Kemoterapi

dr.
Reza Furqon S
Cancer chemotherapy
Growth fraction
`Proliferating cells , Non-proliferating cells
Mechanisms of Antineoplastic Drugs

Toxicity of Antineoplastic Drugs
Classification of Antineoplastic Drugs
phase of proliferation cycle source and
action mechanisms
Principles of combination therapies
Cancer chemotherapy
cancer menjadi penyebab kematian 20 25 %
Prinsip metode :
operation
Radiotherapy
chemotherapy.
Differing from the operation and
radiotherapy that emphasize on the

treatment of local tissues, the
chemotherapy is concerned with that of
the whole body.
chemotherapy
Chemotherapy is the use of drugs to
inhibit or kill proliferating cancer cells,

while leaving host cells unharmed, or at
least recoverable.
Growth fraction
Tumor cells can be classified as proliferating
cells and non-proliferating cells.

The ratio of proliferating cells in the whole tumor
tissue is called growth fraction (GF).

The faster the tumor cells proliferate, the bigger
the GF is and the higher the sensitivity of tumor

to a drug is.
Generally, in the early stage, the GF of a tumor is
bigger and the effect of a drug on the tumor is
better.
Proliferating cells
Based on the DNA changes in cells, proliferating cycle of

tumor cells can be divided into 4 phases
Pre-synthetic phase (Gap 1 phase or G 1 phase). cells chiefly
make preparations for the synthesis of DNA.

Synthetic phase (S phase), cells are synthesizing their DNA.
Post-synthetic phase (Gap 2 phase or G 2 phase). DNA
duplication has been finished and they are equally divided

to the two of future sub-cells.
Mitosis phase (M Phase). each cell is divided into two sub-
cells. Some of these new cells enter the new proliferating

cycle, the others become non-proliferating cells.
Proliferating cells
Proliferating
Proliferating cells
cells
7
7
Non-proliferating cells
Non-proliferating cells include G 0 phase cells
(resting-phase cells),
G0 phase cells have proliferation ability but do not
divide temporally.
When proliferating cells are suffered heavy
casualties, G0 phase cells will get into proliferating

cycle and become the reasons of tumor recurrence.
G0 phase cells are usually not sensitive to
antineoplastic drugs, which is the important

obstacle to tumor chemotherapy.
Mechanisms of Antineoplastic Drugs
Most antineoplastic drugs act on the proliferating cycle
of cell
1. Destruction of DNA or inhibition of DNA duplication
2.
3.
4.
5.
(alkylating agents, mitomycin C )

Inhibition of nucleic acid (DNA and RNA) (e.g. 5fluorouracil, 6-mercaptopurine, methotrexate,
cytarabine, etc.)
Interfering with the transcription to inhibit RNA synthesis
( e.g. dactinomycin, dauoruicin, and doxorubicin )
Inhibition of protein synthesis (e.g. vinca alkaloids,
epipodophylotoxins, and paclitaxel )
Interfering with hormone balance (e.g. adrenal
corticosteroids, estrogens, tamoxifen etc. )
Short-term toxicity
Common side reactions usually appear

earlier and many of them occur in rapidproliferating tissues such as marrow,
gastrointestinal tract, and hair follicle.
Myelosuppression,
gastrointestinal tract symptom
alopecia
Long-term toxicity
The long-term toxicity mainly occurs in the

patients who received chemotherapy many
years ago.
Carcinogenesis
teratogenesis
sterility.
On the basis of antineoplastic action on
the phase of proliferation cycle, drugs are

classified as:
cell cycle non-specific agents (phase nonspecific agents, CCNSA) (e.g. alkylating
agents) act in all proliferating phases, even
the G0 effects are stronger.
cell cycle specific agents (phase specific
agents, CCSA). (e.g. Antimetabolites, vinca

alkaloids) just act on specific phases of the
cell cycle effects are comparatively weaker.
On the basis of source and action
mechanisms, the drugs are also classified

as:
alkylating agents
Antimetabolites
Natural products
hormones and antagonists
miscellaneous agents.
Alkylating Agents
Alkylating agents act via a reactive alkyl (R-
CH2-CH2+ -) group that reacts to form

covalent bonds with nucleic acids.
There follows either cross-linking of the two
strands of DNA, preventing replication, or

DNA breakage.
All alkylating agents are phase-nonspecific.
kill rapidly proliferating cells, also kill non-
proliferating cells.
Alkylating Agents
Examples: Mechlorethamine
the first drug used in the treatment of cancer ,

at present it is mainly used for Hodgkin's
disease and non-Hodgkin's lymphomas.
Examples: Cyclophosphamide
Most widely used in clinical therapy for

treatment of cancer at present. It has no
antineoplastic action outside the body and
must be activated in the liver
Antimetabolites
Antimetabolites are analogues of normal
metabolites and act by competition,

replacing the natural metabolite and then
subverting cellular processes.
Examples of antimetabolites include:
Folic acid antagonists (e.g. Methotrexate ).
Antipyrimidines (e.g. 5-Fluorouracil,
Cytarabine).
Antipurines ( e.g. 6-Mercaptopurine )
Antimetabolites
Example: methotrexate
Mimics folic acid, which is needed for synthesis of
DNA, RNA and some amino acids

It acts mainly on the S phase cells.
has a serious myelosuppression
Example: 6-Mercaptopurine
A structural analogue of hypoxanthin
It must be converted intracellularly to the nucleotide
6-mercaptopurine ribose phosphate and 6methylmercaptopurine ribonucleotide, and then

inhibit purine biosynthesis, causing inhibition of
biosynthesis of nucleic acid.
Antimetabolites
(Example: 5-Fluorouracil (5-FU)

a flurorine-substituted analogue of uracil
must be metabolically activated to a
nucleotide, in this case FdUMP. then its

metabolite inhibits the synthetase of
deoxythymidine monophosphate, blocking
DNA synthesis. Besides, as the fraudulent
substance, its metabolite can also
interfere with the synthesis of RNA.
a phase-specific drug.
Natural Products
This group is determined by the source of the
drug
The major classes of natural products include
Antibiotics
vinca alkaloids
biologic response modifiers
Enzymes
Epipodophyllotoxins
taxanes
Antibiotic antineoplastic agents
Damage DNA in cycling and noncycling
cells Example: Dactinomycin

(actinomycin D)
This drug binds noncovalently to double-
stranded DNA and inhibits DNA-directed

RNA syntheisis
Dactinomycin is a phase-nonspecific
agent, but it is more active agsinst G1

phase cells.
Vinca (plant) alkaloids
Vincristine and vinblastine are alkaloids
derived from the periwinkle plant.

binding to tubulin, interfere with the
assembly of spindle proteins during mitosis..

Act in M phase to inhibit mitosis, blocking
proliferating cells as they enter metaphase.

Both can cause bone marrow suppression
and neurotoxicity
Hormones and antagonists
The growth of some cancers is hormone
dependent.
Growth of such cancers can be inhibited

by surgical removal of hormone glands,
increasingly
Administration of hormones or anti-
hormones is preferred.
Examples:
Adrenocortical steroids to inhibit the
growth of cancers of lymphoid tissue and

blood.
Oestrogen antagonists ( tamoxifen ) is
indicated for breast cancer.

Oestrogen is used for prostatic cancers.
Examples: Hydroxyurea
Hydroxyurea inhibits ribonucleotide
reductase. inhibition of DNA synthesis.

It is specific for the cells of S phase
The major adverse effect of this drug is
bone marrow depression.
combination therapies
In order to enhance curative effect, to decrease the
toxicity and to reduce the drug resistance, combination

therapies are often used in the treatment.
Advantages of drug combinations:
They provide maximal cell kill within the range of
tolerated toxicity.
They are effective against a broader range of cell- cycle
phases.
They may slow or prevent the development of
resistance.
1. Select drugs according to their phase specific
characteristics
The aim of this rule is to urge more G 0 phase cells to enter
the proliferating cycle so as to increase the amount of

tumor cells killed by drugs.
For high GF tumor such as acute leukemia, phase specific
drugs are firstly used to kill S or M phase cells, and then
phase non-speicfic drugs are used to kill tumor cells in
other phases, and finally the above two steps are
repeated once again to kill new cell from G 0 phase.
For low GF tumor such as solid tumors, phase non-specific
drugs are firstly used to kill cells of all phases, and then
phase specific drugs are used, and finally the above steps
are repeated to kill the new cell from G 0 phases.
2. Combinations of antineoplastic drugs
with different action mechanisms.

. can destroy tumor cells from various
biochemical links at same time.

3. Combinations of antineoplastic drugs
with other therapies , Examples:

chemotherapy plus operation,
chemotherapy plus radiotherapy.
4. Combination of low-toxic drugs with high- toxic
ones
. does not obviously increase the toxicity of
antineoplastic drugs while the remarkable

synergism of anticancer action is produced,
Example: bleomycin (light myelosuppression) +
mitomycin (serious myelosuppression), which is
often used to treat carcinoma of cervix.
5. Select drugs according to antineoplastic range
(spectrum)
6. Use right dose
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dr.

Mechanisms of Antineoplastic Drugs

Differing from the operation and

radiotherapy that emphasize on the

Chemotherapy is the use of drugs to

inhibit or kill proliferating cancer cells,

Tumor cells can be classified as proliferating

cells and non-proliferating cells.

tissue is called growth fraction (GF).

the GF is and the higher the sensitivity of tumor

Based on the DNA changes in cells, proliferating cycle of

make preparations for the synthesis of DNA.

duplication has been finished and they are equally divided

cells. Some of these new cells enter the new proliferating

Non-proliferating cells include G 0 phase cells

casualties, G0 phase cells will get into proliferating

antineoplastic drugs, which is the important

Mechanisms of Antineoplastic Drugs

Most antineoplastic drugs act on the proliferating cycle

(alkylating agents, mitomycin C )

Toxicity of Antineoplastic Drugs

Common side reactions usually appear

Toxicity of Antineoplastic Drugs

The long-term toxicity mainly occurs in the

Classification of Antineoplastic Drugs

On the basis of antineoplastic action on

the phase of proliferation cycle, drugs are

cell cycle specific agents (phase specific

agents, CCSA). (e.g. Antimetabolites, vinca

Classification of Antineoplastic Drugs

On the basis of source and action

mechanisms, the drugs are also classified

Alkylating agents act via a reactive alkyl (R-

CH2-CH2+ -) group that reacts to form

strands of DNA, preventing replication, or

the first drug used in the treatment of cancer ,

Most widely used in clinical therapy for

Antimetabolites are analogues of normal

metabolites and act by competition,

DNA, RNA and some amino acids

6-mercaptopurine ribose phosphate and 6methylmercaptopurine ribonucleotide, and then

(Example: 5-Fluorouracil (5-FU)

nucleotide, in this case FdUMP. then its

This group is determined by the source of the

Antibiotic antineoplastic agents

Damage DNA in cycling and noncycling

cells Example: Dactinomycin

stranded DNA and inhibits DNA-directed

agent, but it is more active agsinst G1

Vinca (plant) alkaloids

Vincristine and vinblastine are alkaloids

derived from the periwinkle plant.

assembly of spindle proteins during mitosis..

proliferating cells as they enter metaphase.

Hormones and antagonists

The growth of some cancers is hormone

Growth of such cancers can be inhibited

Administration of hormones or anti-

Hormones and antagonists