Doxorubicin
Doxorubicin–DNA complex
A. Anthracyclin antibiotics

Specific Toxicity:

Cardiotoxicity: arrhythmias and conduction
o
o
abnormalities, pericarditis, and myocarditis
Results from the generation of free radical and lipid
peroxidation
Reduced with:
 Lower weekly doses or continuous infusions of
doxorubicin
 Treatment with the iron-chelating agent dexrazoxane
 Liposomal-encapuslated formulations of doxorubicin
A. Anthracyclin antibiotics




Radiation recall reaction with erythema and
desquamation of the skin observed at sites of
prior radiation therapy
Doxorubicin will impart a reddish color to the
urine for 1 or 2 days after administration
Bone marrow suppression
Hyperpigmentation of nail beds and skin creases, and
conjunctivitis
B. Mitomycin (mitomycin C)


It is sometimes classified as an alkylating agent
b/c it undergoes metabolic activation through an
to generate an alkylating agent that cross-links
DNA
ADRs:
– Hemolytic-uremic syndrome: microangiopathic
hemolytic anemia, thrombocytopenia, and
renal failure
C. Bleomycin




It is a small peptide that contains a DNA-binding
region and an iron-binding domain at opposite ends
of the molecule
CCS drug active in G2 phase
MOA:
It acts by binding to DNA, which results in singlestrand and double-strand breaks following free
radical formation, and inhibition of DNA
biosynthesis. The fragmentation of DNA is due to
oxidation of a DNA-bleomycin-Fe(II) complex and
leads to chromosomal aberrations
C. Bleomycin



Specific Toxicity:
Cause: Bleomycin hydrolase, which inactivates
bleomycin, virtually absent in lungs and skin
Pulmonary toxicity: pneumonitis with cough,
dyspnea, dry inspiratory crackles on
examination, and infiltrates on chest x-ray

physical
Skin toxicity: hyperpigmentation, erythematosus
rashes, and thickening of the skin over the dorsum of
the hands and at dermal pressure points, such as the
elbows
MISCELLANEOUS
ANTICANCER DRUGS
L-Asparaginase



Enzyme that depletes serum L-asparagine to
aspartic acid and ammonia
It is used in treatment of childhood acute
lymphocytic leukemia
ADEs: hypersensitivity reactions, decrease in
clotting factors, liver abnormalities, pancreatitis,
seizures, and coma due to ammonia toxicity
Because tumor cells lack asparagine synthetase, they require
an exogenous source of L-asparagine. Thus, depletion of Lasparagine results in effective inhibition of protein synthesis