CHEMOTHERAPY

Ratih Dewi Y, dr., M.Sc

Pharmacology Departement
Universitas Sebelas Maret

2018
Outlines

 Definition & Goal of Chemoterapy

 Cycle Cell
 Chemotherapy and cancer cell
 Classification
 Mechanism of Action
 Mechanicm of Resistant
 Side Effects
Definition:

Chemotherapy “chemical" and "treatment."

• The treatment of cancer using specific chemical agents or drugs that are
destructive to malignant cells and tissues.
• Treatment to stop the growth of cancer cells, either by killing the cells or by
stopping them from dividing (NCI)

Cytotoxic
‘toxic to cells’
Goal of Chemoterapy

1) Cure : eradication
2) Control: stop the growing and spreading
3) Palliation:
when cure and control are not possible
 - relieve symptoms caused by cancer
- improve QoL
Goal of Chemotherapy

 Must be realistic
 The primary focus of chemo :
preventing cancer cells from multiplying,
invading adjacent tissue or developing metastasis.
 Objective of chemo :
Destroy all malignant cells without excessive
destruction of normal cells
Potential Patient Respon
 Complete response (CR)
complete disappearance of the disease.

 Partial response (PR)

decrease in size or number of the lesions by 30% or more.

 Stable disease (SD)

disease has unchanged in size and number of lesions.
Generally, a less than 50% decrease or a slight increase in s
ize would be described as stable disease.

 Progressive disease (PD)

Disease has increased in size or number on treatment.
The Cell Cycle

The Cell Cycle

Mitosis
Cell Biology: Mitosis

 A cell in mitosis
Cancer Cells and Normal Cells
CANCER CELLS NORMAL CELLS
Frequent
mitoses

Normal
cell

Nucleus
Few
mitoses
Blood vessel

Abnormal
heterogeneous cells

Loss of contact inhibition Oncogene expression is rare

Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Intermittent or coordinated
growth factor secretion
Presence of tumor suppressor
genes 10
Normal Cell Characteristics:
 Metabolism. Strictly controlled &
predictable
 Maturation & Differentiation Strictly
controlled.
 Reproduction = Cell death
 Contact Inhibition. Mechanism for
switching off division when in contact
with different cells
 Recognition
Cancer Cell Characteristics:

 Unchecked & Uncontrolled Growth

 Loss of contact inhibition
 Loss of capacity to differentiate
 Increased growth fraction
 Chromosomal Instability
 Capacity to metastasise
 Altered biochemical properties
Cancer arises by successive mutations
in a clone of proliferating cells
Cancer phenotype results from accumulation
of mutations in the clonal progeny of cells

• Clone of cells overgrows due to

accumulation of mutations controlling
proliferation.
• Disseminates through bloodstream to
other parts of body
• Forms tumor
 Introduction:
The 6 Superpowers
 Introduction:
The 6 Superpowers
Cancer Cell Normal Cell

1
GO

STOP

SLOW

1. Most cells wait for a ‘Go signal before

dividing. Cancer cells don’t bother waiting…
they produce their own ‘Go’ chemical
messages and continue dividing.
 Introduction:
The 6 Superpowers
Cancer Cell Normal Cell

1
GO

2
STOP

SLOW

2. Even if the neighbouring cells produce a

‘Stop’ signal, cancer cells override these
signals and continue dividing.
 Introduction:
The 6 Superpowers
Cancer Cell Normal Cell

1
GO

2
STOP Apoptosis

3
SLOW

3. Normal cells sometimes react to stress by

triggering a ‘Self Destruct’ button and killing
itself, but cancer cells sneak past these self
destruct signals and continue to divide, thus
accumulating more mutations.
 Introduction:
The 6 Superpowers
Cancer Cell Normal Cell

1
GO

2
STOP Apoptosis

3
SLOW

4. Cancer cells make sure they can keep

4 Food Supply dividing by stimulating the growth of new
blood vessels to keep their nutrient supply
lines open.
 Introduction:
The 6 Superpowers
Cancer Cell Normal Cell

1
GO

2
STOP Apoptosis

3
SLOW

5. One of the key superpowers is immortality.

4 Food Supply Unlike normal cells which have a finite life
span, cancer cells manipulate their own DNA
5 Immortality (via repetitive DNA sequences called
telomeres) to keep dividing for a lot longer.
 Introduction:
The 6 Superpowers
Cancer Cell Normal Cell

1
GO

2
STOP Apoptosis

3
SLOW

6. Most tumours that show these traits are

4 Food Supply trouble, but the lethal nature of cancer is due
to its ability to spread to other location or
5 Immortality metastasize. 90% of cancer deaths are due
to metastasis.
6 Metastasis
Types of chemotherapy

• Cell cycle dependent

– Cell cycle phase specific

• Cell cycle independent

– Cell cycle phase non-specific

23
Chemotherapy and Cancer Cells

Cell Cycle specific :

Most active against cells in a specific
phase therefore need prolonged exposure
or repeated doses.

Cell Cycle Non-specific:

Most effective against actively dividing
cells but also effective in G0.
Classification of Chemotherapeutic Agents

25
Chemotherapy Agents
1. Toxic  limited dose
2. Likely to Resistance
3. 1 cycle of treatment  kills < 99,9 %
cancel cells

 Combination
 Repeated Cycle of treatment
Combination of Chemotherapy

 To get synergistic effect

 To minimalize side effect
 To kill cancer cell in any
different steps of cycle cell
 To delay the onset of drug
resistant
Chemotherapy
Over 50 different chemotherapy drugs

Modes of administration include:

 Oral
 IV
 Intracavity e.g pelvic cavity, bladder
 Intrathecal. Can be fatal if wrong drug
administered!
Intrathecal Chemotherapy
ALKYLATING AGENTS
 Alkylating Agents
(Covalent DNA binding drugs)
1. Agen Kemoterapi yang pertama
kali digunakan
2. Alkylating Agents menghentikan
pertumbuhan tumor 
membentuk cross-linking guanine
nucleobases pada untai ganda
DNA  merusak struktur DNA.
3. Untai ganda DNA tidak bisa
terpisahkan
4. Proses replikasi DNA terganggu
 sel tidak bisa melakukan
pembelahan secara lanjut
5. Termasuk Cell-cycle nonspecific
6. Alkylating agents  mutagenik
dan karsinogenik
1. Siklofosfamid
2. Klorambusil
Nitrogen Mustard
3. Busulfan Alkyl Sulfonates
4. Platinum Analog
Platinum Analog

 Inorganic metal complex

 Thought to have cytotoxic effects similar to
alkylating agents

 Cisplatin: broad range of solid tumors

 Nephrotoxicity, ototoxicity, peripheral sensory neuropthy

 Carboplatin (second generation): Same spectrum

as cisplatin
 Less nephrotoxic, myelosuppression
 Alkylating agent yang tersering digunakan di klinis
 Rute : I.V maupun Oral  efikasi sama
 Mekanisme aksi : DNA cross-linking  hambatan sintesis
(replikasi) DNA
 Aplikasi Klinis : CLL, ca mammae, ca ovarium, WT, neuroblastoma
 ES (target : organ yang aktif membelah)
a. Depresi Sutul (jalur myelopoesis : platelet,
granulosit) PBL count turun, bleeding
b. GI tract  Nausea, Vomitus
c. Epidermis  Skin pigmentation
d. Rambut  hair loss, alopecia
e. Hemoraghic Cystitis
Kishore Wary, Ph.D . Pharmacology of Antineoplastic Agents
Mekanisme Aksi Siklofosfamid
 Meningkatnya kemampuan DNA repair
 Penurunan permaebilitas seluler terhadap
Alkylating Agents
 Peningkatan sintesis Gluthatione
 inaktivasi alkylating agents
melalui reaksi konjugasi yang dikatalisis
oleh gluthatione S-transferase
ANTIMETABOLIT
 Senyawa menyerupai struktur metabolik
normal (asam folat, purin atau pirimidin)
 cell cyle specific
 Asam folat  kofaktor  sangat penting
untuk reaksi yang dikatalisis enzim pada
proses transfer gugus metil selama sintesis
purin dan timidilat
Antimetabolites
 Action: Inhibition of DNA or RNA synthesis
 Folic acid analog (antagonist) -- Methotrexate:
 Acute Lymphoblastic Leukemia
 GI tract, myelosuppression and hepatic dysfunction
 Purine analog (prodrug) -- Mercaptopurine:
 Acute leukemia in children
 GI tract, gradual myelosuppression and jaundice
 Pyrimidine analog (prodrug)
Cytosine Arabinose (Ara-C) : AML, ALL
5-Fluorouracil:
 Breast and GI carcinomas, and skin cancer
 Ulcerations of GI tract, myelosuppression
 Rute : I.V, Intratekal, Oral
 Mekanisme :
Menghambat kerja enzim
1. Dihidrofolat reduktase (DHFR)
2. Timidilat Sintase (TS)
Memblok sintesis timidilat, nukleotida purin dan
asam amino (serine, methionine)

Menghambat sintesis DNA, RNA dan protein

 Untuk ALL  Profilaksis SSP & Terapi Pemeliharaan

jangka panjang
Mekanisme Aksi Metotreksat
 Transporter spesifik untuk memasuki sel (RFC1)
 Sulit menembus blood brain barrier  intratekal
 Diabsorbsi di dalam GI tract
 50% berikatan dengan protein plasma
 40-90% diekskresikan melalui urin dalam bentuk
aslinya
 Perhatian : pemberian bersama obat yang
menurunkan aliran darah ke ginjal (misal: AINS) 
meningkatkan resiko toksisitas
 Resistensi Metotreksat
1. Penurunan transport obat ke dalam sel
2. Peningkatan eksport obat ke luar sel  multidrug resistance
P170 glycoprotein transporter
3. Peningkatan konsentrasi
enzim DHFR di dalam sel
4. Penurunan afinitas enzim DHFR
5. Penurunan pembentukan
poliglutamat
Akut :
1. Supresi Sumsum tulang  spontaneous
hemorrhage , infeksi
2. Kerusakan epitel dan gastrointestinal 
mucositis, diare
Kronis :
1. Pneumonitis (batuk, demam, infiltrat intersisial)
2. Fibrosis Hepar
3. Alopecia, dermatitis
6-Merkaptopurin & Thioguanine
 Rute : Peroral
 Untuk terapi ALL
 Ekskresi melalui urin
 Aktivasi: 6-Merkaptopurine HGPRT
(hypoxanthine-guanine phosphoribosyl transferase)
6-thioinosinic acid  menghambat enzim untuk
sintesis purin
 Inaktivasi: 6-Merkaptopurine Xanthin Oxidase
6-thiouric acid
 6-Merkaptopurine berinteraksi dengan Allopurinol
dosis dikurangi 25%
 Thioguanine tidak berinteraksi dengan Allopurinol
Metabolisme 6-Merkaptopurin

XO 6-thiouric acid (Inactive)

Cytarabine (Ara C – Cytosine Arabinoside)
 Rute : I.V
 Bekerja secara spesifik pada fase S
 Untuk terapi AML, ALL (terapi konsolidasi)
 Bentuk aktif : Ara-CTP
 Mekanisme Aksi :
1. Menghambat enzim DNA polymerase 
menghambat elongasi DNA
2. Menyatu dengan untai DNA  mutasi
 Inaktivasi secara deaminasi, dikatalisis oleh enzim
cytidine deaminase
Ara-CTP (active form)
competes with dCTP
-inhibits DNA polymerases
-incorporation into DNA
produces strand breaks;
triggers apoptosis
 Ditentukan keseimbangan antara enzim
deoxycytidine kinase dan enzim cytidine
deaminase
 Toksisitas :
1. Nausea dan Vomitus
2. Depresi Sumsum Tulang
3. Stomatitis
4. Ataxia Cerebellar
 PRODUK NATURAL

1. MICROTUBULE INHIBITOR
ALKALOID VINKA : Vinkristin
TAXANE : Paclitaxel
2. TOPOISOMERASE INHIBITOR
 ANTITUMOR ANTIBIOTIK
(ANTHRACYCLINE):
Doxorubisin, Daunorubisin, Idarubisin
3. ENZIM
L-asparaginase
 Derivat Alkaloid dari Vinca Rosea
 Rute : I.V
 Terapi : ALL dan CLL
 Bekerja spesifik pada fase M (tahap
metafase)
 Mekanisme Aksi :
Berikatan dengan Tubulin (mikrotubul) 
komplek obat & tubulin 
Inhibisi migrasi kromatid
Mitotic arrest
 How it works ?
 Stops division of cells
 Enters cell during mitosis and blocks formation of
microtubules of the mitotic spindle during metaphase
 Sering terjadi reaksi
neurotoksik  Arefleksia,
muscle weakness, neuritis perifer
 Depresi Sutul  Jarang
DOXORUBISIN & DAUNORUBISIN, IDARUBISIN

 ANTHRACYCLINE, diisolasi dari Streptomyces

 Rute : I.V
 Daunorubisin pertama diisolasi, narrow spectrum  AML
 Doxorubisin, broad spectrum  keganasan hematologi dan solid
tumor, ca thyroid, ca bladder and lung cancer
 Idarubisin
Idarubisin+cytarabine  lebih efektif menginduksi remisi komplit pada AML
 Side effects:
acute: conduction problems, myocarditis, and pericarditis
chronical: dilated cardiomyopathy and CHF
 Inhibisi Topoisomerase II
 Interkalasi dengan afinitas tinggi pada DNA 
menghambat sintesis DNA dan RNA
 Berikatan pada inner membran mitokondria sel
otot jantung  Membentuk radikal bebas
semiquinone dan ROS melalui proses reduksi
 peroksidasi lipid inner membran mitokondria
 cardiac toxicity
 Mechanism of Anthracycline Cardiac Toxicity

• As well as intercalating into DNA, daunorubicin avidly binds

mitochondrial inner membrane of cardiac muscle
• Daunorubicin chelates iron, which catalyzes formation of the free
radical semiquinone
• Redox cycling transfers high energy electron to oxygen, generating
oxygen free radicals
• Produce lipid peroxidation damage to mitochondrial membranes
 Supresi Sumsum Tulang
 Cardiac toxicity  aritmia (akut), Kardiomiopati
(kronis)
 Ekskresi rute hepatobillier  pada pasien
gangguan liver, dosis diberikan 50% 
mengurangi toksisitas
 Toksisitas GIT
mukositis, nausea, vomitus, diare
 Diisolasi dari E.Coli
 spesifik pada sel Tumor
 Mekanisme aksi :
L-Asparagine
L-asparaginase

Amonia

Karakteristik sel Tumor :

aktivitas Asparagine synthase minimal  sintesis Asparagine
sangat bergantung pada L-Asparagine dari luar
 Selektif pada sel tumor karena aktifitas
enzim asparagine synthetase minimal
(perlu sumber L-asparagine dari luar untuk
sintesis protein)
 Efek samping : reaksi hipersensitivitas
 demam, menggigil, skin rash, urtikaria
nause dan vomitus
MISCELLANEOUS :

1. Hydroxiurea
2. Hormon (Prednison,
Dexamethasone)
 Rute : Oral, I.V
 Masuk ke dalam sel secara difusi pasif
 Bekerja secara spesifik pada fase S  sel
terakumulasi pada fase S  Apoptosis
 Untuk Terapi CML
Farmakokinetik Hidroksiurea
a. Bioavailibilitas Oral : 80-90%
b. Distribusi luas  ASI, LCS
c. Metabolisme : belum diketahui
d. Ekskresi : 80-90% dlm bentuk asli melalui
ginjal
Pasien dengan CC : 10-50 mL/jam 
dosis 50%
Resistensi Hidroksiurea :
Peningkatan aktivitas seluler enzim
Ribonucleotide Reductase (RR)
 AGEN HORMONAL :
STEROID HORMON
(PREDNISON, DEXAMETHASON)

Kortikosteroid  melewati membran

plasma  berikatan dengan reseptor
intraseluler (family nuclear receptor) 
membentuk kompleks dengan reseptor
glukokortikoid yang teraktivasi  ditransport
ke dalam nukleus  berikatan pada
transcription factor di DNA  mempengaruhi
ekspresi gen-gen di dalam leukosit  Efek
antiinflmasi
Chemotherapy Side Effects

 Chemotherapy targets cells which are

dividing rapidly.
 Chemotherapy cannot distinguish
between normal cells and cancer cells
 Healthy Cells which have a high rate of
growth and multiplication include cells of
the bone marrow, hair, GI mucosa and
skin.
Side Effects: Acute

Tumour Lysis Syndrome.

 Rapid cell lysis (death) & large amounts
of cell metabolites in blood Metabolic
Emergency  acute renal failure,
cardiac arrest and death.
Side Effects: Acute

Neutropenic Sepsis:
Occurs due to Bone Marrow Failure and
poor immune response to infection.
Mortality rate : 40-90%

Predisposing factors include:

Neutropenia
Underlying disease
Chemotherapy
Venous access devices
Side Effects: Acute

Haemorrhage
• Invading tumours e.g gastric MALT
lymphomas
• Haemorrhagic Cystitis related to high
dose Cyclophosphomide

Anaphylactic Reaction
Side Effects:Bone Marrow

Neutropenia:
Increased risk of infection.
Anaemia:
Tiredness, lethargy & breathlessness
Thrombocytopenia:
Increased risk of bleeding
Side Effects: Gastro-Intestinal

 Nausea & Vomiting

 Diarrhea & constipation
 Loss of appetite
 Taste Changes
 Mucositis
Side Effects

 Example of Grade 4 Mucositis

Side Effects: Body Image

 Hair Loss
 Weight Loss/ Weight Gain
 Skin changes (colour, rashes, sensitivity
to sunshine/chlorine, dry)
Summary:

The potential benefit to the patient

of treatment as an option must
always outweigh the toxic effects.
References
 National Cancer Institute : NCI of cancer Term
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/chemotherapy
 Katzung, B. Basic and Clinical Pharmacology. 2007, 10th Ed. Pp 878-898.
 Hejmadi M. DNA & Disease (Cancer Biology)
 Hanahan D & Weinberg RA. The Hallmarks of Cancer
 Amy Sinacola. Haematology Macmillan Clinical Nurse Specialist
 Carlos Linn.2007.Tumor Biology and Kinetics Introduction of Cytotoxic Agents