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
1
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
2
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)
3
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.
4
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
5
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.
7
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
8
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
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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
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
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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
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 Agents
Vincristine,Vinblastine
Paclitaxel, Docetaxel
Cyclophosphamide
Bleomycin
Actinomycin D
M
G0
resting
G2
G1
Hydrocortisone
S
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
H2 N
N
HO
N
N
N
N
O
O
O
N
P
O
NH
N
O
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 arrest and
20
cell death if the crosslink is not repaired.
Alkylating Agents (Covalent DNA binding drugs)
T
A
G
C
C
G
G
T
G
Cancer Chemotherapy
Chapter 55. B.G. Katzung
C
A
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
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:
1.
2.
3.
4.
5.
6.
7.
8.
Breast Cancer
Ovarian Cancer
Non-Hodgkin’s Lymphoma
Chronic Lymphocytic Leukemia (CLL)
Soft tissue sarcoma
Neuroblastoma
Wilms’ tumor
Rhabdomyosarcoma
Cancer Chemotherapy
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25
Cyclophosphamide
Major Side effects
1.
2.
3.
4.
5.
6.
7.
Nausea and vomiting
Decrease in PBL count
Depression of blood cell counts
Bleeding
Alopecia (hair loss)
Skin pigmentation
Pulmonary fibrosis
Cancer Chemotherapy
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 cross-links,
resulting in
inhibition of DNA
synthesis and
function
Hodgkin’s and nonHodgkin’s 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
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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
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30
Summary
Cancer Chemotherapy
Chapter 55. B.G. Katzung
31
Tubulin Binding Agents
Polymerization
Vincristine
tubulin

a
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
32
mitotic arrest.
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, Kaposi’s 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, Kaposi’s 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
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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
MTX
polyglutamates
Are selectively
retained
In tumor cells.
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.
*
Reduced
Folate
Carrier
protein
*
*
*
*
MTX
Kills cells
during
S-phase
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Chapter 55. B.G. Katzung
37
C. Antimetabolites
1. Mechanism of Action
1.
inhibits formation
Methot of FH4
rexate (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.
Cancer Chemotherapy
Chapter 55. B.G. Katzung
2. Clinical application
3. Route
4. Side effects
Choriocarcinoma,
acute
lymphoblastic
leukemia
(children),
osteogenic
sarcoma, Burkitt's
and other nonHodgkin‘s
lymphomas, cancer
of breast, ovary,
bladder, head &
neck
Orally
effecti
ve 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.
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:
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