CHAPTER 54

CANCER
CHEMOTHERAPY
BASIC PRINCIPLES OF CANCER CHEMOTHERAPY
-

Knowledge of

Drug interaction

Clinical Toxicties

Pharmacokinetics
uSe established regimes
choice of a particular drug treatment program should
depend on the disease, histology and stage of the
disease and on an assessment of individual patient
tolerance.
Performance status

Combination chemotherapy uses several drug

simultaneously based on certain empiric principles.
o
Each drug selected has demonstrable
antitumor activity against the neoplasm for
which it is used.
o
Each drug should have a different
mechanism of action
o
the drugs should not have a common
mechanism of resistance.
o
Drug dose-limiting toxicities should not
overlap.
o
Specific combinations chosen should be
based on preclinical and clinical protocol
based evidence of synergistic activity (when
the presence of one chemical enhances the
effects of the second)

CELL KINETICS AND CANCER CHEMOTHERAPY

EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE

SCALE
Performance Status
Definition
0
Asymptomatic
1
Symptomatic, fully
ambulatory
2
Symptomatic, in bed
<50% of the day
3
Symptomatic; in bed
>50% of the day
4
Bedridden
KARNOFSKY PERFORMANCE STATUS SCALE
Level of Functional Capacity
100
Normal, no complaints, no evidence of disease
90
Able to carry normal activity, neither signs or
symptoms of the diseae
80
Normal activity with effort, some signs or symptoms
of disease
70
Cares for self, unable to carry on normal activity or to
do active work
60
Requires occasional assistance but is able to care for
most needs
50
Requires considerable assistance and frequent
medical care
40
Disabled, requires special care and assistance
30
Severely disabled, hospitalization is indicated
although deat is not imminent.
20
Hospitalization is necessary, very sick, actie
supportive treatment necessary
10
Fatal processes progress rapidly
0
Dead

A. CELL CYCLE SPECIFIC AGENTS

o
o
o
o
o

B. NON CELL CYCLE DEPENDENT AGENTS

o
o
o

High dose chemotherapy programs used in stem cell

transplantation result in additional organ toxicities
that are not seen at conventional doses.
Chemotherapy usually targets process of DNA
replication.
Durgs have been introduce to target specific
processes:
a. Receptor signaling
b. Cellular signaling
c. Oncoproteins
d. Angiogenesis
e. Membrane cluster of differentiation antigens

Do not require cells to exposed during a

specific phase of the cell cycle
Total dose of drug is more important than
the duration of exposure
Appropriate dose depends on
cell cycle dependence
toxicity to marrow
pharmacokinetic behavior
interaction with other drugs
patient tolerance

DRUG RESISTANCE
-

COMBINATION CHEMOTHERAPY

Kills cells as they traverse the DNA synthetic

phase S phase of the cell cycle
Antimetabolites
Diminished toxicity for resting cells.
Prolonged exposure to drug is useful for
minimizing effects of asynchronous cell
division
high dose regimens are the most useful

spontaneous concurrence of resistant mutatns

selection of drug-resistant cells under pressure of
chemotherapy (clonal selection)
mechanism such as additional mutational in
mismatched repair genes that blocks apoptosis ->
impair treatment efficacy

MUTATIONS AND CANCER

GENES IMPLICATED IN CANCER:

-

Cellular genes are known that are homologous to the

transforming genes of the retroviruses, a family of
RNA viruses, and induce oncogenic transformation.
These mammalian cellular genes, known as
oncogenes, have been shown to code for specific
growth factors and their corresponding receptors.
These genes may be amplified (increased number of
gene copies) or mutated, both of which can lead to
constitutive overexpression in malignant cells.
The bcl-2 oncogene may be a generalized prosurvival gene that directly inhibits apoptosis, a key
pathway of programmed cell death.
Another class of genes, known as tumor
suppressor genes, may be deleted or mutated,
which gives rise to the neoplastic phenotype.
The p53 gene is the best-established tumor
suppressor gene identified to date, and the normal
wild-type gene appears to play an important role in
suppressing neoplastic transformation.
Of note, p53 is mutated in up to 50% of all human
solid tumors, including liver, breast, colon, lung,
cervix, bladder, prostate, and skin.

PRINCIPLES IN THE SELECTION OF THE

DRUGS
-

Efficacy
Toxicity
Optimum Scheduling
Mechanism of Interaction
Avoidance of Arbitrary Dose changes

DOSAGE FACTOR
Dose intensity
Dose escalation involves increasing the doses
of the respective anticancer agents
Reducing the interval between treatment
cycles
sequential scheduling

10.
11.
12.
13.
14.
15.

DOSE MODIFICATION IN PATIENTS WITH RENAL OR HEPATIC

DYSFUNCTION
Renal dysfunction (Creatinine clearance is <60
ml/min)
Reduce dose in proportion to reduction in creatinine
clearance
Drugs
a. Methotrexate
b. Cisplatin
c. Carboplatin
d. Bleomycin
e. Etoposide
f.
Hydroxyurea
g. Deoxycoformycin
h. Fludarabine phosphate
i.
2-Cholordeoxyadenosine
j.
Topotecan

I.

Sex
Age
Race
Genetic predisposition
Exposure to environmental carcinogens
most important
exposure to ionizing radiation
chemical carcinogens
viruses
oncogenes
tumor suppressor agents

p53 gene
CELL CYCLE ACTIVE AGENTS
1.
2.
3.
4.
5.
6.
7.
8.
9.

METHOTREXATE
CYTARABINE
5-AZACYTIDINE
PURINE ANALOGS
4.1 6- Mercaptopurine (6-MP)
4.2 6- Thioguanine (6 TG)
FLUDARABINE PHOSPHATE
CLADRIBINE (2-CHLORODEOXYADENOSUME)
PENTOSTATIN (2-DEOXYCOFORMYCIN)
HYDROXYUREA
VINCRISTINE and VINBLASTINE

Hepatic dysfunction
for bilirubin > 15 mg/dl reduce initial dose by 50%
For bilirubin >3.0 mg/dl reduce indial dose by 75%
drugs:
a. Amsacrine
b. Doxorubicin
c. Daunorubicin
d. Vincristine
e. Vinblastine
f.
Paclitaxel
g. Mitoxantrone

II.

NON-CELL CYCLE ACTIVE AGENTS

1.
2.
3.

RISK FACTORS DEPEND ON THE FOLLOWING

1.
2.
3.
4.
5.

PACLITAXEL and DOCETAXEL

CAMPOTHECINS (Irinotecan, Topotecan)
ANTHRACYCLINE ANTIBIOTICS
EPIPODOPHYLLOTOXINS (Etoposides)
BLEOMYCIN
ASPARIGINASE

Alkylating Drugs
Cell-Maturing (Terminal-Differentiating) Agent
Arsenic trioxide

PRIMARY INDUCTION CHEMOTHERAPY

-

refers to drug therapy administered as the primary

treatment for patients who present with advanced
cancer for which no alternative treatment exists.
Mainstaty approach to treat patients with advanced,
metastatic disease
The goals of therapy:
To palliate tumor-relate symptoms
To improve overall quality of life
Prolong time to tumor progression and
survival
CURATIVE CANCERS IN ADULTS

1.
2.
3.
4.

Hodgkins lymphoma
Non-Hodgkins lymphoma
Germ cell cancer
Chorlocarcinoma
CURATIVE CANCERS IN CHILDHOOD

1.
2.
3.
4.

Acute lymphoblastic leukemia

Burkitts Lymphoma
Wilms Tumor
Embryonal Rhabdomyosarcoma

NEOADJUVANT CHEMOTHERAPY
-

Refers to the use of chemotherapy for patients who

present with localized cancer for whch alternative
local therapies such as surgery exist but that they
are less than completely effective.
Administered in the treatment of:
a. anal cancer
b. bladder cancer
c. esophageal cancer
d. non-small cell lung cancer
Optimal
clinical
benefit
is
derived
when
chemotherapy is administered with radiation therapy
either concurrently or sequentially.

ADJUVANT CHEMOTHERAPY
-

Refers to giving patients anti cancer drugs after the

primary tumor has been removed, and there is no
evidence that cancer remails in the body.
This form of treatment initially gained popularity
because it showed promise in improving the survival
for patients with certain cancers
A treatment given along with or after surgery for
cancer to reduce the chances that it will come back.
the theory was that adjuvant chemotherapy would
attack microscopic cancer cells that remained after
tumor removal.

BASIC PHARMACOLOGY OF CANCER

CHEMOTHERAPEUTIC DRUGS
I.
o
o
o

o
o
o
o
o

o
o

II.

ALKYLATING AGENTS
Used as a single agent or in combination
All form covalent bonds with electron-rich sites on
DNA
Involves
intramolecular
cyclization

ethyleneimonium ion directly or through formation

of carboniun ion transfer an alkyl group to a cellular
constituent.
Major site of alkylation is N7 position of guanine
Adverse effects are generally dose related
Major acute toxicities:
a. Myelosuppresion
b. Mucositis
Major delayed toxicities
a. Pulmonary Fibrosis
b. Secondary Leukemia
Cyclophosphamide and ifosfamide produce a toxic
metabolite known as acrolein.

Acrolein
excreted in the urine hemorrhagic cystitis
May
be
detoxified
by
sodium
2mercaptoethane (mesna)
All alkylating agents can produce pulmonary fibrosis.
Rapidly eliminated by chemical conjugation to
sulfhydryl groups or by oxidative mechanism
Examples:
Cyclophosphamde,
ifosfamide, busulfan

Procarbazine potent in inducing secondary

leukemia.

o
o

Highly lipid-soluble and crosses the blood-brain

barrier
Eliminated by the kidneys
Alkylation responsible for cytotoxity appears
O6 position of guanine -> G-C crosslinks in DNA
Lomustine- peak levels: 1-4 hours

III.

NONCLASSIC ALKYLATING AGENTS

1.

PROCARBAZINE

mechanism of action: uncertain

o
Inhibit DNA, RNA and protein biosynthesis.
o
Prolongs interphase
o
Produces chromosome breaks.

Oxidative metabolism azoprocarbazine and water

increase risk of secondary cancer (Acute Leukemia

2.

DACARBAZINE

synthetic compound
parententeral
Treatment of:
a. malignant melanoma
b. Hodgkins lymphoma
c. soft tissue sarcoma
d. neuroblastoma

Main dose-limiting toxicity: MYELOSUPPRESION

nausea, omitting
Potent vesicant

3.

BENDAMUSTINE

is a bifunctional alkylating agent

Purine benzamidazole ring and a nitrogen mustarf
moitety
Cross links with DNA -> single double-breaks ->
inhibition of DNA synthesis and function
treatment for
a. CLL
b. NHL
c. HL
d. MM
e. breast cancer
Dose limiting toxicities : myelosuppresion
mild nausea, vomiting

IV.
o

PLATINUM ANALOGS
There are three platinum analogs:
1.
2.
3.

CISPLATIN
CARBOPLATIN
OXALIPLATIN

o
o
o
o

Mechanism of Action is unclear

Same as alkylating agents
Kill tumor cells in all stages of cell cycle
Bind DNA through formation of intrastrand and
interstrand corss-links -> inhibition of DNA synthesis
and function

1.

CISPLATIN

High dose alkylating agent therapy

NITROSOUREAS

has major antitumor activity in a broad range of solid

tumors, including 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.
When used in combination regimens, cisplatin-based
therapy has led to the cure of nonseminomatous
testicular cancer.
In terms of clinical pharmacology, cisplatin and the
other platinum analogs are extensively cleared by
the kidneys and excreted in the urine.
As a result, dose modification is required in the
setting of renal dysfunction.

2.

CARBOPLATIN

second generation platinum analog

mechanism of action is similar to cisplatin
Less renal and gastrointestinal toxicity

3.

OXALIPLATIN

Oxaliplatin is a third-generation diaminocyclohexane

platinum analog.
Its mechanism of action and clinical pharmacology
are identical to those of cisplatin and carboplatin.
However, tumors that are resistant to cisplatin or
carboplatin on the basis of mismatch repair defects
are not cross-resistant to oxaliplatin, and this finding
may explain the activity of this platinum compound
in colorectal cancer.
Oxaliplatin was originally approved for use as
second-line therapy in combination with the
fluoropyrimidine 5-fluorouracil (5-FU) and leucovorin,
termed the FOLFOX regimen, for metastatic
colorectal cancer.
Main dose-limiting toxicity : neurotoxicity ( Pripheral
sensory neuropathy)

c.
d.
-

2.

PEMETREXED

pyrrolopyrimidine antifolate analog with activity in

the S phase of the cell cycle.
As in the case of MTX, it is transported into the cell
via the reduced folate carrier and requires activation
by FPGS to yield higher polyglutamate forms.
This agent targets DHFR and enzymes involved in de
novo purine nucleotide biosynthesis,
main mechanism of action is inhibition of
thymidylate synthase.
At present, this antifolate is approved for use:
a.
in combination with cisplatin in the treatment of
mesothelioma
b. as a single agent in the second-line therapy of
non-small cell lung cancer
c. and in combination with cisplatin for the first-line
treatment of non-small cell lung cancer.
As with MTX, pemetrexed is mainly excreted in the
urine, and dose modification is required in the setting
of renal dysfunction.
The main adverse effects include:
a. myelosuppression
b. skin rash
c. mucositis
d. diarrhea, and
e. fatigue.
f.
hand-foot syndrome

V.

CELL-CYCLE SPECIFIC AGENTS

ANTIMETABOLITES

A. ANTIFOLATES
1.

METHOTREXATE

used for:
o
maintenance therapy of ALL
o
combination therapy for lymphomas
o
treatment and phrophylaxis for meningeal
leukemia
Inhibits dihydrofolate reductase that leads to:
o
depletion of cellular folate coenzymes
o
inhibition of DNA synthesis
o
cessation of cell replication
Acquired resistance is due to:
o
increased levels of dihydrofolate reductase
via gene amplification
o
Defective polyglutamylation
o
Impaired cellular uptake

absorbed orally 5 to 10 mg
intravenously 25 mg
Secreted primarily unchagend by the kidneys
Contrindication to therapy: renal impairment
Care must also be taken when MTX is used in the
presence of drugs such as
a. aspirin
b. penicillin

cephalosporins, and
nonsteroidal anti-inflammatory agents, as they
inhibit the renal excretion of MTX.
The biologic effects of MTX can be reversed by
administration of the reduced folate leucovorin (5formyltetrahydrofolate) or by L-leucovorin, which is
the active enantiomer.
Leucovorin rescue is used in conjunction with highdose MTX therapy to rescue normal cells from undue
toxicity, and it has also been used in cases of
accidental drug overdose.
Resistance to Methotrexate due to:
o
decreased drug transport via the reduced
folate carrier or folate receptor protein
o
Decrease formation of cytototoxic MTX
polyglutamates
o
Increased levels of the target enzyme DHFR
through gene amplification and other
genetic mechanism
o
Altered DHFR protein with reduced affinity
for MTX
Dose limiting toxicities:
o
myelopsuppresion
o
gastrointestinal effects
mucositis
Diarrhea
Bleeding
Intrathecal methotrexate:
o
may produce:
a. acure arachnoiditis
b. Dementia
c. Seizures
d. coma

B. FLUOROPYRIMIDINES
1.

5-FLUROURACIL

5-Fluorouracil (5-FU) is inactive in its parent form and

requires activation via a complex series of enzymatic
reactions to ribosyl and deoxyribosyl nucleotide
metabolites.
o
One
of
these
metabolites,
5-fluoro-2'deoxyuridine-5'-monophosphate (FdUMP), forms

a covalently ternary complex with the enzyme

thymidylate synthase and the reduced folate
5,10-methylenetetrahydrofolate,
a
reaction
critical for the de novo synthesis of thymidylate.
o
This results in inhibition of DNA synthesis
through "thymineless death."
o
5-FU
is
converted
to
5-fluorouridine-5'triphosphate (FUTP), which is then incorporated
into RNA, where it interferes with RNA
processing and mRNA translation.
o
5-FU is also converted to 5-fluorodeoxyuridine5'-triphosphate
(FdUTP),
which
can
be
incorporated into cellular DNA, resulting in
inhibition of DNA synthesis and function.
o
Thus, the cytotoxicity of 5-FU is thought to be
the result of combined effects on both DNA- and
RNA-mediated events.
Given intravenously
Highly scheduled-dependent
Half-life is 10 -15 minutes
Treatment of colorectal CA
Major toxicities
a. myelosuppression
b. GI toxicity ( mucositis, diarrhea)
c. hadn-foot syndrome
d. neurotoxicity
5-FU remains the most widely used agent in the
treatment of colorectal cancer, both as adjuvant
therapy and for advanced disease.
It also has activity against a wide variety of solid
tumors, including cancers of the breast, stomach,
pancreas, esophagus, liver, head and neck, and
anus.

2.

CAPECITABINE

Capecitabine is a fluoropyrimidine carbamate

prodrug with 7080% oral bioavailability.
It undergoes extensive metabolism :

a.

in the liver by the enzyme carboxylesterase to

an intermediate, 5'-deoxy-5-fluorocytidine.
b. This is converted to 5'-deoxy-5-fluorouridine by
the enzyme cytidine deaminase.
These two initial steps occur mainly in the liver.
The 5'-deoxy-5-fluorouridine metabolite is then
hydrolyzed by thymidine phosphorylase to 5-FU
directly in the tumor.
The expression of thymidine phosphorylase has been
shown to be significantly higher in a broad range of
solid tumors than in corresponding normal tissue,
particularly in breast cancer and colorectal cancer.
This oral fluoropyrimidine is used in the treatment of:
metastatic breast cancer either as a single agent or
in combination with other anticancer agents,
including docetaxel, paclitaxel, lapatinib, ixabepilone,
and trastuzumab.
It is also approved for use in the adjuvant therapy of
stage III and
high-risk stage II colon cancer as well as for
treatment of metastatic colorectal cancer as
monotherapy

C. DEOXYCYTIDINE ANALOGS
1.

CYTRABINE

Cytarabine
(ara-C)
is
an
S
phase-specific
antimetabolite that is converted by deoxycytidine
kinase to the 5'-mononucleotide (ara-CMP).
o
Ara-CMP is
further
metabolized
to
the
diphosphate and triphosphate metabolites, and
the ara-CTP triphosphate is felt to be the main
cytotoxic metabolite.

o
o
o
-

Ara-CTP competitively inhibits DNA polymerase and DNA polymerase-, thereby resulting in
blockade of DNA synthesis and DNA repair,
respectively.
This metabolite is also incorporated into RNA
and DNA.
Incorporation into DNA leads to interference
with chain elongation and defective ligation of
fragments of newly synthesized DNA.
The cellular retention of ara-CTP appears to
correlate with its lethality to malignant cells.

After intravenous administration, the drug is cleared

rapidly, with most of an administered dose being
deaminated to inactive forms.
The stoichiometric balance between the level of
activation and catabolism of cytarabine is important
in determining its eventual cytotoxicity.
parenteral
May be given intrathecally for meningeal leukemia
Usual dose is 100-150 mg/m2, intravenously q12 h
for 5 to 10 days.
Higher doses: neurologic, hepatic, GI toxicities
Patients older than 50 years may develop cerebellar
toxicity, confusion, dementia and death.
Severe conjunctivitis may occur
The clinical activity of this drug is highly scheduledependent and because of its rapid degradation, it
must be given by continuous infusion over a 57 day
period.
Its
activity
is
limited
exclusively
to
hematologicmalignancies,
including
acute
myelogenous
leukemia
and
non-Hodgkin's
lymphoma.
This agent has absolutely no activity in solid tumors.
The main adverse effects associated with cytarabine
therapy include myelosuppression, mucositis, nausea
and vomiting, and neurotoxicity when high-dose
therapy is administered.

2.

GEMCITABINE

is a fluorine-substituted deoxycytidine analog that is

phosphorylated:
a.
initially by the enzyme deoxycytidine kinase to
the monophosphate form and
b. then by other nucleoside kinases to the
diphosphate and triphosphate nucleotide forms.
The antitumor effect is considered to result from
several mechanisms:
o
inhibition of ribonucleotide reductase by
gemcitabine diphosphate, which reduces
the
level
of
deoxyribonucleoside
triphosphates required for DNA synthesis;
o
inhibition by gemcitabine triphosphate of
DNA polymerase- and DNA polymerase-,
thereby resulting in blockade of DNA
synthesis and DNA repair; and
o
incorporation of gemcitabine triphosphate
into DNA, leading to inhibition of DNA
synthesis and function.
Following incorporation of gemcitabine nucleotide,
only one additional nucleotide can be added to the
growing DNA strand, resulting in chain termination.
now widely used to treat a broad range of
malignancies, including:
non-small cell lung cancer
bladder cancer
ovarian cancer
soft
tissue
sarcoma,
and
non-Hodgkin's
lymphoma.
Myelosuppression in the form of neutropenia is the
principal dose-limiting toxicity.
Nausea and vomiting occur in 70% of patients
flu-like syndrome has also been observed.

1.

In rare cases, renal microangiopathy syndromes,

including hemolytic-uremic syndrome and thrombotic
thrombocytopenic purpura have been reported.

D.

PURINE ANTAGONISTS

6- THIOPURINE

6-Mercaptopurine (6-MP)
o
o

o
o
o

was the first of the thiopurine analogs found to

be effective in cancer therapy.
This agent is used primarily in the treatment of
childhood acute leukemia, and a closely related
analog,
azathioprine,
is
used
as
an
immunosuppressive agent
As with other thiopurines, 6-MP is inactive in its
parent form and must be metabolized by
hypoxanthine-guanine
phosphoribosyl
transferase (HGPRT) to form the monophosphate
nucleotide 6-thioinosinic acid, which in turn
inhibits several enzymes of de novo purine
nucleotide synthesis.
The
monophosphate
form
is
eventually
metabolized to the triphosphate form, which can
then get incorporated into both RNA and DNA.
Significant levels of thioguanylic acid and 6methylmercaptopurine ribotide (MMPR) are also
formed from 6-MP.
These metabolites may contribute to its
cytotoxic action.

6-Thioguanine (6-TG)
also inhibits several enzymes in the de novo
purine nucleotide biosynthetic pathway.
o
Various metabolic lesions result, including
inhibition of purine nucleotide interconversion;
decrease in intracellular levels of guanine
nucleotides, which leads to inhibition of
glycoprotein synthesis; interference with the
formation of DNA and RNA; and incorporation of
thiopurine nucleotides into both DNA and RNA.
o
6-TG has a synergistic action when used
together with cytarabine in the treatment of
adult acute leukemia.
6-MP is converted to an inactive metabolite (6thiouric acid) by an oxidation reaction catalyzed by
xanthine
oxidase,
whereas
6-TG
undergoes
deamination.
This is an important issue because the purine analog
allopurinol, a potent xanthine oxidase inhibitor, is
frequently used as a supportive care measure in the
treatment of acute leukemias to prevent the
development of hyperuricemia that often occurs with
tumor cell lysis.
Because allopurinol inhibits xanthine oxidase,
simultaneous therapy with allopurinol and 6-MP
would result in increased levels of 6-MP, thereby
leading to excessive toxicity.
In this setting, the dose of mercaptopurine must be
reduced by 5075%.
In contrast, such an interaction does not occur with
6-TG, which can be used in full doses with allopurinol.
myelotoxic
with
peak
neutropenia
and
thrombocytopenia in 7 days.

3.

CLADRIBINE

2.

Purine analog active in CLL and low grade lymphoma

Mechanism of action:
o
rapidly
dephosphorylated
to
2-fluoroarabinofuranosyladenosine
and
then
phosphorylated intracellularly by deoxycytidine
kinase to the triphosphate.

Cladribine (2-chlorodeoxyadenosine) is a purine

nucleoside analog with high specificity for
lymphoid cells.
Inactive in its parent form, it is initially
phosphorylated by deoxycytidine kinase to the
monophosphate form and eventually metabolized
to the triphosphate form, which can then be
incorporated into DNA.
Cladribine is indicated for the treatment of hairy cell
leukemia, and it also has activity in CLL and lowgrade non-Hodgkin's lymphoma.
It is normally administered as a single continuous 7day infusion; under these conditions, it has a very
manageable safety profile with the main toxicity
consisting of transient myelosuppression.
As with other purine nucleoside analogs, it has
immunosuppressive effects, and a decrease in CD4
and CD8 T cells, lasting for over 1 year

NATURAL PRODUCTS CANCER CHEMOTHERAPY

DRUGS
A. VINCA ALKALOIDS
-

vinca alkaloids binf to microtubules and inhibit

mitotic spindle formation.
Resistance occurs by acquisition of multidrug
resistance phenotype or development of
microtubules with decreased vinca alkaloid binding.

1.

VINCRISTINE

o
o
o

administerd intravenously
metabolized in the liver 70%
Indicated for:
a. NHL
b. HL
c. ALL
d. MM
e. Ewings sarcoma
f.
Wilms tumor
g. Rhabdomyosarcoma
Dose limiting toxicity :

FLUDARABINE
-

The triphosphate metabolite interferes with the

processes of DNA synthesis and DNA repair
through inhibition of DNA polymerase- and DNA
polymerase-.
o
The triphosphate form can also be directly
incorporated into DNA, resulting in inhibition of
DNA synthesis and function.
o
The diphosphate metabolite of fludarabine
inhibits ribonucleotide reductase, leading to
inhibition
of
essential
deoxyribonucleotide
triphosphates.
o
Finally,
fludarabine
induces
apoptosis
in
susceptible cells through as yet undetermined
mechanisms
It is given intravenously
up to 2530% of parent drug is excreted in the urine
The main dose-limiting toxicity is myelosuppression.
This agent is a potent immunosuppressant with
inhibitory effects on CD4 and CD8 T cells.
Patients are at increased risk for opportunistic
infections, including fungi, herpes, and Pneumocystis
jiroveci pneumonia (PCP).
Patients should receive PCP prophylaxis with
trimethoprim-sulfamethoxazole (double strength) at
least three times a week, and this should continue for
up to 1 year after stopping fludarabine therapy.
o

o
o
o

Neurotoxicity(paresthesia of the
fingers and lower legs, loss of deep
tendon reflexs)
Constipation is common
Cranial nerve palsies, ataxia, seizure, coma
Bone marrow suppression is not common

2.

VINBLASTINE

o
o
o

Alkaloid derived from VInca rosea

Metabolized by the liver p450 system
Majority of the drug excreted in the feces via the
hepatobiliary system
Potent vesicant
Adverse effect: Nausea, vomiting, bone marrow
suppression, alopecia
Indicatedn in
a. NHL
b. HL
c. breast cancer

o
o
o

IRINOTECAN, TOPOTECAN
-

antimitotic drugs that bind to microtubules

modest activity on lymphoma

1.

PACLITAXEL
O
alkaloid ester derived from the Pacific yew
(Taxus brevifolia)
O
and the European yew (Taxus baccata).
O
The drug functions as a mitotic spindle poison
through high-affinity binding to microtubules
with enhancement of tubulin polymerization.
O
This promotion of microtubule assembly by
paclitaxel occurs in the absence of microtubuleassociated proteins and guanosine triphosphate
and results in inhibition of mitosis and cell
division.
O
Metabolized by the liver P450 system
O
80% excreted in the feces
O
Hypersensitivity reaction noted in 5% of patients

2.
3.

DOCETAXEL
O
Semisynthetic taxane

A. ANTHRACYCLINES
-

1.

CABAZITAXEL
O
O
O

Intravenously given
Irinotecan should be used with caution in patiens
twith hepatic dysfunction
Topotecan toxicity principally myelosuppresion and
mucositis.

ANTITUMOR ANTIBIOTICS

B. TAXANES AND RELATED DRUGS

-

targets topoisomerase I, preventing resealing of

single strand DNA breaks

isolated from Streptomyces peucetius var caesius,

are among the most widely used cytotoxic anticancer
drugs.
Four major mechanisms:
1. inhibition of topisomeraase II
2. High affinity binding to DNA through
intercalation with consequent blockade of the
synthesis of DNA and RNA and DNA strant
scission.
3. Generation of semiquinolone free radicals and
oxygen free radicals through an iron-dependent
enzyme-mediated reductive process.
4. Binding to cellular membranes to alter fluidity
and iron transport.
Free radicals cause cardiac toxicity
Intravenous
Can produce reaction in previously irradiated tissues
Can produce tissue necrosis if extravasated.
Metabolized in the liver
Acute cardiac effectsL
A. arrhythmia
B. conduction disturbances
C. pericarditis
Chronic cardiac effects: diminished ejection fraction
and congestive heart failure with high mortality.
DOXYRUBICIN
O

Poor substrate for the multi drug resistance

P glycoprotein efflux pump
useful for treating multidrug resistant tumors

O
C. EPIPODOPHYLLOTOXINS

1. ETOPOSIDE
O
O
O
O
O
O
O
O
O
O
O

Semisynthetic derivative
VP-16 binds to DNA and induces double stranded
breaks
Resistance is a result of expression of multidrug
resistance phenotype or diminished drug binding
Orally or intravenously
Clinical activity is scheduled depended
Daily dose for 3-5 days are required.
Single conventional doses are ineffective
Hypotension may occur with rapid intravenous
administration
Major toxicity: LEUKOPENIA
Thrombpcytopenia is less common
May induce secondary AML

D. CAMPOTHECINS

O
O
2.

DAUNORUBICIN
O
O
O

3.

most important anticancer drugs in clinical

practice, with major clinical activity in cancers of
the breast, endometrium, ovary, testicle, thyroid,
stomach, bladder, liver, and lung; in soft tissue
sarcomas
treatment for acute leukemia, HL, Lymphomas,
solid tumors
It is generally used in combination with other
anticancer agents (eg, cyclophosphamide,
cisplatin, and 5-FU), and clinical activity is
improved with combination regimens as opposed
to single-agent therapy.s
usually giver 3-4 weeks
may produce mucositis

First agent to be isolated

still used in the treatment of acute myeloid
leukemia.
Its efficacy in solid tumors appears to be limited.

IDARUBICIN
O
O

Semisynthetic anthracycline glycoside analog

More active than daunorubicin when combined
with cytarabine in producing complete remission
in AML.

4.

O
O
5.

EPIRUBICIN
Adjuvant therapy in early stage, node-positive
breast cancer
Also used in the treatment of metastatic breast
cancer and gastroesophageal cancer

MITOXANTRONE
O
O
O
O

It binds to DNA to produce strand breakage and

inhibits both DNA and RNA synthesis.
It is currently used in the treatment of advanced,
hormone-refractory prostate cancer and lowgrade non-Hodgkin's lymphoma.
It is also indicated in breast cancer and in
pediatric and adult acute myeloid leukemias
A blush discoloration of the fingernails, sclerae,
and urine is observed 1-2 days after drug
administration.

MAIN DOSE LIMITING TOXICITIES OF ALL ANTRHTACYCLINES

-

myelosuppresion, neutropenia, thrombocytopenia

mucositis dose llimiting
two forms of cardiotoxicuty
a. Acute form
o
occurs within 2-3 days
o
transient and asymptomatic
arrhythmias
conduction abnormalities
ECG changes
Pericarditis
Myocarditis
b. Chronic form
o
dose dependent
o
dilated cardiomyopathy associated with
heart failure
o
increased production of free radicals within
the myocardium
o
total doxorubicin dosage: 500-550 mg/m2

Antitumor activity is caused by formation of single

and double- stranded DNA breals
Resistance is a result of:
a. accelerated drug inactivation
b. enhanced DNA repair capacity or
c. decreased drug accumulation.
administered intravenoulsly or intramuscularly
Renal excretion
Major toxicity: pulmonary fibrosis IRREVERSIBLE

D.

ASPARAGINASE

Asparaginase (L -asparagine amidohydrolase) is an

enzyme used to treat childhood ALL.
The drug is isolated and purified from Escherichi coli
or Erwinia chrysanthemi for clinical use.
It hydrolyzes circulating L-asparagine to aspartic acid
and ammonia.
Because tumor cells in ALL lack asparagine
synthetase, they require an exogenous source of Lasparagine.
Thus, depletion of L-asparagine results in effective
inhibition of protein synthesis
The main adverse effect of this agent is a
hypersensitivity reaction manifested by fever, chills,
nausea and vomiting, skin rash, and urticaria.
Severe cases can present with bronchospasm,
respiratory failure, and hypotension.

E. IMATINIB, DASATINIB, & NILOTINIB

1.

IMATINIB MESYLATE
inhibit activity of mutant oncogenic tyrosine kinase
by blocking ATP binding site
Starting dose in CML, chronic phase: 400 mg/day
(oral)
Usally takes 3-9 months to achieve major cytogenetic
response.
Side effects
nausea
vomiting
edema (periorbital)
muscle cramps
diarrhea
headache
abdominal pain

Given to patients with GIST and ALL

B. MITOMYCIN
-

antibiotic
isolated
caespitosus

It undergoes metabolic activation through an

enzyme-mediated
reduction
to
generate
an
alkylating agent that cross-links DNA.
Hypoxic tumor stem cells of solid tumors exist in an
environment conducive to reductive reactions and
are more sensitive to the cytotoxic actions of
mitomycin than normal cells and oxygenated tumor
cells.
It is active in all phases of the cell cycle, and is the
best available drug for use in combination with
radiation therapy to attack hypoxic tumor cells.
Its main clinical use is in the treatment of squamous
cell cancer of the anus in combination with 5-FU and
radiation therapy.
In addition, it is used in combination chemotherapy
for squamous cell carcinoma of the cervix and for
breast, gastric, and pancreatic cancer.
One special application of mitomycin has been in the
intravesical treatment of superficial bladder cancer.
Because virtually none of the agent is absorbed
systemically, there is little to no systemic toxicity
when used in this setting.

from

Streptomyces

2. DASATINIB
-

oral inhibitor of several kinases, including Bcr-Abl,

Src, c-kit, and PDGFR-.
It differs from imatinib in that it binds to the active
and inactive conformations of the Abl kinase domain
overcomes imatinib resistance resulting from
mutations in the Bcr-Abl kinase.

3.

NILOTINIB

is a second generation phenylamino-pyrimidine

molecule that inhibits Bcr-Abl, c-kit, and PDGFR-
tyrosine kinases.
It has a higher binding affinity (up to 20- to 50-fold)
for the Abl kinase when compared with imatinib, and
it overcomes imatinib resistance resulting from BcrAbl mutations.
It is approved for chronic phase and accelerated
phase CML with resistance or intolerance to prior
therapy that included imatinib.

C. BLEOMYCIN
-

Used in combination chemotherapy for HL germ cell

tumors

F.

GROWTH FACTOR RECEPTOR INHIBITORS

1.

2.

CETUXIMAB
o
Binds to the epiderma growth factor receptor
(EGRF)
o
Inhibits downstream EGFR signaling.
o
Enhances response to chemotherapy and
radiotherapy
o
Colorectal CA, Head and Neck
SUNITINIB
o
Inhibits the RTKs, including vascular endothelial
growth factor (VEGF-R1)
o
Inhibition
of
angiogenesis,
invasion
and
metastasis
o
Renal cell CA, GIST
o
Toxicity
a. Hypertension
b. Skin rash
c. fatigue
d. bleeding complications
e. cardiac toxicity
Rituximab Mechanism of Action in RA
CD20
found on pre B cells through plasmacytoid B cells
Not found on hematopoietic stem cells, pro-B cells or
normal plasma cells
RTX
Anti CD20 monoclonal antibody
Induces B-cell death (ADCC, CDC, apoptosis [without
inflammation])

CHEMOTHERAPY
INTENSIVE GLUCOCORTICOID THERAPY
AND/OR VAD
High dose glucocorticoid therapy
(dexamethasone at 40 mg. day PO on
days 1 to 4 each week.
Continuous infusion of VINCRISTINE and
-

DOXORUBIXIN and oral DEXAMETHASONE (VAD)

resistant to MP
Thalidomide + Dexamethasone

BORTEZOMIB (VELCADE)
o Target therapy
o classified as a proteasome inhibitor
o administered as a 3-5 second bolus IV
injection for nin 6-week treatment
cycles.

a.

Cycles 1-4: administered twice weekly (days 1,

4, 8, 11, 22, 25, 29 and 32)
Cycles 5-9 : administered once weeklt (days 1,
8, 22 and 29). At least 72 hours should elapse
between consecutive doses of VELCADE

b.

LENALIDOMIDE

TREATMENT
aim: to achieve complete remission (no
evidence of leukemia in the body and the
marrow)
Four stages
1. Induction therapy
2. CNS prophylaxis
3. Consolidation
4. Maintenance
Induction Therapy
Standard Induction Therapy:
o 4 drug regimen
a. vincristine
b. prednisone
c. anthracycline
d. cyclophosphamide or L
asparaginase
5 drug regimen
a. vincristine
b. prednisone
c. anthraclcine
d. cyclophosphamide
e. L-asparaginase
course is 4-6 weeks
complete remission: 65-85%
rapditiy with which a patients disease enters
complete remission is correlated with
treatment outcome
treatment for at least 3 years
o