Cancer Pharmacology

Lecture Outline

1. Cancer Biology:
What is Cancer?
What are the difference between a normal and cancer cell?
How does cancer take place?

2. Principle and strategy for cancer therapy

3. Anti-Cancer drugs and their Pharmacology

4. Chemotherapy: Pros and Cons

What is a cancer?
Cancer or Neoplasm is an abnormal mass of
tissue as a result of abnormal proliferation of cells.

Neo-plasm: novel swelling mass in the body.

Some neoplasms do not form a tumor

Some blood cancers

such as leukemia don’t
form a tumor, it widely
spread in the
bloodstream and bone
marrow.

Acute myelogenous leukemia

What differences between Cancer
Cells and Normal Cells?
Normal cells

• Committed Cells—divide only a defined number of

times, and are limited in capacity for self-renewal.

• Specialized Cells—carry out organ function and are

incapable of cell division.

• Restricted to its functional area.

Normal and Cancer Cell Structure
Genetic Aberrations

Centromere
Genetic Aberrations
• Chromosomal Translocation
• Chromosomal Deletion
• Gene mutation
Chromosomal Translocation

Philadelphia chromosome
Genetic Aberrations

Gleevec for CML

Distinguish Features of Cancer Cells

•The origin of a tumor is from the existing cells or tissues of the body.
•The tumor grows following its own laws and is not regulated by the existing
laws of biology. ---(Uncontrollably)
•The rate of growth and multiplication > the ordinary healthy cells--(rapid
growth)
•Anaplasia: Generally, cells divide from their embryonic cells into smaller
independent entities. In case of cancer cells, they have the ability to form
the undifferentiated cells back from being differentiated. (undifferentiated)
• Do not perform the tasks carried out by healthy cells. (mal-functional)
• Lose the contact from the tumor from which they originate and can spread
to fresh locations of the body to grow and survive independently. (--
Invasive and metastasis)
• Genetic instability
Causes of Cancer

1. Sex: male>women

2. Age: most cancers in people> 50 YO

3. Race

4. Genetic predisposition

5. Environment—living and
working Chemicals
Viruses

6. Lifestyle—smoking, alcoholism, preserved

food, BBQ…
Polluting Environment
1. Ionizing radiation
-Acute leukemia
-Thyroid cancer
-Breast cancer
-Lung cancer
-Basal cell skin cancers.

2. Chemical exposure:
-azo dyes
-aflatoxins
-asbestos
-benzene
Azo Dyes
• synthetic colours that cont ain an azo group, -N=N-, as part of th e
structure. Azo groups do n ot occur naturally.

• Azo dyes account for appr oximately 60-70% of all dyes used in food
and textile manufacture.

• Most colored textile and le ather articles are treated with azo dy es
and pigments

• Bladder cancer (dye factor y workers, Azo dye workers still have a
tremendous increase in ur othelial cancer
Oncovirus: that induce cancers
DNA Viruses –
Epstein-Barr virus Burkitt's
lymphoma
Hepatitis B virus liver cancer
Human papilloma
virusescervical cancer
Human herpes virus-8 Kaposi
sarcoma

RNA Viruses
Human T lymphotrophic virus
type 1 (HTLV-I), a retrovirus,
 T-cell leukemia.

Hepatitis C virus  liver cancer

Lifestyles

• Smoking --- What Cancer?

• Alcoholism---

• Preserved food---

• BBQ ---
Genetic Aberrations
Genetic Aberrations

• Chromosomal Translocation
• Chromosomal Deletion
• Gene mutation
Chromosomal Translocation

Philadelphia chromosome
Genetic Aberrations

Gleevec for CML

Cancer Therapeutic Modalities
Cancer Therapeutic Modalities

Surgery Isolated solid cancers

Chemotherapy Almost all cases, in combined

with other treatments. It alone
cure 10-15% of all patients.

Radiation therapy Used for half of all cases to

either cure or improve the
symptoms of cancer.

Palliative care Symptom management

The log-kill hypothesis

Infrequent scheduling of treatment

courses with low (1 log kill) dosing and
a late start prolongs survival but does
not cure the patient (i.e., kill rate <
growth rate)

Chemotherapy
More intensive and frequent treatment,
with adequate (2 log kill) dosing and an
earlier start is successful (i.e., kill rate
> growth rate)

Early surgical removal of the primary

tumour decreases the tumour burden.
Chemotherapy will remove persistant
secondary tumours, and the total
duration of therapy does not have to be
as long as when chemotherapy alone is
used.
Cell Cycle and Cancer

Time spent in
each phase

The cell cycle and Cancer: both Normal and Cancer cells must
traverse before and after cell division.
.GURE11.12 The1hr, Image courtesy of Go osle 1maE:es
Cell cycle and anti-cancer drugs
CCS DRUGS
primary action only during
specific phase of the cell cycle final toxicity may be manifested
• plant alkaloids: G2-M
• DNA synthesis inhibitors: S
•only proliferating cells killed
(high growth factor tumors
preferentially eliminated)
•schedule dependent
(duration and timing rather than
dose)
CCNS DRUGS
any phase, including G0, although
during a specific phase
• crosslinking agents
• anthracycline antibiotics
•both proliferating and non-
proliferating cells killed (attack
both high and low growth factor
tumours)
•dose dependent
(total dose rather than schedule)
Resistance to anti-Cancer drugs

1. Resistance to cancer chemotherapeutic drugs is a major limitation

to treatment.

2. PRIMARY RESISTANCE occurs when some inherent

characteristic of the cancer cells prevents the drugs from working;

3. ACQUIRED RESISTANCE occurs when cancer cells become

resistant during treatment.

4. MULTIDRUG RESISTANCE is particularly problematic; this occurs

when tumour cells become cross-resistant to a wide range of
chemically dissimilar agents after exposure to a SINGLE (typically
natural product) drug.
Resistance Mechanisms
The P-Glycoprotein Structure

Encoded by ABCB1 gene.

Multidrug resistance-associated protein 1

Encoded by ABCC1 gene.

A member of the ATP-

binding cassette
transmembrane transporter
that consist 9 mermbers
(MRP1-9).

Overexpression increases
resistance to natural product
drugs such as antracyclines,
vinca alkaloids, taxanes et
al

Function as a drug export

pump.
Factors affecting clinical outcomes
CANCER side PATIENT side

Growth fraction Performance status

(% of cells not in G0) (measured using the
Karnofsky scale)

Doubling time Bone marrow capacity

Type Liver function

Stage Kidney function
Resistance Age
Compliance
Review Questions
• What is the difference between normal cells and cancer
cells?

• What is the Kill-log curve? How does it guide the cancer

therapy?

• What is the importance of the cell cycle and anti-cancer

drugs?

• How do cancer cells develop resistance to anticancer

drugs? How to avoid chemical resistance in anti-cancer
therapy?
 BASIC PHARMACOLOGY OF
CANCER
CHEMOTHERAPEUTIC DRUGS
Classification of Anti-Cancer Drugs
• Alkylating Agents: Cyclophosphamide, Melphelan, Nitrosourea,

Platinum analogs: Cisplatin, Carboplatin

• Antimetabolites: Cytarabine, Fludarabine, Methotrexate

• Plant alkaloids: Camptothecins, Etoposide, Paclitaxel, Vinblastine

• Antitumor antibiotics: Bleomycin, Doxorubicin, Mitomycin

• Hormonal Agents: Flutamide, Leuprolide,Tamoxifen,

• Differential Inducer: Arsenic trioxide, Retinoic acid derivatives

• Gene targeted drugs: Cetuximab, Dasatinib, Gefitinib, Imatinib

• Immunomodulators: including cytokines and growth factors

• Antiangiogenesis drugs: sorafenib, sunitinib, pazopanib

Summary of Mechanisms of Action
Drugs that Prevent DNA Synthesis
1. Classification by Mechanism (labels):
I. Nucleotide synthesis inhibitors
II. Drugs that block DNA synthesizing enzymes
III. Supporting agents
2. Classification by Chemical Class (cards):
I. Antimetabolites (structural analogues of nucleotides):
5 FLUOROURACIL (5-FU), 6-MERCAPTOPURINE,
6 THIOGUANINE, ALLOPURINOL
CAPECITABINE, CYTARABINE
GEMCITABINE, LEUCOVORIN,
METHOTREXATE, PEMETREXED

II. Miscellaneous: HYDROXYUREA

Drugs that Disrupt DNA

I. Crosslinking agents
chemical classes include alkylating agents, natural products
(antibiotics) and miscellaneous

II. Intercalating agents

chemical classes include natural products (anthracyline and other
antibiotics)

III. Drugs that cause strand breaks

chemical classes include natural products (antibiotics and plant
alkaloids) and miscellaneous
 Protein Inhibitors

I. Signal transduction inhibitors: DASATINIB, ERLOTINIB,

GEFITINIB, IMATINIB, LAPATANIB, NILOTINIB, PAZOPANIB,
SORAFENIB, SUNITINIB

• II. L-ASPARAGINASE

• III. Proteosome inhibitor: BORTEZOMIB

• IV. HDAC inhibitor: VORINOSTAT

CELLS AFFECTED BY CYTOTOXIC DRUGS

• Cancer Cells
• Bone marrow (most common dose-limiting complication)
• GI mucosa (nausea and vomiting)
• Hair follicles (alopecia)
• Taste buds (resuling in dysgeusia)
• "Radiation recall reaction" - erythema and desquamation of the skin
at sites of prior (or simultaneous) radiation therapy
– most commonly associated with anthracycline antibiotics (esp.
DOXORUBICIN) but can occur with any cytotoxic drug
• others that produce this reaction in >10% of patients: 5-
FLUOROURACIL/CAPECITABINE, DACTINOMYCIN,
HYDROXYUREA, METHOTREXATE and PACLITAXEL
• Fetus (absolute contraindication in pregnancy)
Treatment strategies

Surgery + Radiotherapy + Chemotherapy

Combined Chemotherapy: various classes of drugs in combination

MP: Melphalan, prednisone
VAD: Vincristine, Adriamycin, dexamethasone
CHOP: Cyclophosphomide, doxorubicin, vincristine, prednisone

Correct selection of drugs in a regimen can result in decreased

development of resistance, synergistic effects and decreased toxic
effects.
Other common chemotherapeutic strategies include pulse and rescue
therapy, recruitment and synchrony.
Cell Recovery and Drug Scheduling

1. Cancer chemotherapeutics are typically given in CYCLES --- to

allow normal cells time to recover from the treatment.
Unfortunately, stopping the drug therapy also allows any remaining
cancer cells to recover --- and develop resistance.
2. In order to reduce the impact of the recovery/resistance problem,
the key principles to antineoplastic drug therapy are:
• Use high doses (including increasing doses during treatment;
called DOSE ESCALATION)
• Minimize recovery intervals
• Employ sequential scheduling during combination
chemotherapy.
I CELL CYCLE SPECIFIC DRUGS I CELL CYCLE NON-SPECIFIC DRUGS

• primary act ion only during specifi c • any phase, including Go, alt hough fi nal t ox icit y
phase of t he cell cycle may be manifest ed during a specifi c phase
• plant alkaloids: GrM • crossli nkinq agent s
• DNA synt hesis inhibit ors: S • ant hracycline ant ibiot ics

• only prolif erat ing cells kill ed (high • bot h prolif erat ing and non-prolif erat ing cells
growth factor tumors preferentially eliminated) kiIled (att ack both high and low growth factor tumours)

• schedule dependent • dose dependent

(durat ion and t iming rat her t han (t otal dose rat her t han schedule)
dose)
Cell Cycle Specifc (CCS) Cell Cycle NonSpecifc (CCNS)
Antimetabolites Alkylating agents
Capecitabine Busulfan
Cytarabine Carmustine
Fludarabine Melphalan
5-Fluorouracil Thiotepa
Gemcitabine
Anthracyclines
Antitumor antibiotic Daunorubucin
Bleomycin Doxorubicin
Idarubicin
Epipodophyllotoxins
Etoposide Antitumor Antibiotics
Teniposide Dactinomycin
Mtomycin
Taxanes
Docetexel Camptothecins
Paclitaxel Irinotecan

Vinca Alkaloids Platinum analogs

Vinblastine Cisplatin
Vincristine Carboplatin
The Role of Drug Combinations
• Efficacy:

• Toxicity:

• Optimum scheduling:

• Mechanism of interaction:

• Avoidance of arbitrary dose changes:

Application of Chemotherapy

• Is curative for some disseminated cancers that have undergone

either gross or microscopic spread by the time of diagnosis.
• Include germ cell cancer, choriocarcinoma, and hematological
malignancies, such as Non-Hodgkin’s lymphoma, Hodgkin’s
lymphoma, acute lymphoblastic leukemia, multiple myeloma, and so
on.
•Chemotherapy + Radiotherapy + Surgery will significantly
increase the cure rate, for several types of solid tumors, including
bladder cancer, breast cancer, esophageal cancer, head and neck
cancer, rectal cancer and osteogenic sarcoma.
•For patients with widespread disseminated disease,
chemotherapy will provide a palliative rather then curative therapy
by improving symptoms and overall quality of life.
Current Chemical Agents

• Signal transduction inhibitors—block the critical signaling pathways

essential for cancer cell growth and proliferation
• Microtubule inhibitors— directed against the mitotic spindle
apparatus
• Differentiation agents– force cancer cells to differentiate into end-
stage cells with little or no proliferative potential
• Anti-metastatic--- perturb surface properties of cancer cells to
reduce invasive and metastatic potential
• Anti-angiogenic agents– inhibit tumor vasculature
• Tumor radiosensitizing agents—increase cancer cell sensitivity to
radiation therapy, protect normal tissue from radiation damage.
• Biological responsive modifiers– alter tumor-host metabolic and
immunologic relationship.
General Concepts

1. The GOAL is to eradicate the cancer cells without

affecting normal tissues  the concept of
DIFFERENTIAL SENSITIVITY).

2. The REALITY is that all cytotoxic drugs affect

normal tissues as well as malignancies  aim for a
favourable therapeutic index.
 Myelomacells
Proteasome inhibitors Cellqde/transcriptlon
Bortezomib Myelomacell

0
CDK lnhlbkors
Carfilzomib PD 03 3 29 91
NPl-00 5 2

0
P27600
CEP-1 87 70 ..... _, AT-75 19
ONX091 2
MLN9 70 8 Telomeraseinhibitors
GRN163L
lmmunomodulatorydrugs l+- -1-- - -----l Aurora kinase inhibitors
Thalidomide MLN8 237
Lenalidomide (CC-6013)
Pomalidomide (CC4047)
Cell surface
Monoclonal Abs
HDACinhibitors i-- -----l ant i -CD38 (HUMAX-C03 8)
Vorinostat (SAHA) ant i! L-6 (CNT03 28)
LBH 589 ant i-CS1 (Elotuzum ab )
Romidepsin BAFF-neutralizingAb
ACY 12 15

mTOR inhbi itors

Temsirolimus {CCl-779)
(Q) Ost eob la sts Cellcytoplasm
HSP90 inhbiitors
'---''-------< (17 AAG; KOS 9 5 3 )

@)
E.e rolimus (RAD001) Pl3K/Akt inhibitors (Perifosine)

Multi-kinase inhibitors
Sorafenib
(@ (PKC inhi bitors [Enzastaurin ]
FTls (Zame stra)

Osteoclasts

BAFFeutralziingAb I- - -, lmmunomodulatorydrugs
ACE 01 1 Anti-KIR antibody
DKK-1 antibody
Vaccination
IKK inhibitors
p38MAPK inhi bito rs
Polyfunctional Alkylating Agents
Alkylation is the transfer of an alkyl group from one molecule to
another.

Receptor Alkyl donor Alkylated

An alkylating antineoplastic agent is an alkylating agent

used in cancer treatment that attaches an alkyl group (CnH2n+1)
to DNA, especially on the guanine base of DNA, at the
number 7 nitrogen atom of the purine ring.
Alkylating agents

Carrier Alkyl group

1. Nitrogen mustards:
Mechlorethamine,Melphalan,Cyclophosphamide,Chlorambu
cil
2. Ethyleneimines: Thiotepa
3. Nitrosoureas: Carmustine,Lomustine
4. Alkylsulfonates: Busulphan
5. Platinum Coordination complexes:
Cisplatin,Carboplatin,Oxaliplatin 55
Nitrogen mustards

Carrier Alkyl group 2

2

3
Melphalan
Chlorambucil

O
P Cl
O
N N Cl . H 2O
H

Cyclophosphamide

56
Structures of alkylating agents

Bis(chloroethyl)amines

Cyclophosphamide Melphalan
Nintrosoureas

Carmustine R=CH2CH2Cl Iormustine R=

(BCNU) (CCNU)
Aziridines Alkysulfonate
Alkylation: Mechanisms

Attach an alkyl group to various cellular constituents:

• DNA—the major attacking subjects: Guanine (N7) , Adenine (N1,
N3), Cytosine (N3) and Guanine (O6).

• Proteins in various groups,

including: Sulfhydryl Amino
Hydrocyl Carboxyl
Phosphate group

• Carbomoylation of lysine residues by nitrosourea through formation

of isocyanates.

• Non cell cycle specific, but preferentially attack cells at late G1 and
S phases, thus blocking cells at G2.
Mechanisms of Alkylating Action in DNA

Attach an alkyl group to Guanine

Fragmented by DNA repair enzymes

Mechanisms of Alkylating Action in DNA
Mechanisms of Alkylating Action in DNA
Resistance to Alkylating agents
• Acquired resistance

1.Increased capability to repair DNA lesions.

2. Decreased transport of the alkylating drug into the cell.

3.Increased production of glutathione and glutathione-associated

proteins, which are needed to conjugate the alkylating agent, or
increased glutathione S-transferase activity, which catalyzes the
conjugation.
 Pharmacological Effects
Oral administration is great clinical value in killing various cancer cells.

Toxicity:
To both cancer cells and normal tissues, especially rapidly growing tissues,
including bone marrow, gastrointestinal tract, reproductive systems.

Nausea and vomitting 30-60 min after administration of mechlorethamine,

cyclophosphamide, or carmustine.

Frequent monitoring of blood classification, -- leukopenia, thrombocytopenia.

As a class, alkylating agents are carcinogenic in nature, and there is an

increased risk of secondary malignancies, especially acute myelogenous
leukemia

Recovery：
Drugs have been stopped to let patients get recovery from the drug toxicity.
Alkylating Mechanism Clinical Acute Delayed
Agent of Action Applications Toxicity Toxicity
Mechlorethamine Forms DNA cross- Hodgkin's and non- Nausea and Moderate
links, resulting in Hodgkin's vomiting depression of
inhibition of DNA lymphoma peripheral blood
synthesis and count; excessive
function doses produce
Chlorambucil Same as above CLL and non- Nausea and severe bone
Hodgkin's vomiting marrow depression
lymphoma with leukopenia,
thrombocytopenia,
Cyclophosphamide Same as above Breast cancer, Nausea and and bleeding;
ovarian cancer, vomiting alopecia and
non-Hodgkin's hemorrhagic
lymphoma, CLL, cystitis occasionally
soft tissue sarcoma, occur with
neuroblastoma, cyclophosphamide;
Wilms' tumor, cystitis can be
rhabdomyosarcoma prevented with
adequate
Bendamustine Same as above CLL, non-Hodgkin's hydration; busulfan
lymphoma is associated with
skin pigmentation,
pulmonary fibrosis,
Melphalan Same as above Multiple myeloma, Nausea and and adrenal
breast cancer, vomiting insufficiency
ovarian cancer

Carmustine Same as above Brain cancer, Nausea and Myelosuppression;

Hodgkin's and non- vomiting rarely: interstitial
Hodgkin's lung disease and
lymphoma interstitial nephritis
Lomustine Same as above Brain cancer Nausea and
vomiting
Mechanisms of Alkylation of DNA Guanine
Cyclophosphamide Metabolism
Nitrosoureas

Non-cross-resistant with other alkylating agents

All require biotransformation by nonenzymatic decomposition

Alkylating and carbamoylating activities

Highly lipid-soluble

Able to cross the blood-brain barrier, making them effective in

the treatment of brain tumors

O6 but not N7 alkylation of guanine, which leads to G-C crosslinks in DNA.

Oral and intravenous injection.

 Non-classic alkylating agents
Procarbazine (Matulane)
Methylhydrazine derivative
Active in Hodgkin's disease (combination therapy)
Teratogenic, mutagenic, leukemogenic.
Side effects:
nausea, vomiting, myelosuppression ; hemolytic anemia ; pulmonary effects
Dacarbazine (DTIC)
Clinical use:
Melanoma ; Hodgkin's disease ; soft tissue sarcoma
Synthetic drug; requires activation by liver microsomal system.
Parenteral administration
Side effects:
nausea, vomiting, myelosuppression
Altretamine (Hexalen)
Clinical use: alkylating agent-resistant: ovarian carcinoma
Activated by biotransformation (demethylation)
Side effects:
nausea, vomiting, central and peripheral nervous system neuropathies.
relatively mild myelosuppressive effects.
Platinum Analogs

Cisplatin Carboplatin Oxaliplatin

1. Inorganic metal complex

2. They kill tumor cells in all stages of the cell cycle
3. Bind DNA through the formation of intrastrand and interstrand cross-links
4. Leading to inhibition of DNA synthesis and function.
5. N7 Guanine, N3 Adenine,O6 cytosine can also occur.
6. Nephrotoxicity acould be attenuated by i.v. saline infusion.
7. Used for NSCLC, GU, gastric, head and neck, ovarian and bladder cancers
8. Synergistic with other anticancer agents :Alkylating agents, taxanes, and
Comparisons of Platinum Drugs

Cisplatin Carboplatin Oxaliplatin

1. NSCLC, GU, NSCLC, GU, Colorectal Cancer

gastric, head and gastric, head and With 5-FU, lecucovorin
neck, ovarian; neck, ovarian;
bladder cancers bladder cancers
myelosuppression, less Reversible peripheral
2. Nephrotoxicity rental/GI toxicity neuropathy; less rental
GI toxicity
toxicity
Not cross-resist to
Cross-resist to Cisplatin
Cisplatin or Carboplatin

Cross-links intrastrand (>90%) or interstrand (<5%).

Inhibition of DNA synthesis and transcription.
Binding to nuclear and cytoplasmic proteins.
,.,n.,,_ 1,: 4'C,CI
..
,.-w
Antimetabolic Agents

1. Structural analogues: Neoplastic cells' metabolic differences --

increased susceptibility to actions of antimetabolites.

2. Most antimetabolites interfere with nucleic acid synthesis or

nucleotide synthesis.

3. Folic acid antagonist: methotrexate, pemetrexed

4. Purine Antagonists: 6-Thiopurines, Fludarabine,

5. Pyrimidine Antagonists: 5-Fluorouracil, Cytarabine,

gemcitabine

6. DNA synthesis (S phase –specific)

74
75
Methotrexate

Folic Acid

Methotrexate
Methotrexate: MOA

1. binds with high affinity to

the active catalytic site of
DHFR.
2. interfering with the
synthesis of
tetrahydrofolate (THF)
3. THF for de novo synthesis
of thymidylate, purine
nucleotides, and the
DHFR amino acids serine and
methionine.
4. DNA, RNA, and key
cellular proteins
Methotrexate: Summary
Mechanism of Action: Folic acid antagonist: acts at catalytic side of
dihydrofolate reductase
Polyglutamate: increases methotrexate duration of action in cancer cells.
Tumor resistance to methotrexate:
1. decreased drug transport into the cell
2. altered dihydrofolate reductase enzyme -- lower affinity for
methotrexate
3. decreased polyglutamate formation
4. quantitative increase in dihydrofolate reductase enzyme
concentration in the cell (gene amplification, increased message)
Adverse effects:
1. Bone marrow suppression
2. Dermatologic
3. GI mucosa
4. Adverse effects reversed by leucovorin (citrovorum factor)
Leucovorin "rescue" may be used in cases of over dosage or in
high-dose methotrexate protocols
Other uses:
Treatment of rheumatoid arthritis
In combination with a prostaglandin: induces abortion
Fluorouracil

1. Uridine derivatives
2. One derivative, 5-fluoro-2'-
deoxyuridine 5'-phosphate (FdUMP),
inhibits thymidylate synthase and its
cofactor,a tetrahydrofolate derivative,
resulting in inhibition of thymidine
nucleotide synthesis.
3. Another derivative, 5-fluorouridine
triphosphate is incorporated into O
RNA, interfering with RNA function. F
NH
4. Cytotoxicity:effects on both RNA
and DNA N O
H

79
80
1. Flurouracil (5-FU), normally given by IV
administration (oral absorption erratic)

2. Clinical Use: Systemically -- adenocarcinomas;

Topically: skin cancer

3. Floxuridine (FUDR): similar to 5-FU, used for

hepatic artery infusion.

4. Major Toxicity: myelosuppression, mucositis.

Cytarabine (ara-C)
IV administration

MOA: S phase-specific antimetabolite

Biotransformed to active forms: ara-CTP, competitive inhibitor
of DNA polymerase.
Blocks DNA synthesis; no effect on RNA or protein synthesis
cytarabine incorporated into RNA and DNA -- interfering with
chain elongation

S phase specificity: highly schedule-dependent

Clinical Use: almost exclusively for acute myelogenous leukemia

AE: nausea, alopecia

stomatitis ,
severe myelosuppression
Natural Products for Cancer Chemotherapy

Plant Alkaloids:
VIncristine, vinblastine, vinorelbine, Etoptosides
Camptothecin

Taxanes: Paclitaxel, Doxetaxel

Anti-tumor antibiotics:
Anthracyclines: doxorubicin, daunorubicin
Mitoxantrone, Dactinomycin
Mitomycin
Bleomycin
Plant Alkaloids

vinca rosea

Resource: plant products, from periwinkle plant—vinca rosea.

Vinorebline: semisynthetic.
Mechanisms of Action

inhibition of tubulin polymerization, which disrupts assembly of

microtubules, an important part of the cytoskeleton and the mitotic
spindle. This inhibitory effect results in mitotic arrest in metaphase,
bringing cell division to a halt, which then leads to cell death.
Applications

Vinblastine Vincristine

Cure for: Cure for:

Hodgkin’s disease Hodgkin’s disease
Non-Hodgkin’s disease Non‐Hodgkin’s disease
Breast cancer ALL in children
Germ cell cancer Multiple Myeloma
Neuroblastoma
Wilm’s tumor…..

AE: Nausea and vomitting AE: Peripheral sensory neuropathy

bone marrow Bone marrow suppression
suppression alopecia
alopecia
Epipodophyllotoxins
Etoposide, VP-16
Teniposide, VM-26
Both are semisynthetic derivatives from mayapple root.

Administration: intravenous and oral formulations

MOA: Block cell cycle in late S-G2 phase

inhibition of topoisomerase II -- DNA damage
Indications:
Etoposide (VP-16,VePe-sid):
NHL, HL, monocytic leukemia
testicular cancer
oat cell lung carcinoma, NSCLC, gastric cancer
Teniposide (Vumon): lymphomas
AE: nausea, Vomiting
Alopecia
significant hematopoietic toxicity and lymphoid toxicity
Camptothecins
• Resource: camptotheca acuminata tree
• MOA: inhibition of topoisomerase I, the key enzyme responsible for
cutting and religating single DNA strands –DNA damage
• Indications:
• Topotecan---
• 2nd line therapy for: Advanced ovarian cancer, small cell lung
cancer
• Irinotecan---metastatic colorectal cancer as a monotherapy
who has failed to 5-FU. Or used as 1st line in combination with 5-
FU and leucovorin
• AE: myelosuppression and diarrhea
Mechanisms of Topotecan and Irinotecan
Taxanes
Paclitaxel

Docetaxel

Semisynthetic from
European Yew tree.
Taxanes: Mechanism of Action

1. Mitotic spindle poison

through high-affinity
binding to microtubules
with enhancement of
tubulin polymerization
2. This promotion of
microtubule assembly by
paclitaxel occurs in the
absence of microtubule-
associated proteins and
guanosine triphosphate
and results in inhibition of
mitosis and cell division.
Taxanes: Applications
A broad range of solid tumors:
ovarian advanced breast non-small cell and small cell
lung
head and neck esophageal prostate
bladder cancers AIDS-related Kaposi's sarcoma.

A novel albumin-bound paclitaxel formulation (Abraxane) is approved

for use in metastatic breast cancer.

Docetaxel :second-line therapy for advanced breast cancer and non-

small cell lung cancer has major activity in head and neck cancer,
small cell lung cancer, gastric cancer, advanced platinum-refractory
ovarian cancer, and bladder cancer.
Antitumor Antibiotics

• From microbes: Streptomyces

• bind to DNA through intercalation between specific bases and block
the synthesis of RNA, DNA, or both
• Cause DNA strand scission; and interfere with cell replication.
• Include the anthracyclines, bleomycin, and mitomycin
Anthracyclines

Idarubicin
Epirubicin
Mitoxantrone.
Anthracyclines

1. inhibition of topoisomerase II;

2. high-affinity binding to DNA through intercalation, with consequent
blockade of the synthesis of DNA and RNA, and DNA strand
scission;
3. generation of semiquinone free radicals and oxygen free radicals
through an iron-dependent, enzyme-mediated reductive process;
4. binding to cellular membranes to alter fluidity and ion transport.
Indications
Doxorubicin—Most used one
• Solid cancers :
breast, endometrium, ovary, testicle, thyroid, stomach, bladder,
liver, and lung
• Soft tissue sarcomas
• Childhood cancers, including neuroblastoma, Ewing's sarcoma,
osteosarcoma, and rhabdomyosarcoma.
• Hematologic malignancies
acute lymphoblastic leukemia
multiple myeloma
Hodgkin's and non-Hodgkin's lymphomas.
Daunorubicin—First identified one
Acute myeloid leukemia.

Limited for solid tumors.

Mitomycin C

• MOA:
Metabolic activation through an enzyme-mediated reduction;
An alkylating agent that cross-links DNA.
Active for all cell cycles.

• Used in combination with radiotherapy:

Hypoxic tumor stem cells , the most sensitive one to MMC.
Squamous cell cancer of the anus
Squamous cell carcinoma of the cervix
Breast, gastric, and pancreatic cancer.
Superficial bladder cancer--intravesical treatment while no systemic
toxicity
• AE:
Hemolytic-uremic syndrome
Microangiopathic hemolytic anemia, thrombocytopenia, and renal
failure, as well as occasional instances of interstitial pneumonitis
Bleomycin
• Features:
Glycopeptide antibiotics isolated from Streptomyces verticillus.
Contains a DNA-binding region and an iron-binding domain
• MOA:
Binding to DNA, which results in single-stranded and double-
stranded breaks following free radical formation
Inhibition of DNA biosynthesis.
DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II)
complex , which leads to chromosomal aberrations.
• Bleomycin is a cell cycle-specific drug that causes accumulation of
cells in the G2 phase of the cell cycle.
• Indications:
Hodgkin's and non-Hodgkin's lymphomas
Germ cell tumor, head and neck cancer, and squamous cell
cancer of the skin, cervix, and vulva.
• Administration: SubQ, intramuscularly, intravenously
• AE: Pulmonary toxicity (Pneumonitis), dose-limiting
Hormonal Agents

• Estrogen inhibitors:
Tamoxifen-- antiestrogen, for breast cancer, endometrial cancer
• Androgen inhibitor:
Flutamide—binds to Androgen receptor; Prostate cancer
Bicalutamide
• Gonadotropin-releasing hormone
agonists: Leuprolide—synthetic peptide,
Goserelin
• Aromatase Inhibitors:
Aminoglutethimide
Anastrozole
• Glucocorticoids
Dexamethasone
Prednisone
Tamoxifen

1. Binds to the ER of the breast tumor

2. Competitive inhibitor of the ER
3. Suppresses IGF1 and TGF-

4. Therapies for:
breast cancer, earlier or metastatic

Prevention for:
Breast cancer
Tamoxifen AE: mild, well tolerated.
Molecularly Targeted Anti-cancer Drugs
PI3K-AKT Signaling

Nature 411, 355-365(2001)

PI3K Pathway Inhibitors
Pertuzumab Bevacizumab

Cetuximab
Gefitinib

PI3K Inhibitors
Dual Inhibitors

AKT Inhibitors

mTOR Inhibitors

Nature Rev Drug Dis., 2009

Genetic Aberrations

Ch22 Ch9

Gleevec for CML

Imatinib (Gleevec)
Imatinib
• MOA: inhibition of the tyrosine kinase Bcl/ABL, prevents its
phosphorylation by ATP.

• Indications:
Approved for Ph+ chronic phase of CML,balst crisis that ahs
progressed on prior interferon .
Gastrointestinal stromal tumors expressing the c-kit tyrosine
kinase
Dasatinib (Sprycel)
The main targets:
BCR/ABL, Src, c-Kit,
ephrin receptors, and
several other tyrosine
kinases, but not erbB
kinases such as EGFR
or Her2.

Oral inhibitor.
Indications: CML , ALL
with Ph+.
AE:
Neutropenia
myelosuppression
Crystal structure of Abl kinase domain
(blue) in complex with dasatinib (red).
Gefitinib (Iresa) and Erlotinib (Tarcera)
1. Gefitinib is an EGFR inhibitor, like erlotinib, which
interrupts signaling through the epidermal growth factor
receptor (EGFR) in target cells. Therefore, it is only
effective in cancers with mutated and overactive EGFR,
such as breast and lung cancers.
2. Is a drug used for certain breast, lung and other cancers.
3. It is not a chemotherapeutic in the traditional sense, since
it does not cause the destruction of tumor cells. Instead,
gefitnib interferes with the growth and spread of new
cancer cells. Anti-tumor but not cytotoxic.
4. Patients who don’t smoke with a bronchoaleolar subtype
have a good resposiveness.
5. Tarcera approved for advanced pancreatic cancer in
combination with gemcitabine.
6. AE: diarrhea, acneifrom skin rash.
Cetuximab
• MOA:
Epidermal growth factor receptor inhibitor.
Chimeric monoclonal antibody directly against the extracellular
domain of EGFR

• Indications:
For metastetic colorectal cancer in combination with irinotecan
or oxaliplatin.
For locally advanced head and neck cancer in combination with
radiation therapy.

• AE: Well tolerated, main adverse effects—acneiform skin rash,

hypersensitivity effects.
Bortezomib
(Velcade)
the first and only FDA approved anti-cancer agent
among proteasome inhibitors
•highly selective Phenylalanine

•Reversible
•26S proteasome complex
•Most effective on Myeloma

•Effects the bone metabolism in MM Pyrazinoic acid

Leucine
•Sensitizes them toward conventional chemotherapy

•Prolongs patients’ survival by overcoming resistance to

conventional drugs.
Proteasome and protein degradation
三酶级联反应
 Binding site of
5AHQ

 antechamber

 Proteolytic
chamber
Binding site of
 Bortezomib

 antechamber
Binding site of
5AHQ

Full 20S proteasome

Applications of Bortezomib

• 1st line for mutliple myeloma

• 2nd line for mantle cell lymphoma

• An overall response rate (ORR) of 84 percent was

observed in one study of VELCADE, cyclophosphamide
and dexamethasone (VcCD) as induction therapy, with a
12.5% CR. (German Group)

• An ORR of 97 percent was observed in a study of

VELCADE, lenalidomide, doxorubicin and
dexamethasone (VcRDD), with a 22% CR and near CR.
Differentiation Inducers

Retinoic acid derivatives

Arsenic trioxide
• Specific for APL, acute promyelocytic leukemia by
induction of terminal differentiation thus losing its ability
to proliferate.
 cAMP-PKA

►
Transcr iptional
repressin
AT R A
I•• D egrada t ion
l
I •

Degradation

Sumoylation
..
-- - >os. Mf.--
.01~2µMI
As0 3
< .05M
cAMP-PKA

- -
t'mitochondrium
2

>O.SµM
' - . _ n - n-reglaution

ROS t---. t \--

PTP {
Bcl-2

AIF -------rpr
opening
Cytochrome C
{
Apaf-1 } .. Caspase - 3
Cas pase- 9
All-trans-Retinoic Acid (ATRA, Tretinoin)

• Specific for APL, acute promyelocytic leukemia by

induction of terminal differentiation thus losing its ability
to proliferate.
Arenic Trioxide (As2O3)

Indications: 2nd line for APL with t(15:17) translocation, refractory to ATRA
or anthracyclines.

MOA: (1) degradation of the chimeric proteinPML/RARa.

(2) mitochondria-dependent cell apoptosis

Administration: intravenous.
AE: fatigue, electrocardiographic changes (QT prolongation), arrhythmias.
Chemotherapy: Pros and Cons

• A broad spectrum : almost all kinds of cancers from all

organs, including Brain cancer, blood cancers, breast
cancer, colon cancer, gastric cancer, lung cancer
cancer, prostate cancer….
• Kill cancer cells that rapidly grow, or specific genetic
presented cancers
• More effective when used in combination with other
drugs or other methods, such as surgery or
radiotherapy.
• No anticancer drugs are perfect that kill cancer cells
only.
• Most adverse effects are:
1.Myelosuppression—anemia, hemorrhage, prone to
infection
2. Somatitis
3. Alopecia
4. Gastrointestinal effects.
Review Questions

1. Classification of anti-cancer drugs

2. Understanding of the mechanisms of action of
the prototype of each class？
3. Is there no toxic effects for molecularly targeted
cancer drugs?
4. Why is it suggestive to use combined therapy?
Give an example of such combined therapy.
The most important indicator of the effectiveness of chemotherapy is:
A. Achievement of a minor response
B. Achievement of a partial response
C. Achievement of a complete response
D. Achievement of stable disease

A partial response is defined as:

A. At least a 50% reduction in measurable tumor mass
B. At least a 10% reduction in measurable tumor mass
C. Improvement in quality of life
D. Improvement in survival

Anticancer activity of bortezomib is due to the inhibition of:

A. Proteasome
B. Bcl-2
C. Thymidylate synthase
D. MDM2
Drug resistance in advanced tumors is thought to be due to:
A. Mutations in important genes in cell-cycle regulation
B. Drug-specific spontaneous mutations
C. Wild-type p53
D. Low tumor growth rate

The final stage of the programmed cell death pathway is mediated by:
A. Bcl-2
B. p53
C. Tumor necrosis factor
D. Caspase cascade

Cyclin-dependent kinases are inhibited by:

A. Bortezomib
B. Cetuximab
C. Flavopiridol
D. Trastuzumab
Which of the following is true regarding the use of time to progression as
an end point in clinical trials?
A. Uses a smaller sample size when compared with using overall survival
as an end point.
B. Not confounded by subsequent therapies.
C. The study can be completed in a shorter amount of time.
D. All of the above.