Cancer

chemotherapeutic
agent
Oncology Division of UPH

Samuel J. Haryono
Surgical Oncologist
MRCCC Siloam Hospital
 Limitations of current cancer
therapies
Today, surgery, radiotherapy, and
chemotherapy, i.e. scalpel, ray, and
infusion, remain the standard tumor
therapies. Novel therapies like gene
therapy or immunotherapy are only
administered in the setting of
experimental studies. In addition, outside
school medicine, a variety of
alternative treatments are sought by
patients and their families who do not
have full confidence in standard
therapies.
 olecular-based cancer therap have not been successful, advances in the
nowled e of Mortalities
cancer biolo allowof selected
to understand wh thesecancers
failures have occurre
nd to improve on them.
Incidence Inand
(grey) fact, this knowled
mortality e selected
(black) of has also cancers
elucidated the causes
in males in wh
urrent cancer c emot erapy s on yGermany
eff cac in
ous up to a certa n po nt.
2000.

Fi ure22. Mortalities o selected cancers

Incidence ( re ) and mortalit (black) of selected cancers in males in German in 2000.
Anticancer frequent use
Selected target drugs emploied
in clinic or clinical trials
Why cancer is
so dangerous?
 We need to find THE
mechanisms to cure cancer.
1. Surgery
2. Radiation
3. Chemotherapy
4. Hormonal
5. Targeted Therapy
 What is
Chemotherapy?
The treatment of disease by the use of chemical
substances, especially the treatment of cancer
by cytotoxic and other drugs.
Chemotherapy is the use of drugs to inhibit or
kill proliferating cancer cells, while leaving host
cells unharmed, or at least recoverable.
 Chemotherapy

Curativ
e Adjuvant
Control Neoadjuva
Palliativ nt
e
 1
HOW CHEMOTHERAPY KILLS
CANCER CELLS?
Encouraging the
Selectively normal bodys
poison for cancer tissues to reject
cells cancer tissue.
Changing
(selectively) the Not of topic of
regulation of growth discussion for
of cancer cells today lecture
Chemotherapy are poison for cells that are in
the process of splitting into 2 new cells.

Do you all remember the process

of cell division by mitosis?
Uups
..
Time Actually this is how normal body tissues grow.
toBut cancer cells divide much more often than
guys divide Hi! I am Cell.
! Let normal cells.
Rock sSo they are more likely to be killed by
I am ready for the
!
cell division
chemotherapy
process!

v v vv I will copy
all of my
gene
exactly
 Lets take a look that cell division process more closely..
 Have the
Its a yes! time for
Lets duplicate
prepare! come yet?

The G1 (gap) phase begins when the cell is first

stimulated to proliferate.

G
During G1 cell contents other than the DNA are
duplicated and the volume of the cell increase.
At about 8-10 hours into G1, the cell crosses a
restriction point, or a point-of-no-return. if the cell
senses that it is capable of division, it passes this
point and then cannot stop the replication process.
 All of the organels
and sitoplasma are
ready Its time for
DNA replication
dude!

The S phase is where DNA synthesis takes

S
place.
Many cell-cycle-specific drugs act only on
cells that are in the S phase.
These drugs interfere with DNA synthesis in
some way
Was my DNA
synthesized NO!!
properly?
Lets !
suicide!
 Wasprepare
Lets my DNA
synthesized
the YES!
chromosomes
properly?
for mitosis
!
step!!

During the G2 (gap) phase, the cell arranges

chromosomes for later division (mitosis).

G
At the G2/M checkpoint, a cell either continuous with
mitosis or, if DNA was not synthesized properly, it
undergoes apoptosis (programmed cell death).
It is better for the body if a damaged cell dies rather
than having it pass on altered DNA to daughter cells.
Cancer cells learn to ignore or override the suicide
program, and therefore can divide even with
malformed DNA.
 Yeiy!!
Its time for
MITOSIS!!!!!

v v vv

M The cell physically divides in a process called mitosis.

A copy of the DNA from the parent is passed along to
the daughter cells
 Okay
I am tired!
Lets take a
rest

The cell can enter the G0 (resting)phase, which is

G
outside the cell cycle proper.
In the G0 the cell is not actively proliferating.
Cells can spend long periods in G0 before they reenter
the cell cycle in G1.
Cell-cycle-spesific drugs cannot kill cancer cells that
are in the resting phase. Typically cells in G0 are
termed quiescent.
Deficiency in checkpoint
control forcancer therapy
Antineoplastic agents (chemotherapy) that is
selectively poison for cancer cells can be divided
into 2 major category based on their act in cell-cycle

Cell-cycle nonspecific neoplastic agents (CCNS)

refers to a class of pharmaceutical that act as
antitumor agents at all or any phases of cell cycle.

Cell- cycle specific neoplastic agents (CCS) refers to

a class of pharmaceutical that act in only one part
of cell cycle (S phase) or only when cell are is in a
specific part of the cell cycle.
Antineoplastic agents (chemotherapy) that is
selectively poison for cancer cells can be divided
into 4 major category based on their biological
activity
1.Mitotic Poison
2.DNA-reactive drugs
3.Inhibitor of DNA replication
4.DNA topology as a target
for drugs development
1.Mitotic Poison

This drugs disrupt mitotic progression by

targeting the microtubule formation or
rearrangement during mitosis CCS
(M phase)

Anti-mitotic drugs that showed much success

against a number of cancer are the taxanes and
vinca alkaloids. Taxanes is commonly used in the
treatment of breast and ovarian cancers, and
vinca alkaloids, such as vincristine, are often used
in combination therapies to treat hematological
malignancies.
This drugs are cell-cycle specific drugs (M
phase)
1.Mitotic Poison
Drugs mechanism :
Anti mitotic When cells are
drugs
exposed to certain
anti mitotic agent,
v such as taxol, they
v arrest in mitosis
due to chronic
activation of the
spindle-assembly
The cells then undergo checkpoint.
one of several fates

Death in Exit
Unequal
mitosis without
division
division

4N
2. DNA-reactive drugs
Anti-cancer agent that target DNA are some of the most
effective agents in clinical use and have produce
significant increases in the survival of cancer patients
when use in combination with drugs that have different
mechanism of action.
DNA-reactive drugs directly damage DNA to
prevent the cancer cells from reproducing.
This agents mostly are not phase specific (CCNS). In
other words, they works in all phases of cell cycle.

DNA-reactive drugs discovery

timeline :
Alkylating
agent
191 Antitumor
0 antibiotics
194 Code-reading drugs
0
198
0
 Alkylating
agent
191
0
Alkylating agent are the oldest group of chemotherapeutics in
use today.
They are so named because of their ability to alkylate many
molecules, including proteins, RNA and DNA. This ability to bind
covalently to DNA via their alkyl group is the primary cause for
their anti-cancer effects
Alkylating agents will work at any point in the cell cycle and
thus are known as cell cycle-independent drugs. For this reason
the effect on the cell is dose dependent
The fraction of cells that die is directly proportional to the dose
of drug. Characterized by high reactivity and short half-life,
protein bound and urinary excretion at 24 hour.

The alkylating agents are frequently used in combination

therapy to treat a variety of cancer types.
The toxicity is suppression of bone marrow function (red cells,
leucocytes, platelet) and limiting effects on the proliferating
cells of intestinal mucosa.
 Alkylating
agent
191
0

Drug mechanism

The drugs may bind :DNA is made of two strand

1. once to one
strand of DNA If the cell tries to replicate
(monoalkylated) crosslinked DNA during cell
division, or tries to repair it,
2. once to the DNA strands can break.
each strand
of DNA This leads to a form of
(interstrand programmed cell death
crosslink) called apoptosis
3. twice to
one strand of
DNA
(intrastrand
crosslink)
 Alkylating
agent
191
0
 Antitumor antibiotics
194
0

Antitumor antibiotics are anti-neoplastic drugs

that are made from micro-organisms. These
antibiotics do not act like the antibiotics used to
treat infections.
They either break up DNA strands or slow down or
stop DNA synthesis that cells need to grow.

Antitumor antibiotics seems to have greater

selectivity for cancer cell rather than normal cells,
based on their improve clinical efficacy compared
to alkylating drugs.
 Code-reading drugs
198
0

Code-reading drugs are anti-neoplastic intercalating

agents that showing a sequence selectivity.

The drugs are small molecule 13-16bp that could

recognize minor or major groove of DNA.
3. Inhibitor of DNA Replication

Nitrogen bases are the

building blocks of DNA. It
consist of purines and
pyrimidines.
For example : The base
Purines thymine
nitrogen : are
SOLUTION
- Adenine (A)
missing.
Study says, (G)
- Guanine
It willPyrimidine
lead to the analogs
phenomenon that
and
called thymineless death whereby
Pyridimine
the that :unable
cellPurine analogs
to synthesis the
- Cytosine
DNA (C)
base thymine died in its
- Thymine (T)
absence.
Based
- Uracylon that
(U) discovery,
researcher tried to find several
inhibitor for enzyme that
How if Antimetabolite
one of
responsible forthe nitrogen the
biosynthesis
basecompound
pyrimidine areandmissing?
purine nucletide
precursor.
3. Inhibitor of DNA Replication
Antimetabolite compound

Antimetabolites are similar to chemicals needed for

normal biochemical activity, but differ enough so
that they interfere with normal cell function
Antimetabolites mechanism in inducing cell death in
cancer cell:
1. Incorporated into RNA and DNA which will either
inhibit subsequent replication cycles or result in
miscoding
Pyrimidine analogs: needed
2. Inhibit enzymes for analogs:
Purine nucleic acid production
1. 5-Fluorouracil (5-FU) 1. 6-Mercaptopurine
2. Cytosine Arabinose 2. Thioguanine
3. 5-Azacytidine 3. Allopurinol
4. 2,2-Difluoro-2- 4. Deoxycoformycin
Deoxycytidine 5. 2-Fluoroadenine Arabinoside-
AMP
Folate analogs :
6. 2-Chlorodeoxyadenosine
1. Methotrexate
7. Hydroxyurea
2. Pemetrexed
This drugs are cell
specific agents (S-phase)
4. DNA topology as a target for drugs
development

Do you all agree with me that DNA

are consist of double-helix
polynucleotide?
In the process of DNA replication
or transcription, the DNA have to
open its double helix shape, to be
like the picture in the left.

Do you all know who responsible for

that?
DNA Topoisomerase I
How about DNA topoisomerase II?

DNA topoisomerase I & II

animation video
4. DNA topology as a target for drugs
development

Rationalize about how important the DNA

topoisomerases enzyme in DNA replication process
made the researcher developing inhibitor for that
enzyme.

Topoisomerases inhibitor
drugs
Topoisomerases control DNA structure by maintaining the
correct superhelical state within the cell, as well as by
resolving intertwined DNA strands. This requires the
formation of transient breaks in DNA.
1. Topoisomerase I generates single-stranded breaks
2. Topoisomerase II introduces double-stranded breaks
The cytotoxicity of topoisomerase I and II poisons is due to
stabilization of the enzymeDNA covalent cleavage
intermediates, which are referred to as cleavage complexes.
Stages in drug
development
 HOW CHEMOTHERAPY KILLS
2CELLS?
CANCER

Encouraging the
Selectively normal bodys
poison for cancer normal tissues to
cells reject cancer tissue.
(Cancer Changing
Chemotherapy) (selectively) the
regulation of growth
of cancer cells
 Controlling cell cycle growth
During the 1960s and 1970s, studies of
cultured cells, both normal and tumor,
indicated that a diverse series of
polypeptide growth factors were
essential for cell growth, more specific
for certain tissue types breast
about 80% of breast cancer, once cancer
establish, rely on supplies of the
hormone estrogen to grow. they are
known as hormone sensitive or estroge
hormone receptor positive cancer. n

Suppression of this production of

ovaries
estrogen in the body is a treatment for
these cancer.

antiestroge
n
Antiestrogen

Antiestrogen inhibit estrogen-dependent synthesis and the

autocrine growth-promoting action of transforming growth
factor- (TGF-B)
This agent are drugs that compete with estrogen for binding
receptors on cell membranes

Antiestrogen drugs : tamoxifen, toremifene

This drugs are most effective in patients who have

estrogen receptor-positive tumors

Tamoxifen is also used as adjunctive therapy to

oophorectomy and leuprolide or goserelin in premenopausal
women with estrogen receptor-positive tumors. It is also used
as a prophylactic agents in woman at high-risk for breast
cancer
Moderate nausea, vomiting, and hot flashes are the major
adverse effects of long-term therapy.
 Another steroid hormones:

Adrenocortocosteroid

These drugs are lymphocytic and

antimitotic agents
They are useful in acute leukemia in children and
malignant lymphoma

Adrenocorticostreroid hormones :
- Prednisone
- Hydroxycortisone
- dexamethasone

These drugs have significants systemic effects and

long-term use is not recommended
Principles of Combination Therapies

1. Select drugs according to their phase specific characteristics

2. Combinations of antineoplastic drugs with different action
mechanism

3. Combinations of antineoplastic drugs with other therapies

4. Select drugs according to antineoplastic range (spectrum)

5. Use right dose.

THANK YOU
dilema in cancer chemotherapy

1. Chemotherapy Resistant
2. For the same drugs : different person are
giving a different result

Personalized Medicine
Selection of resistant cancer
cells during drug therapy
Roles of altered apoptosis in cancer cells in

resistanceand hypersensitivity to therapy

 Personalized medicine
The goal of personalized medicine is to tailor a patients treatment
strategy on the basis of his/her unique genetic make up.

The field of oncology is beginning to incorporated many of the

strategies of personalized medicine, especially with the realm of
pharmacogenomics.

Pharmacogenomics : the study of how inter-individual genetic

variation determines drug response to toxicity.

A main objective of pharmacogenomics is to facilitate physician

decision-making regarding optimal drug selection, dose and
treatment duration on a patient-by-patient basis.
 Problems with conventional
chemotherapy
One strategy to circumvent the problems associated with
conventional chemotherapy is to develop drugs against more
specific targets in the cancer.
This is not a fundamentally novel idea. Many drugs in current
use interact with highly specific targets such as microtubular
proteins or topoisomerase enzymes. Their targets are not
specific to cancers, though.

Those drugs called biological agents come closer to the ideal,

since they act on specific receptor proteins which may occur
preferentially in certain tissues, but, more importantly, are
essential for the growth of specific cancers. These, then, are the
forerunners of a novel drug generation.
 The Delema of target therapy
Optimists assume that many of these alterations are essential for the
growth and survival of the cancer and conclude that the multitude of
changes in carcinomas offer a wide choice of targets for therapy.
Pessimists point out that the more alterations have already occurred,
the higher the chance that some of them may be passenger
alterations.
Optimists suggest that cancer pathways activated in specific cancers
present excellent targets, as they are crucial for driving tumor
growth.
Pessimists point out that these same pathways are also important
for normal cells which might mean a narrow therapeutic window.
In practice, potential targets for cancer-specific therapy are defined
based on a variety of considerations (Table 22.3).
Molecule target for cancer
therapy
Drugable activities of receptors
tyrosine kinases
 EGFR
SEBAGAI MODEL STUDI PADA TARGET TERAPI
KANKER
EGFR
EGFR adalah protein reseptor
yang terletak pada membran
sel.

Protein EGFR tersusun atas 3

domain protein yang terdiri
a.Ekstraseluler domain protein
b.Transmembran domain
protein
c. Intraseluler domain protein
EGFR Terdapat dua domain
penting yang
meregulasi mekanisme
sinyal EGFR
MEKANISME EGFR
 Growth Factors & Cell Cycle
r s
to
c
Fa
Gene Transcription
th
row Receptors
G + S

G0 G1
Cell Cycle G2

M
Human EpidermalNoGrowth
specific Factor Receptor NRG2
Family
EGF, TGF ligands - NRG3
Cellulin often acts as Heregulins
dimer partner Heregulins -cellulin
Amphiregulin, HB-
EGF

TK TK TK

erbB1 erbB erbB4

HER1 erbB HER4
2 3
EGFR HER HER
EGFR Stimulation &
dimerisation

TK TK TK TK

EGFR Homo
Dimerisation erbB2 erbB3 erbB4
erbB1 HER2 HER4
HER1 HER3
neu
EGFR
EGFR stimulation cont

TK TK TK

Hetero Dimerisation

erbB1 erbB2 erbB3 erbB4

HER1 HER2 HER3 HER4
Risk for
EGFR neu
cancer
 EGFR Function in Normal Cell

ATP ATP
TK TK

Gene Transcription
Cell Cycle
Progression Antiapoptosi
Cell
Proliferation s
Angiogenesis
EGFR signal transduction in tumour cells

TK TK
PI3-K pY pY GRB2
pY SOS
STAT3 RAS RAF
PTEN AKT
MEK

Gene transcription MAPK

G1
M S
Proliferation/ Survival
maturation (anti-apoptosis)
G2
Chemotherapy /
radiotherapy
Angiogenesis Metastasis
resistance
 Other mechanisms of EGFR
stimulation
Steroid
hormon
e
MMP HB-EGF

P P
G protein
+ Ras +
Src
Ca++ Pyk2
MAPK

Transcription Steroid
hormon
erbB Ligand e
Gene recepto
r
BAGAIMANA KARAKTERISTIK
EGFR PADA SEL KANKER
DIORGAN TERTENTU ?
 Head and Neck Cancer :
EGFR expressed in > 90% of head
& neck cancers.
EGFR over expression associated
with decreased survival.
Increased EGFR expression is an
early event in carcinogenesis &
even present in premalignant
lesions.
Inhibition of EGFR TK slows the
growth of xenograft tumour
models of head & neck.

Non Small Cell Adenocarsinoma

Lung :
High level of receptor
expression compared with
healthy tissue.
EGFR - Key role in tumour cell
growth & function.
EGFR inhibition can inhibit
downstream activity.
EGFR inhibitors have no
severe toxicity.
MUTASI EGFR
 Seventy samples were
randomly chosen from a cohort
of 653 triple negative breast
tumours for EGFR mutation
Teramatinya perubahan gen EGFR
analysis. These samples were
pada jaringan kanker payudara,
immunostained for EGFR
yang sama dengan perubahan
protein expression and
genetik EGFR pada kanker paru,
consisted of negatively stained
berupa delesi pada exon 19, dan
and positively stained cases.
substitusi pada exon 21 yang
DNA was extracted from
berkorelasi dengan sensitivitas
paraffin blocks and polymerase
terhadap terapi TKIs-EGFR,
chain reaction was performed
memberikan harapan terapi kanker
to amplify exon regions 18 to
payudara triple.
21 of the EGFR gene. Direct
sequencing of the purified PCR
products was performed.
BAGAIMANA DENGAN INDONESIA?
KARAKTER EGFR
Ekspresi EGFR pada kanker
kepala dan leher : .........
%

Mutasi EGFR pada kanker

kepala dan leher : .............
%
Ekspresi EGFR pada kanker
Payudara : ......... %

Mutasi EGFR pada kanker

Payudara : ............. %

Ekspresi EGFR pada kanker

paru (NSCL) : ......... %

Mutasi EGFR pada kanker

paru (NSCL)
: 30% (500 pemeriksaan)
data kalgen
METODE DIAGNOSIS EGFR
SEQUENCING RT-PCR
TETAP PENILAIAN
TINGGI BIAYA MURAH

KEBERADAAN PROTEIN
UNTUK PENELUSURAN
PERUBAHAN GENETIK
TELAH TERDAPAT TARGET
EGFR Exon 18, 19, 20, 21

DENGAN
JUMLAH SAMPEL
TERBATAS
JUMLAH SAMPEL TAK
TERBATAS

MEMPERHATIKAN IHK
MEMAKAN WAKTU WAKTU SINGKAT

ATAUPUN ELISA
JUMLAH PERALATAN
TERBATAS
JUMLAH PERALATAN TAK
TERBATAS
DAPAT DIMODIFIKASI

SANGAT PERLU PADA PCR konfensional

 PEMAHAMAN SERTA METODE
EKSPERIMEN YANG LEBIH TEPAT SEMAKIN
MENARGETKAN SEL KANKER DAN
MELINDUNGI PENDERITA
 Why we need to know how
the chemotherapy drug work?
 To predicting side effect
This help oncologist decide which drugs are
work well together
How to measuring response
of treatment?
The activity of anti-cancer drugs is evaluated by measuring
changes in tumor size in response to treatment.

In early 1980s, the World Health Organization (WHO)

developed recommendation in an attempt to standardize
criteria for response assessment and WHO response
criteria were adopted as the standard method for
evaluating tumor response.
Furthermore, the development of new classes of
anti-cancer agents required the establishment of a
new methodology and has led to a number of
different modification of WHO criteria.

In 1998, new response evaluation criteria in

soloid tumors (RECIST) were proposed by the
RECIST working group in order to minimize the
risk of measurement error and prevent
overestimation of response rate
The Southwest Oncology Group (SWOG)
incorporation with the NCI has participated in the
development of new criteria for reporting the
results of cancer clinical trial.
WHO criteria uses bidimensional measurement to
evaluate the size of the tumors, whereas the RECIST
criteria uses unidimensional measurement (the sum of the
longest diameter of the tumor)

In several analysis concluded that the WHO and RECIST

criteria were equivalent in terms of response rate
All the three criteria have their own limitation with regards to
response evaluation in solid tumors.
It is clearly indicate that each of the three guidelines has its
own applicability during routine clinical practice and that
none of the guidelines can be replaced by another.
Thank you