Pharmacology of Antineoplastic Agents

Outline of Lecture Topics:

Antineoplastic Agents:
a. Cell Cycle Specific (CCS) agents
b. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents

2. Mechanisms of action and side effects

3. Drug Resistance

http://www.ncbi.nlm.nih.gov/pubmedhealth/
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/
http://clinicaltrials.gov/ct2/results?term=cancer

Kishore Wary, Ph.D.

Dept Pharmacology
kkwary@uic.edu
312-413-9582
1

2009 Estimated US Cancer Deaths*

Lung & bronchus

30%

Men
292,540

Women
269,800

26%

Lung & bronchus

15%

Breast

Prostate

9%

Colon & rectum

9%

9%

Colon & rectum

Pancreas

6%

6%

Pancreas

Leukemia

4%

5%

Ovary

Liver & intrahepatic

bile duct

4%

4%

Non-Hodgkin
lymphoma

Esophagus

4%

3%

Leukemia

Urinary bladder

3%

3%

Uterine corpus

Non-Hodgkin
lymphoma

3%

2%

Liver & intrahepatic

bile duct

Kidney & renal pelvis

3%

2%

Brain/ONS

25%

25%

All other sites

ONS=Other nervous system.

Source: American Cancer Society, 2009.

All other sites

Cancer
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:
Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial
cells. 80-90% reported cancer cases are carcinomas.
Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or
supportive tissue.
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.
Lymphoma - cells of the immune system that affects lymphatic system.
Myeloma - B-cells that produce antibodies- spreads through lymphatic system.
Central nervous system cancers - cancers that begin in the tissues of the
brain and spinal cord.
http://www.ncbi.nlm.nih.gov/pubmedhealth/
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/

(*National Cancer Institute, NCI)

Cancer Therapeutic Modalities (classical)

Surgery

Radiation

Chemotherapy

Cancer Chemotherapy
Chapter 55. B.G. Katzung

1/3 of patients without metastasis

Respond to surgery and radiation.
If diagnosed at an 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 chemotherapeutic 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 a 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. 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 dose-limiting 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

Antineoplastic Agents
Alkylating agents
busulfan
carboplatin
carmustine
cisplatin
cyclophosphamide
dacarbazine
ifosfamide
lomustine
mechlorethamine
melphalan
oxaliplatin
procarbazine
temozolomide
thiotepa

Topoisomerase
inhibitors
dactinomycin
daunomycin
doxorubicin
etoposide
etoposide phosphate
idarubicin
irinotecan
liposomal daunomycin
liposomal doxorubicin

mitoxantrone
teniposide
topotecan

Antimetabolites
cytarabine
clofarabine
fludarabine
gemcitabine
mercaptopurine
methotrexate
nelarabine
thioguanine
Tubulin binders
docetaxel
ixabepilone
vinblastine
vincristine
vinorelbine
paclitaxel

Molecularly
targeted
erlotinib
imatinib
sorafenib
sunitinib
tretinoin
Herceptin
Miscellaneous
arsenic trioxide
asparaginase
bleomycin
dexamethasone
hydroxyurea
mitotane
PEG-asparaginase

prednisone
12

Chemotherapy: classification based on the

mechanism of action
Antimetabolites: Interfere with the formation of key biomolecules
including nucleotides, the building blocks of DNA.
Genotoxic Drugs: Alkylate or intercalate the DNA causing the loss of its
function.
Plant-derived inhibitors of mitosis: 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: Inhibit cell division by mechanisms that
are not covered in the categories listed above.

13

Cancer Chemotherapy
Chapter 55. B.G. Katzung

14

CELL CYCLE

G2

G0

G1

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

Cell cycle specificity of Anti-Neoplastic Agents

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

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

16

Pharmacology of Antineoplastic Agents

PART II
2. Mechanisms of action
3. Side Effects
3. Drug Resistance

Cancer Chemotherapy
Chapter 55. B.G. Katzung

17

Chemotherapy: Mechanisms of Action

Topoisomerase Inh.

DNA

Alkylating agents

Purines and
Pyrimidines

RNA
Antimetabolites

Asparaginase

Protein
e.g., 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)

G
T

Cancer Chemotherapy
Chapter 55. B.G. Katzung

1. The first class of chemotherapy

agents.
2. Stop tumor growth by crosslinking 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

Cyclophosphamide
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

Cyclophosphamide
Clinical Applications:
2.
3.
4.
5.
6.
7.
8.
9.

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

Cancer Chemotherapy
Chapter 55. B.G. Katzung

25

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

Cancer Chemotherapy
Chapter 55. B.G. Katzung

26

Ifosphamide
Mechanisms of Action
Similar to cyclophosphamide
Application
4.Germ cell cancer,
5.Cervical carcinoma,
6.Lung cancer
7.Hodgkins and non-Hodgkins lymphoma
8.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 cross-links,
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. Cyclophosphamide

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

Cancer Chemotherapy
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

Bone marrow depression,

pulmonary fibrosis, and
hyperuricemia

c. Nitrosoureas

1. Mechanism of Action

2. Clinical application

3. Route

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
blood-brain barrier

Hodgkins and nonHodgkins lymphoma,

malignant melanoma and
epidermoid carcinoma of
lung

Orally effective

Nausea and vomiting,

Nephrotoxicity, nerve
dysfunction

C. Streptozotocin

DNA damage

pancreatic cancer

Given I.V.

Nausea and vomiting,

nephrotoxicity, liver toxicity

b. Alkyl Sulfonates

29

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. Hexamethylmelamine
(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.

Cancer Chemotherapy
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 function

Hodgkins and non-Hodgkins

lymphoma, brain tumors, breast
carcinoma, chriocarcinoma,
neuroblastoma

I.V.

Nausea and vomiting,

neurotoxicity, thrombocytosis,
hyperuricemia.

2. Antimitotic Drugs

Paclitaxel (Taxol)

1. Mechanism of Action

2. Clinical application

3. Route

4. Side effects

Cytotoxic: binds to tubulin,

promotes microtubule
formation and retards
disassembly; mitotic arrest
results

Melanoma and carcinoma of

ovary and breast

I.V.

Myelodepression and
neuropathy

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, small-cell

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
(ACTINOMYCIN 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 .

fragment DNA chains and

inhibit repair

Germ cell tumors of testes and

ovary, e.g., testicular
carcinoma (can be curative when
used with vinblastine & cisplatin),
squamous cell carcinoma

Given
I.V. or
I.M.

Mucosocutaneous reactions and

pulmonary fibrosis; bone
marrow depression much less than
other antineoplastics

Doxorubicin
(ADRIAMYCIN)

c. Bleomycin
(BLENOXANE)

Inhibit DNA and RNA syntheses

Cancer Chemotherapy
Chapter 55. B.G. Katzung

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 L-asparagine (to

L-aspartic 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

Cancer Chemotherapy
Chapter 55. B.G. Katzung

37

C. Antimetabolites

1.

Methot
rexate

1. Mechanism of Action

2. Clinical application

3. Route

4. Side effects

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

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

Orally
effect
ive as
well
as
given
I.V.

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

Cancer Chemotherapy
Chapter 55. B.G. Katzung

38

2 Pyrimidine Analogs:
Cytosine Arabinoside

2 Purine analogs:
6-Mercaptopurine (6MP) and Thioguanine

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

Orally
effective

bone marrow
depression

1. Mechanism of
Action

2. Clinical application

3. Route

4. Side effects

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 in purine
synthesis by
feedback inhibition

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,

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:
5.Mutation in p53 tumor suppressor gene occurs in 50% of all tumors.
This leads to resistance to radiation therapy and wide range of
chemotherapy.
7.Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon
cancer no longer respond to fluoropyrimidines, the thiopurines, and
cisplatins.
9.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. Early diagnosis is the key.
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. Combination therapy and adjuvant chemotherapy are effective for small
tumor burden.
4. Two major classes of antineoplastic agents are:
a. Cell Cycle Specific and
b. Cell Cycle Non-Specific agents

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.

Drug resistance is often associated with loss of p53 function, DNA

mismatch repair system, and increased MDR1 gene expression.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/

41