Pharmacology of Antineoplastic Agents

Outline of Lecture Topics:

1. Background
2. Antineoplastic Agents: classification
a. Cell Cycle Specific (CCS) agents
b. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents
4. Mechanisms of action
5. Side Effects
6. Drug Resistance

Kishore Wary, Ph.D.

Dept Pharmacology
kkwary@uic.edu

PART I
1. Background
2. Antineoplastic Agents
a. Cell Cycle Specific (CCS) agents
b. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents

Cancer
Definition:
Cancer* is a term used for diseases in which abnormal cells divide without
control and are able to invade other tissues. Cancer cells can spread to other
parts of the body through the blood and lymph systems, this process is called
metastasis.
Categorized based on the functions/locations of the cells from which they
originate:
1.Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial
cells. 80-90% reported cancer cases are carcinomas.
2.Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or
supportive tissue.
3.Leukemia - White blood cells and their precursor cells such as the bone
marrow cells, causes large numbers of abnormal blood cells to be produced and
enter the blood.
4.Lymphoma - cells of the immune system that affects lymphatic system.
5.Myeloma - B-cells that produce antibodies- spreads through lymphatic system.
6.Central nervous system cancers - cancers that begin in the tissues of the
brain and spinal cord.
(*National Cancer Institute, NCI)

Cancer Therapeutic Modalities (classical

1. Surgery

2. Radiation

3. Chemotherapy

Cancer Chemotherapy
Chapter 55. B.G. Katzung

1/3 of patients without metastasis

Respond to surgery and radiation.
If diagnosed at early stage,
close to 50% cancer
could be cured.

50% patients will undergo chemotherapy,

to remove micrometastasis. However,
chemotherapy is able to cure only about 10-15%
of all cancer patients.

New types of cancer treatment

Hormonal Treatments: These drugs are designed to prevent cancer cell growth by
preventing the cells from receiving signals necessary for their continued growth
and division. E.g., Breast cancer tamoxifen after surgery and radiation
Specific Inhibitors: Drugs targeting specific proteins and processes that are limited
primarily to cancer cells or that are much more prevalent in cancer cells.
Antibodies: The antibodies used in the treatment of cancer have been
manufactured for use as drugs. E.g., Herceptin, avastin
Biological Response Modifiers: The use of naturally occuring, normal proteins to
stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmab
Vaccines: Stimulate the body's defenses against cancer. Vaccines usually contain
proteins found on or produced by cancer cells. By administering these proteins,
the treatment aims to increase the response of the body against the cancer cells.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

Cancer Chemotherapy (Background)

A. Most of the recent progress using antineoplastic therapy is based on:
1. Development of new combination therapy of using existing drugs.
2. Better understanding of the mechanisms of antitumor activity.
3. Development of chemotherpeutic approaches to destroying
micrometastases
4. Understanding the molecular mechanisms concerning the initiation of
tumor growth and metastasis.
5. Recognition of the heterogeneity of tumors
B. Recently developed principles which have helped guide the treatment of
neoplastic disease
1. A single clonogenic cell can produce enough progeny to kill the host.
2. Unless few malignant cells are present, host immune mechanisms do not
play a significant role in therapy of neoplastic disease.
3. A given therapy results in destruction of a constant percentage as opposed
to a constant number of cells, therefore, cell kill follows first order kinetics.
6

Cancer Chemotherapy
C. Malignancies which respond favorably to chemotherapy:
1. choriocarcinoma,
2. Acute leukemia,
3. Hodgkin's disease,
4. Burkitt's lymphoma,
5. Wilms' tumor,
6. Testicular carcinoma,
7. Ewing's sarcoma,
8. Retinoblastoma in children,
9. Diffuse histiocytic lymphoma and
10. Rhabdomyosarcoma.

D. Antineoplastic drugs are most effective against rapidly dividing tumor

cells.

E. The Main Goal of Antineoplastic Agents

IS to eliminate the cancer cells without affecting normal tissues (the concept of
differential sensitivity). In reality, all cytotoxic drugs affect normal tissues as
well as malignancies - aim for a favorable therapeutic index (aka therapeutic
ratio).

LD50
Therapeutic Index = ----ED50
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50)
divided by the minimum effective dose for 50% of the population (ED50).

Cancer Chemotherapy
Chapter 55. B.G. Katzung

F. The effects of tumor burden, scheduling, dosing, and

initiation/duration of treatment on patient survival .
Untreated patients
Infrequent scheduling of
treatment courses.
Prolongs survival but does not cure.

More intensive and

frequent treatment.
Kill rate > growth rate.

Early surgical removal of the

primary tumor decreases the tumor
burden. Chemotherapy will remove
persistant secondary tumors.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

General rules of
chemotherapy
Aggressive high-dose chemotherapy

Dose- limiting is toxicity towards normal cells

Cyclic regimens - repeated administrations with
appropriate intervals for regeneration of normal cells
(e.g., bone marrow cells)
Supportive therapy - to reduce toxicity
hematotoxicity bone marrow transplantation,
hematopoietic growth factors
Specific antagonists: antifolate (methotrexate)
folate (leucovorin)
MESNA - donor of SH groups, decreased urotoxicity
of cyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced anthracycline
cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity and
neurotoxicity of alkylating agents
10

General rules of
chemotherapy
Combination of several drugs with different mechanisms of
action, different resistance mechanisms, different doselimiting toxicities.
Adjuvant therapy: Additional cancer treatment given
after the primary treatment to lower the risk that the cancer
will come back. Adjuvant therapy may include
chemotherapy, radiation therapy, hormone therapy,
targeted therapy, or biological therapy.
Neoadjuvant therapy: Treatment given as a first step to
shrink a tumor before the main treatment, which is usually
surgery, is given. Examples of neoadjuvant therapy include
chemotherapy, radiation therapy, and hormone therapy. It is
a type of induction therapy.

11

General rules of
chemotherapy
Supportive therapy:
-Antiemetics (5-HT3 -antagonists)
-Antibiotic prophylaxis and therapy (febrile neutropenia)
-Prophylaxis of urate nephropathy (allopurinol)
-Enteral and parenteral nutrition
-Pain analgesic drugs
-Psychological support

Cancer Chemotherapy
Chapter 55. B.G. Katzung

12

Antineoplastic Agents
Alkylating agents

Topoisomerase
inhibitors

Antimetabolites

Molecularly
targeted

busulfan

dactinomycin

cytarabine

erlotinib

carboplatin

daunomycin

clofarabine

imatinib

carmustine

doxorubicin

fludarabine

sorafenib

cisplatin

etoposide

gemcitabine

sunitinib

cyclophosphamide

etoposide phosphate mercaptopurine

tretinoin

dacarbazine

idarubicin

methotrexate

Herceptin

ifosfamide

irinotecan

nelarabine

Miscellaneous

lomustine

liposomal daunomycin

thioguanine

arsenic trioxide

mechlorethamine

liposomal doxorubicin

melphalan

mitoxantrone

docetaxel

bleomycin

oxaliplatin

teniposide

ixabepilone

dexamethasone

procarbazine

topotecan

vinblastine

hydroxyurea

temozolomide

vincristine

mitotane

thiotepa

vinorelbine

PEG-asparaginase

paclitaxel

prednisone

Tubulin binders

asparaginase

13

Chemotherapy: classification based

on the
mechanism of action
Antimetabolites: Drugs that interfere with the formation of key
biomolecules including nucleotides, the building blocks of DNA.
Genotoxic Drugs: Drugs that alkylate or intercalate the DNA causing the
loss of its function.
Plant-derived inhibitors of mitosis: These agents prevent proper cell
division by interfering with the cytoskeletal components that enable the
cell to divide.
Plant-derived topoisomerase inhibitors: Topoisomerases unwind or
religate DNA during replication.
Other Chemotherapy Agents: These agents inhibit cell division by
mechanisms that are not covered in the categories listed above.
14

Cancer Chemotherapy
Chapter 55. B.G. Katzung

15

Cell cycle specificity of Anti-Neoplastic Agent

Vincristine, Vinblastine
Paclitaxel, Docetaxel

Cyclophosphamide
Bleomycin
Actinomycin D
M

G0

resting

G2

G1

Hydrocortisone

Purine antagonists
Methotrexate
Cyclophosphamide
5-Fluorouracil
Cytosine arabinoside
Daunomycin

Actinomycin D
5-Fluorouracil
Cytosine arabinoside
Methotrexate
6-Mercaptopurine
6-Thioguanine

G0 = resting phase
G1 = pre-replicative phase
G2 = post-replicative phase
S = DNA synthesis
M = mitosis or cell division

16

Pharmacology of Antineoplastic Agents

PART II
4. Mechanisms of action
5. Side Effects
6. Drug Resistance

Cancer Chemotherapy
Chapter 55. B.G. Katzung

17

Chemotherapy: Mechanisms of Action

1
Topoisomerase Inh.

DNA

Alkylating agents

Purines and
Pyrimidines

RNA
Antimetabolites

Asparaginase

Protein
tubulin
Cancer Chemotherapy
Chapter 55. B.G. Katzung

Tubulin binders

18

Major Clinically Useful Alkylating Agents

Bis(mechloroethyl)amines

Nitrosoureas

Cancer Chemotherapy
Chapter 55. B.G. Katzung

Aziridines

19

An Example of DNA Crosslinking

R

O
HN
H2N

HO

O
O

NH
N

NH2
OH

O
P
O

Crosslinking: Joining two or more molecules by a covalent bond. This can

either occur in the same strand (intrastrand crosslink) or in the opposite strands
of the DNA (interstrand crosslink). Crosslinks also occur between DNA and
protein. DNA replication is blocked by crosslinks, which causes replication
20
arrest and cell death if the crosslink is not repaired.

Alkylating Agents (Covalent DNA binding

drugs)

A
G

G
T

Cancer Chemotherapy
Chapter 55. B.G. Katzung

1. The first class of chemotherapy

agents used.
2. They stop tumour growth by
cross-linking guanine
nucleobases in DNA double-helix
strands - directly attacking DNA.
3. This makes the strands unable to
uncoil and separate.
4. As this is necessary in DNA
replication, the cells can no longer
divide.
5. Cell-cycle nonspecific effect
6. Alkylating agents are also
mutagenic and carcinogenic
21

E.g., Mechlorethamine (Nitrogen Mustards)

Cancer Chemotherapy
Chapter 55. B.G. Katzung

22

Cyclophosphamid
e
Cyclophosphamide is an alkylating agent. It is a widely used as
a DNA crosslinking and cytotoxic chemotherapeutic agent.
It is given orally as well as intravenously with efficacy.
It is inactive in parent form, and must be activated to cytotoxic
form by liver CYT450 liver microsomaal system to 4Hydroxycyclophamide and Aldophosphamide.
4-Hydroxycyclophamide and Aldophosphamide are delivered to
the dividing normal and tumor cells.
Aldophosphamide is converted into acrolein and
phosphoramide mustard.
They crosslink DNAs resulting in inhibition of DNA synthesis23

Cyclophosphamide Metabolism
Inactive

24

Cyclophosphamid
e
Clinical Applications:
1.
2.
3.
4.
5.
6.
7.
8.

Breast Cancer
Ovarian Cancer
Non-Hodgkins Lymphoma
Chronic Lymphocytic Leukemia (CLL)
Soft tissue sarcoma
Neuroblastoma
Wilms tumor
Rhabdomyosarcoma

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Chapter 55. B.G. Katzung

25

Cyclophosphamid
e
Major Side effects
1. Nausea and vomiting
2. Decrease in PBL count
3. Depression of blood cell counts
4. Bleeding
5. Alopecia (hair loss)
6. Skin pigmentation
7. Pulmonary fibrosis

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Chapter 55. B.G. Katzung

26

Ifosphamide
Mechanisms of Action
Similar to cyclophosphamide
Application
1.Germ cell cancer,
2.Cervical carcinoma,
3.Lung cancer
4.Hodgkins and non-Hodgkins lymphoma
5.Sarcomas
Major Side Effects
Similar to cyclophosphamide

27

A. Alkylating agents
1. Mechanism
of Action

2. Clinical
application

3. Route

4. Side effects

A.
Mechlorethamine

DNA crosslinks, resulting

in inhibition of
DNA synthesis
and function

Hodgkins and nonHodgkins lymphoma

Must be
given Orally

Nausea and vomiting,

decrease in
PBL count, BM
depression, bleeding,
alopecia, skin
pigmentation,
pulmonary fibrosis

B.
Cyclophosphamid
e

Same as above

Breast, ovarian, CLL,

soft tissue sarcoma,
WT, neuroblastoma

Orally and
I.V.

Same as above

C. Chlorambucil

Same as above

Chronic lymphocytic
leukemia

Orally
effective

Same as above

D. Melphalan

Same as above

Multiple myeloma,
breast, ovarian

Orally
effective

Same as above

E. Ifosfamide

Same as above

Germ cell cancer,

cervical carcinoma,
lung, Hodgkins and
non-Hodgkins
lymphoma, sarcomas

Orally
effective

Same as above

a. Nitrogen
Mustards

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Chapter 55. B.G. Katzung

28

A. Alkylating agents
1. Mechanism of
Action

2. Clinical
application

3. Route

4. Side effects

A. Busulfan

Atypical alkylating
agent.

Chronic granulocytic
leukemia

Orally effective

c. Nitrosoureas

1. Mechanism of
Action

2. Clinical
application

3. Route

Bone marrow
depression, pulmonary
fibrosis, and
hyperuricemia
4. Side effects

A. Carmustine

DNA damage, it can

cross blood-brain
barrier

Hodgkins and nonHodgkins lymphoma,

brain tumors, G.I.
carcinoma

Given I.V. must

be given
slowly.

Bone marrow
depression,
CNS depression, renal
toxicity

B. Lomustine

Lomustine alkylates
and crosslinks DNA,
thereby inhibiting
DNA and RNA
synthesis. Also
carbamoylates DNA
and proteins, resulting
in inhibition of DNA
and RNA synthesis
and disruption of RNA
processing. Lomustine
is lipophilic and
crosses the bloodbrain barrier

Hodgkins and nonHodgkins lymphoma,

malignant melanoma
and epidermoid
carcinoma of lung

Orally effective

Nausea and vomiting,

Nephrotoxicity, nerve
dysfunction

DNA damage

pancreatic cancer

b. Alkyl
Sulfonates

C. Streptozotocin

Given I.V.

29
Nausea and vomiting,

A. Alkylating agents
d. Ethylenimines

1. Mechanism of
Action

2. Clinical
application

3. Route

4. Side effects

A. Triethylene
thiophosphoramide
(Thio-TEPA)

DNA damage,
Cytochrome
P450

Bladder cancer

Given I.V.

Nausea and vomiting,

fatigue

B.
Hexamethylmelami
ne
(HMM)

DNA damage

Advanced ovarian
tumor

Given orally
after food

Nausea and vomiting,

low blood counts,
diarrhea

d. Triazenes

1. Mechanism of
Action

2. Clinical
application

3. Route

4. Side effects

A. Dacarbazine
(DTIC)

Blocks, DNA, RNA

and protein
synthesis

Malignant Melanoma,
Hodgkins and nonHodgkins lymphoma

Given I.V.

Bone marrow
depression,
hepatotoxicity,
neurotoxicity, bleeding,
bruising, blood clots,
sore mouths.

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Chapter 55. B.G. Katzung

30

Summary

Cancer Chemotherapy
Chapter 55. B.G. Katzung

31

Tubulin Binding
Agents
Polymerization
Vincristine

tubulin

Depolymerization
Paclitexal (taxol)

e.g., Vincristine,
Vinblastine, Vindesine
Vinorelbine: Inhibition
of mitotic spindle
formation by binding to
tubulin.
M-phase of the cell
cycle.

e.g., Paclitexal: binds

to tubulin, promotes
microtubule formation
and retards
disassembly; results in
mitotic arrest.
32

B. Natural Products
1. Antimitotic Drugs
1. Mechanism of
Action

2. Clinical application

3. Route

4. Side effects

A. Vincristine

Cytotoxic: Inhibition
of mitotic spindle
formation by binding
to tubulin.
M-phase of the cell
cycle.

Metastatic testicular
cancer, Hodgkins and
non-Hodgkins lymphoma,
Kaposis sarcoma, breast
carcinoma,
chriocarcinoma,
neuroblastoma

I.V.

Bone marrow depression,

epithelial ulceration, GI
disturbances,
neurotoxicity

B. Vinblastine

Methylates DNA and

inhibits DNA
synthesis and
Drugs
function

Hodgkins and nonHodgkins lymphoma,

brain tumors, breast
carcinoma,
chriocarcinoma,
2. Clinical application
neuroblastoma

I.V.

Nausea and vomiting,

neurotoxicity,
thrombocytosis,
hyperuricemia.

3. Route

4. Side effects

Melanoma and
carcinoma of ovary and
breast

I.V.

Myelodepression and
neuropathy

2. Antimitotic

1. Mechanism of
Action
Paclitaxel (Taxol)

Cytotoxic: binds to
tubulin, promotes
microtubule formation
and retards
disassembly; mitotic
arrest results

33

3. Epipodophyllotoxins (These are CCS)

Act on Topoisomerase II

1. Mechanism of
Action

2. Clinical application

3. Route

4. Side effects

A. Etoposide

Binds to and inhibits

Topoisomerase II and
its function.
Fragmentation of DNA
leading to cell death,
apoptosis.

Testicular cancer, smallcell lung carcinoma,

Hodgkin lymphoma,
carcinoma of breast,
Kaposis sarcoma
associated with AIDS

I.V.

Myelosuppression,
alopecia

B. Teniposide

Same as above

Refractory acute
lymphocytic leukemia

I.V.

Myelosuppression,

Accumulation of
single- or doublestrand DNA breaks,
the inhibition of
DNA replication and
transcription, and
apoptotic cell death.

Etoposide acts
primarily in the
G2 and S
phases of the
34
cell cycle

4. Antibiotics (CCS)
1. Mechanism of
Action

2. Clinical application

3.
Route

4. Side effects

a.
Dactinomycin
(ACTINOMYCI
N D)

It binds to DNA and

inhibits RNA
synthesis, impaired
mRNA production, and
protein synthesis

Rhabdomyosarcoma and
Wilm's tumor in children;
choriocarcinoma (used
with methotrexate

I.V.

Bone marrow depression,

nausea and vomiting,
alopecia,
GI disturbances, and
ulcerations of oral mucosa

b.
Daunorubicin
(CERUBIDIN)

inhibit DNA and RNA

synthesis

Acute
lymphocytic/granulocytic
leukemias; treatment of
choice in nonlymphoblastic
leukemia in adults when
given with cytarabine

I.V.

Side effects: bone marrow

depression, GI disturbances
and cardiac toxicity (can be
prevented by dexrazoxane)

inhibit DNA and RNA

synthesis

Acute leukemia, Hodgkin's

disease, non Hodgkin's
lymphomas (BACOP
regimen), CA of breast &
ovary,
small cell CA of lung,
sarcomas, best available
agent
for metastatic thyroid CA

I.V.

Cardiac toxicity, Doxorubicin

mainly affects the heart
muscles, leading to
tiredness or breathing
trouble when climbing stairs
or walking, swelling of the
feet .

Doxorubicin
(ADRIAMYCIN
)

c. Bleomycin
(BLENOXANE)

fragment DNA chains

and inhibit repair

Cancer Chemotherapy
Chapter 55. B.G. Katzung

Germ cell tumors of testes

Given
and ovary, e.g., testicular
I.V. or
carcinoma (can be curative I.M.
vinblastine
Inhibitwhen
DNAused
andwith
RNA
syntheses
& cisplatin), squamous cell
carcinoma

Mucosocutaneous reactions
and pulmonary fibrosis;
bone
marrow depression much
less than other
antineoplastics
35

5. Enzymes: L-asparaginase

L-asparaginase

Cancer Chemotherapy
Chapter 55. B.G. Katzung

1. Mechanism of
Action

2. Clinical application

3.
Route

4. Side effects

Hydrolyzes Lasparagine (to Laspartic acid) an

essential amino acid
to many leukemic
cells

Acute lymphocytic
leukemia, induction of
remission in acute
lymphoblastic leukemia
when
combined with
vincristine, prednisone,
and anthracyclines

I.V. or
I.M.

Nausea and vomiting, Poor

appetite, Stomach
cramping, Mouth sores,
Pancreatitis. Less common:
blood clotting

36

C. Antimetabolites

(Folic acid analog)

Folic acid is a growth factor that provides single

carbons to the precursors used to form the
nucleotides used in the synthesis of DNA and
RNA. To function as a cofactor folate must be
reduced by DHFR to THF.

MTX
polyglutamates
Are selectively
retained
In tumor cells.

Reduced
Folate
Carrier
protein

*
MTX
Kills cells
during
S-phase

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Chapter 55. B.G. Katzung

37

C. Antimetabolites

1.

Meth
otrex
ate

1. Mechanism of Action

2. Clinical application

3.
Route

4. Side effects

inhibits
formation of
FH4
(tetrahydrofolat
e) from folic
acid by
inhibiting the
enzyme
dihydrofolate
reductase
(DHFR); since
FH4 transfers
methyl groups
essential to
DNA synthesis
and hence DNA
synthesis
blocked.

Choriocarcinom
a, acute
lymphoblastic
leukemia
(children),
osteogenic
sarcoma,
Burkitt's and
other nonHodgkins
lymphomas,
cancer of
breast, ovary,
bladder, head
& neck

Orall
y
effec
tive
as
well
as
give
n I.V.

bone marrow
depression,
intestinal
lesions and
interference
with
embryogenesis.
Drug
interaction:
aspirin and
sulfonamides
displace
methotrexate
from plasma
proteins.

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Chapter 55. B.G. Katzung

38

2 Pyrimidine
Analogs: Cytosine
Arabinoside

1. Mechanism
of Action

2. Clinical application

3. Route

4. Side effects

inhibits DNA
synthesis

most effective agent for induction

of remission in acute myelocytic
leukemia; also used for induction
of remission acute lymphoblastic
leukemia,
non-Hodgkin's lymphomas;
usually used in combination
chemotherapy
2. Clinical application

Orally
effective

bone marrow
depression

3. Route

4. Side effects

most effective agent for induction

of remission in acute myelocytic
leukemia; also used for induction
of remission acute lymphoblastic
leukemia,
non-Hodgkin's lymphomas;
usually used in combination
chemotherapy

Orally
effective

bone marrow
depression,

1. Mechanism
of Action
2 Purine analogs:
6-Mercaptopurine
(6-MP) and
Thioguanine

Blocks DNA
synthesis by
inhibiting
conversion of
IMP to AMPS and
to XMP as well as
blocking
conversion of
AMP to
ADP; also blocks
first step in
purine synthesis.
Feedback
inhibition
blocks DNA
synthesis by
inhibiting
conversion of IMP
to
XMP as well as
GMP to GDP; also
blocks first step

39

6. Drug Resistance
One of the fundamental issue in cancer chemotherapy is the development
of cellular drug resistance. It means, tumor cells are no longer respond to
chemotherapeutic agents. For example, melanoma, renal cell cancer,
brain cancer often become resistant to chemo.
A few known reasons:
1.Mutation in p53 tumor suppressor gene occurs in 50% of all tumors. This
leads to resistance to radiation therapy and wide range of chemotherapy.
2.Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon
cancer no longer respond to fluoropyrimidines, the thiopurines, and
cisplatins.
3.Increased expression of multidrug resistance MDR1 gene which
encodes P-glycoprotein resulting in enhanced drug efflux and reduced
intracellular accumulation. Drugs such as athracyclines, vinca alkaloids,
taxanes, campothecins, even antibody such as imatinib.

Cancer Chemotherapy
Chapter 55. B.G. Katzung

40

Summary
1. The main goal of anti-neoplastic drug is to eliminate the cancer cells
without affecting normal tissues.
2. Log-Kill Hypothesis states that a given therapy kills a percentage of
cells, rather then a constant number, therefore, it follows first order
kinetics. Aim for a favorable therapeutic index.
3. Early diagnosis is the key.
4. Combination therapy and adjuvant chemotherapy are effective for small
tumor burden.
5. Two major classes of antineoplastic agents are:
a. Cell Cycle Specific and
b. Cell Cycle Non-Specific agents
5. Because chemotherapeutic agents target not only tumor cells, but also
affect normal dividing cells including bone marrow, hematopoietic, and
GI epithelium. Know what the side effects are.
6. Drug resistance is often associated with loss of p53 function, DNA
mismatch repair system, and increased MDR1 gene expression.

41