ANTICANCER

Akhmad Edy Purwoko

Pharmacology & Toxicology Dept.
Medical Faculty MUY
17/12/2010

KNOWLEDGE BASE
BASIC BIOLOGY OF CELLS
Molecular/Cellular-intervention /therapies
(Pharmacodynamic & Pharmacokinetic)
Single organ/Organ system-Therapeutic
intervention
Pharmacological interventions
Potential side effects of pharmacological
intervention
Manifestation of drug toxicity

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Terminology and General

Principles of Therapy

The anticancer drugs

usually follow the
antimicrobials. This is
because the drugs, in many
cases, are similar. In
antimicrobial therapy, the
object is to kill the invading
bacteria without harming
the host. In anti-cancer
therapy, the object is to kill
the cancer cells without
harming the normal cells.

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Mechanism of action

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Antimetabolite
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Antimetabolite

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Anticancer therapy is
aimed at killing
dividing cells. The log
kill is an important
concept to understand.
The anticancer drugs
kill a constant fraction
of cells instead of an
absolute number

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% of surviving cells

Log scale of drug concentration

There is a linear relationship

between the concentration of an
anticancer drug and the number
of surviving cells, when the
number of cells is plotted on a
log scale. This means that the
anticancer drugs act by
first-order kinetics. A constant
fraction of cells is killed by each
dose of drug.

Drug Resistance
Drug resistance to anticancer drugs is analogous to

resistance to antimicrobials
Drug resistance is a major problem in cancer chemotherapy.
Mechanisms of resistance include following:
Increased DNA Repair
Formation of trapping agent
Changes in target enzymes
Decreased activation of prodrugs
Inactivation of anticancer
Decreased drug accumulation
(increase thiol trapping agent eg glutatione)

(dyhidrofolate reductase)

decrease tumor cell enzyme activity to convert prodrugs

increased enzyme activity of metabolism

increased expression of a normal gene (MDR1 gene) for a cell surface

glycoprotein increase the efflux of druga

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Adverse Effects

Bone marrow toxicity is caused by

destruction of proliferating hematopoietic
stem cells. This results in a decrease in all
blood elements, including white cells and
platelets.
Gastrointestinal toxicity takes two
forms. The nausea and vomiting associated
with cancer chemotherapy is felt to be due
to a central effect. These drugs can also
directly damage the proliferating
mucosa of the GI tract.

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Most anticancer drugs damage hair

follicles and produce hair loss.
Renal tubular damage is the major side
effect of cisplatin and high-dose
methotrexate. Cyclophosphamide can
cause hemorrhagic cystitis.
Cardiotoxicity is associated with the use
of doxorubicin and daunorubicin (the
anthracyclines).

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 Bleomycin

can cause pulmonary fibrosis,

which can be fatal.
Vincristine is known for its nervous system
toxicity.

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James Olson, MD.,PhD

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Organization of Class

Cytotoxic drugs-drugs which block cell replication

Alkylating agents, including nitrogen mustards and
nitrosoureas Antimetabolites, including folate
antagonists, purine, and pyrimidine analogues
Antibiotics and other natural products, including
anthracyclines and vinca alkaloids Antibodies to
improve specificity Other cytotoxic drugs

Hormonal agents-drugs for hormone-sensitive

tumors
Miscellaneous agents

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Kinase inhibitors, including imatinib and getitinib

Proteasome inhibitor-bortezomib

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Cytotoxic Drugs
ALKYLATING AGENTS
Alkylating agents all work by adding an alkyl group to DNA.

Nitrogen mustards chlorambucil

cyclophosphamide ifosfamide mechlorethamine
(nitrogen mustard) melphalan
Nitrosoureas carmustin lomustine
Other alkylating agents busulphan carboplatin
cisplatin carboplatin dacarbazine temozolomide
thiotepa

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ANTIMETABOLITES

Methotrexate competitively inhibits dihydrofolate

reductase.
Leucovorin provides reduced folate to "rescue"
normal cells from the action of methotrexate.
Purine analogues
Cladribine, fludarabine, mercaptopurine (6- mercaptopurine )
pentostatin, thioguanine (6-thioguanine)

Pyrimidine analogues
capecitabine (prodrug for 5-FU) cytarabine (cytosine
arabinoside, ara-C) fluorouracil (5-FU) gemcitabine

The purine and pyrimidine analogues all have to be activated

(phosphory-lated) before they are effective

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Action

Sintesis

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 ANTIBIOTICS AND OTHER NATURAL PRODUCTS

Anthracyclines, daunorubicin (daunomycin),

doxorubicin, epirubicin, idarubicin

Other antibiotics bleomycin,dactinomycin

(actinomycin D) mitomycin (mitomycin C) plicamycin
(mithramycin)

Vinca alkaloids vinblastine vincristine vinorelbine

Other natural products docetaxel paclitaxel
etoposide teniposide irinotecan

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ANTIBODIES

alemtuzumab-CD52
bevacizumab-vascular endothelial
growth factor cetuximab-epidermal
growth factor receptor gemtuzumab
ozogamicin-CD33
ibritumomab tiuxetan labeled with
yttrium 90-CD20 tositumomab labeled
with I-131-CD20 trastuzumab-HER2

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OTHER CYTOTOXIC DRUGS

Asparagmase, hydroxyurea,
mitotane, mitoxantrone,
procarbazine (N-methyl-hydrazine,
? alkylating)

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 HORMONAL AGENTS

Glucocorticoids
Aromatase Inhibitors anastrozole, exemestane,
formestane, letrozole

Estrogens! Antiestrogens fulvestrant tamoxifen

citrate, toremifene

Androgen receptor antagonists bicalutamide,

flutamide, nilutamide

GnRH Analogs and Antagonists abarelix (antagonist)

gosrelin (analog) leuprolide (antagonist) triptorelin (analog)

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 Aromatase

inhibitors block estrogen

formation and are used to treat
estrogen-dependent tumors (breast cancer)
resistant to tamoxifen.
Tamoxifen and toremifene are competitive
antagonists of the estrogen receptor, used
in the treatment of breast cancer.

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The "lutamides" are competitive

testosterone antagonists that are
used to treat prostate cancer.
Both GnRH analogs and antagonists
will decrease serum levels of
estrogen and testosterone and are
used to treat androgen-dependent
prostate cancer.

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 MISCELLANEOUS AGENTS
Gefitinib and erlotinib are inhibitors of the
tyrosine kinase linked to epidermal growth
factor receptor.
Imatinib inhibits the Bcr-Abl tyrosine kinase
found in chronic myelogenous leukemia
(CML).

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Strategies in Cancer
Chemotherapy
Principles of combination therapy

to achieved

synergistic effect increases log kill

Each drug should be active when used

alon against the particular cancer
The drugs should be different
mechanism of action
Cross-resistance between drugs should
be minimal
The drugs should be different toxic
effects
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Additional Strategies

Pulse Therapy
Recruitment and synchrony
Rescue Therapy

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