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Chemotherapy

Definition
Cancer:
Uncontrolle
d
multiplicati
on &
spread
within the
body of
abnormal
forms of
body's own
cells
Neoplasm:
mass of
tissue d/t
abnormal,
excessive,
uncoordina
ted,
autonomou
s&
purposeles
s
proliferatio

Intro
Guiding principle cancer chemotherapy

Characteristics
1. Cancer therapy not successful as
antimicrobial chemotherapy
Metabolism in parasite differs
qualitatively from host cell while
chancer differs quantitatively from
normal host cells
o Target selectivity > difficult in
cancer
o No substantial IR in cancer
o Diagnostic complexity: delay
institution of Rx
2. Modalities of Rx
Surgery & radiotherapy (1/3 can be
cured, effective when tumor not
metastasize)
Chemotherapy: 50% can be treated,
15-20% can be cured, essentially
required w/ surgery/irradiation when
metastasized
3. It can be curative
Acute leukemia, Wilm/s tumour,
Ewings Sarcoma, ChorioCa,
Hodgkins Ds, Lymphosarcoma,
Burkitts Lymphoma, Testicular
Teratoma, Seminoma

1.

2.

Achieve total cell kill must be tried


Aimed at destroying all malignant cells
Ensure early recovery, prevent relapse, prolongs survival
Pharmacological modalities
Early Dx & early institution of Rx
Survival time inversely related to initial no of cell ( cell,
survival time)
Aging cancer cell less susceptible to chemotherapy
because there is:
o cell cycle time (prolonged cell cycle)
o no actively dividing cells w/ > resting cell
o cell death within tumor
o Overcrowding of cell poor blood supply & nutrition &
defective access of drug
3. Combination chemotherapy
Heterogenicity: cell remained in different phase of growth
cycle showing different level sensitivity
o Nature of drug (w/ diff biochemical site of action)
o Avoid emergence drug resistance
Monotherapy: adequate in Burkitts lymphoma & chorioCa
4. Intermittent regimen
Favor risk-benefit ratio
Allows time for damaged normal host cell to recover
Pulse therapy: employ highest tolerated dose wothin short
administration period
Based on principle: Drug concentration= constant /

Toxicity
cytotoxic drug
1. N&V
2. BM
suppressio
n
3. Alopecia
4. Gonads:
oligosperm
ia,
impotence
,
ovulation
5. Fetus:
abortion,
fetal
death,
teratogeni
city
6. Carcinogenicity
7. Hyperuricemia
8. Immunosuppressio
n:
fludarabin

n of cells
Some
malignanci
es can be
transmitted
buy
inoculation

4. Give palliative effect


Breast Ca, ovarian Ca, endometrial
Ca, prostatic Ca, CLL,CML, head &
neck Ca, lung Ca
5. It is less sensitive (not effective) in
Colorectal Ca, Gatric Ca, esophageal
Ca, Renal Ca, hepatoma,
bronchogenic ( non-small cell) Ca,
malignant melanoma, sarcoma
6. Cancer cell differ from normal cell by:
uncontrolled proliferation,
dedifferentiation, loss of fx,
invasiveness, metastasis

duration drug exposure (T)


5. Adjuvant & neoadjuvant chemotherapy
1. Adjuvant: after surgery/irradiation to destroy
micrometastasis * prevent dev secondary neoplasm
2. Neo-adjuvant: 4 surgery/radiotherapy to diminish vol of
large primary neoplasm

e
9. Hazards to
staff

InheritedAcquired
mutation:
environment
interaction,
gene
mutation:
chemicals,
irradiation,
virus
Expression TSG
(p53, Rb)

Proto-oncogenes
oncogenes
Apoptosis, alterationsin telomerase
Uncontrolled cell proliferation,

Development primary tumor

Production metalloproteinases

Invasion of nearby tissue by tumor cells

Angiogenesis

Metastasis

Development secondary tumors

Classification
I : Specific & Non-specific
Specific
Kills actively dividing cells
1. G1: vinblastine
2. S: methotrexate, 6-mercaptopurine, %fluorouracil
3. G2: bleomycin, etoposide,, topotecan,
daunorubicin
4. M: vincristine, vinblastine, paclitaxel,
docataxel
1.
2.
3.
4.
5.
6.
7.

Signal transduction inhibitor


Microtubule inhibitors
Differentiation agents
Antimetastatic drugs
Antiagiogenic agents
Hypoxic tumor stem cell specific agents
Tumor radiosensitizing & normal tissue
radioprotecting drugs
8. Cytoprotective agents

Non-Specific

Kills resting cells &


dividing cells
1.
2.
3.
4.
5.

Cyclophosphamide
Chlorambucil
Ciplastin
Actinomycin-D
L-asparaginase

II: depends on mechanism at cell level


Directly Acting Cytotoxic
Indirectly acting by hormonal
Drug
balance
1. Alkylating agents
1. Corticosteroids
2. Antimetabolites
2. Estrogens & ERMs
3. Natural products
3. 5 alpha reductase inhibitors
4. Miscellaneous:
4. Gnrh antagonist
ciplastin, carboplatin, 5. Progestins
hydroxurea,
procarbazine,
mitotane, imatinib

Classes of new drugs


Inhibitor of growth factors receptor:
1. Imatinib: CML (BCR-ABL gene)
2. Gefinitib: non-small cell cancer of
lung (EGFR)
3. Nilonitib: CML (tyrosine kinase
inhibitor)
4. Dasatinib: CML (tyrosine kinase
inhibitor)
5. Lapatinib: metastatic breast CA

Monoclonal Ab:
1. Trastuzumab: breast CA
(HER2/neu)
2. Bevacizumab: metastatic
colon cancer (VEGF)
3. Rituximab: non hodgkins
lymphoma (CD20)
4. Panituzumab: metastatic
colon CA (EGFR)

9. Biologic response modifier

Polyfunctional Alkylating agents


1. Nitrogen mustards 3. Alkyl sulfonate
busulfan
(Bischloroethylami
4. Nitroureas
ne)
Carmustine
Cyclophospham
Lomustine
ide
Streptozocin
Meclorethamin
5. Triazines
e
Dacarbazine
Melphalan
Temozolamide
Chlorambucil
Ifosfamide
2. Ethyleneimine
(Aziridines)
Thiotepa
1. Corticosteroids
Prednisolone

(HER2/neu)
6. Sunitinib: renal cell CA (VEGF)
7. Sorafinib: renal cell Ca (VEGF)

DACD
Antimetabolites
1. Folate antagonist
Methotrexate
2. Purine antagonist
6-mercaptopurine
6-thioguanine
Azathiopurine
3. Pyrimidine antagonist
5-fluorouracil
Cytarabine
Gemcitabine

5. Alemtuzumab: CLL (CD52


Ag)
6. Iodine tositumonab: nonhodgkin

Natural
1. Antibiotics
Actinomycin D
Doxorubicin
Daunorubicin
Belomycin
Mitomycin C
2. Vinca alkaloids
Vincristine
Vinblastine
Vinolrelbine
3. Taxanes
Paclitaxel
docetaxel

Hormones & Antagonist


6. Progestins
Hydroxyprogesterone

products
4. Enzymes
L-asparaginase
5. Epipodophyllotoxins
Ectoposide
Tenoposide
6. Camptothecin analogs
Topotecan
Irinotecan
7. Biological response
modifiers
Interferons
Interleukins

2. Estrogens
Ethinyl estradiol
3. SERM
Tamoxifen
Toremifen
4. SERD
Fulvestrant
5. Aromatase inhibitors
Letrozole
Anastrozole
Exemestane

Drugs
PAA

Nitrosureas

MOA
Transfer alkyl group to various
cellular constituent alkylation
of DNA apoptosis

Require biotransformation

7. Anti-androgens
Flutamide
Bicalutamide
8. 5- reductase inhibitor
Finasteride
Dutasteride
9. GnRH analogs
Naferelin
Goserelin
Leuprolide

Resistance
1.
capability
to repair
damage
DNA
2.
productio
n of
glutathion
e
3.
permeabil
ity

PK
Parenteral (IV):
direct tissue
damage at site
of injection
Oral (common)

Exretion by

Toxicity / A/E
1. Tissue toxicity: esp
rapidly growing tissue
(bone, GIT, reproductive
system)
2. N&V: pretreat w/
antiemetics,
myelosuppressionj
3. Delayed toxicity: severe
BM depression
leukopenia,
thrombocytopenia,
bleeding, nephrotoxicity,
peripheral neuropathy

Uses

In brain tumor

Methotrexa
te

6thiopurine
Mercaptopu
rine
Thioguanin
e
Fludarabine
phosphate

Claddribine

Fluorouracil

active metabolites
Highly lipid soluble cross BBB
Folic acid antagonist:
Interrupt synthesis of
thymidylate, purine nucleotides,
AA serine & methionine
interrupt DNA, RNA & protein
formation
Polyglutamate (derivatives):
Selectively retained within cancer
cell & inhibit enzyme involve in
folate metabolism (dihydrofolate
reductase)
Purine antagonist

renal
Do occur

IV
Intrathecal*
Oral

A/E:
1. Mucositis
2. Diarrhea
3. BM depression

Oral

Childhood leukemia

Parenteral

Low grade nonhodgkin


CLL

Inhibit number of enzymes of


purine nucleotide interconversion

Purine antagonist
Inhibit DNA -polymerase &
ribonucleotide reductase inhibit
DNA synthesis apoptosis
Incorporated into DNA DNA
strand breakage

Pyrimidine antagonist

Parenteral:
IV infusion
(single
continues 7
days infusion)
IV

A/E
1. Transient
myelosuppression
2. CD4 & CD8

Hairy cell leukemia


CLL
Low grade nonhodkins

A/E
1. Nausea

Most widely in
colorectal cancer

Inhibit DNA synthesis & fx

Capecitabin
e

Pyrimidine antagonist
Prodrug that converted to
fuorouracil

Cytarabine

Vinblastine

Vincristine

2.
3.
4.
5.

Mucositis
Diarrhea
Myelosuppression
Hand & foot
syndrome
6. Neurotoxicity
Single agent /
combine w/
taxane
docetaxel

A/E
1. Diarrhea
2. Hand & foot
syndrome
3. Myelosuppression
4. N&V

Incorporated into DNA interfere


w/ chain elongation
S-phase specific
Alkaloid from periwinkle plant /
vinca rosea
Affect mitosis at metaphase
interfere w/ chromosome
segregation
Same w/ vinblastine

(adjuvant & advanced


ds)
Solid tumors: breast,
stomach, pancreas,
esophagus, liver, head
& neck)
Metastatic colorectal
cancer

Myelogenous leukemia

A/E
1. N&V
2. BM suppression
3. Alopecia

A/E:
1. Neurotoxicity
Peripheral & autonomic
neuropathy & muscle
weakness (CNS)
2. Constipation
3. Marrow sparing
effect
4. Alopecia (>common)

Hodgkin & nonhodgkin


Breast cancer
Germ cell cancer
Breast cancer
Testicular cancer
Childhood cancer:
Remission induction in
ALL
Hematologic,alignanci
es, hodkins,
lymphosarcoma, wilms
tumor, ewings
sarcoma

Anthracyclin
e:
Doxorubicin
Daunorubici
n

Dactinomyci
n

Bleomycin

Antibiotics
Bind to DNA block synthesis RNA, DNA / both interfere
Inhibit topoisomerase II
Dose limiting
toxicity:
affinity bind to DNA by
1. Myelosuppre
intercalation block DNA & RNA
ssion
2.
Mucositis
synthesis
3. Cardiotoxicit
y: ECG
Bind to cellular membranes to
changes
alter fluidity & ion transport
(acute),
dilated
Generation of semiquinone free
cardiomyopa
radicals thru an enzymethy (chronic)
mediated reductive process
Bind to DNA inhibit DNA
dependent RNA synthesis

Pulmonary
toxicity

w/ cell replication
Doxorubicin w/ cyclophosphamide, ciplastin,
5-FU:
1. Cancer of breast, endometrium, ovary,
Testicle, thyroid, stomach, bladder, liver,
lung
2. Soft tissue sarcoma, childhood cancer:
neuroblastoma, Ewings, osteosarcoma,
rhabdomyosarcoma
3. Hematolgic malignancy, Hodgkin/nonhodgkin
Daunorubicin:
Narrower spectrum. AML
Pediatric tumors (Wilms)
Rhabdomyosarcoma
Ewings
Germ cells tumors
Gestational trophoblastic ds
Hodgkins & non-Hodgkins lymphoma
Germ cell tumor
Head & neck CA
SCC of skin, cervix, uvula

Hormonal Agents
Drug
Corticosteroid:
Glucocorticoids

Selective
estrogen
receptor
modulators
(SERMs):
Tamoxifen

MOA
Steroid binds to receptor protein in cancer cells
(highly specific receptor on neoplastic cells
have been identified)

Mobile steroid-receptor complex formed

Binds to DNA

General
Most steroid sensitive
tumor have specific
receptor
Measurement of
estrogen receptor (ER) &
progesterone receptor
(PR) standard clinical
test
Patient w/ +ve ER & PR
response better to
endocrine ablation

Effects
1. Dissolution of lymphocytes
2. Regression of LN
3. Inhibit growth of certain mesenchymal
tissue

Competitive partial agonist-inhibitor of


estrogen binds to estrogen receptors of
estrogen sensitive tissues & tumors

1. Non-steroidal antiestrogen
2. Has 10 fold lower affinity
to ER compare to
estradiol
Indicate importance of
ablation of endogenous
estrogen for optimal
anti-estrogen effects

Role in other tumor (ovarian)


Suppress insulin-like-growth-factor 1 levels &
upregulates production of transforming growth
factor (TGF-)

Advantages
1. Antiinflammatory
effect
2. appetite
3. Prevent
anaemia
4. Sense of wellbeing
5. body weight
6. Suppress HS
rxn
7. Control
hypercalcemia
& bleeding
8. Non-specific
antipyretic
effect
antiemetic
effect on
ondansetron
Advanced CA: 4050% show clinical
improvement
(mainly in patient
lack endogenous
estrogenoophorectomy /
post-menopausal)

Uses
1. Breast CA: &
, high dose
estrogen (antiestrogen
largely
replaced
estrogen)
2. Prostate CA:
estrogen
suppress
androgen
tissue growth
stimulating
effect

1. Extremely
useful in
breast CA
2. Progesteroneresistant
endometrial
CA
3. Patient w/
demonstrable
ER & PR
protein

Anti-androgen:
Flutamide

GnRH agonist
Leuprolide
Goserelin

Leuprolide

Aromatase
inhibitor:
Aminogluthate
mide &
anstrozole)

Antagonize residual androgenic effect after


orchidectomy

Also use together w/


leuprolide

Acts as GnRH agonist on pituitary w/ paradoxic


result (> potent than naturally occurring
hormone) initial stimulation followed by
inhibition of release FSH & LH testicular
androgen synthesis (explain role of drug in
metastatic cancer of prostate)
Effects comparable to diethylstilbestrol (DES)

Synthetic peptide analog of


naturally occurring
gonadotrophin releasing
hormone

Inhibit adrenal steroid


Inhibit extra adrenal synthesis of estrone &
estradiol. Inhibit aromatase enzyme

PK: depot & IV


Disadvantages: > expensive
than DES
Aromatization can occur
in body fat
Estrogen promote
growth breast CA
estrogen synthesis in
extra gonadal adipose
tissue important in
breast CA in postmenopausal woman

1. Prostate CA
2. Benign
prostatic
hyperplasia
(finasteride:
non-steroidal
inhibitor of testosterone
reductase)
1. Metastatic
prostate CA

Less side effects


than DES
Aminogluthatemid
e
1. Metastatic
breast CA w/
+ve ER & PR
2. 2nd line post
tamoxifen

Imatinib, Dasatinib, Nilotinib


Imatinib:
For CML
MOA: inhibit BCR-ABL tyrosine kinase
Dasatinib:
For CML & Philadelphia chromosome
+Ve ALL
MOA: Oral inhibitor BCR-ABL, Src,ckit & PDGFR- kinases
Nilotinib:
MOA: Inhibit BCR-ABL, c-kit &
PDGFR- kinases

Miscellaneous
Growth factor receptor inhibitor
Epidermal grwth factor receptor (EGFR) over expressed
in solid tumor: colorectal, head & neck, non-small lung
cancer, pancreatic CA
Cetuximab:
monoclonal Ab directed against extracellular
domain EGFR
Panituximumab:
fully human monoclonal Ab directed against EGFR &
works thru inhibition of EGFR signaling pathway

Asparaginase
an enzyme to Rx childhood
ALL
isolated & purified from
bacteria
MOA: hydrolyze circulating
L-asparigine to aspartic acid
& ammonia
Tumor cell in ALL lack
asparagine synthase for
protein synthesis (normal
cell can synthesized own
asparagine)

Factors affecting chemotherapy


1. Drugs that affect cycling cells
can be used most effectively
2. Drug synergism: Recognition of
true drug synergism
3. Cytotoxic drugs: Preferably use
cytotoxic agents in intensive
pulse course every 3-4 weeks
rather than continuous
Allow max effects on cancer cell
w/ complete hematologic &
immunologic recovery b/w
courses: side effects but not

Leukemia
Acute leukemia
& childhood
leukemia (ALL)good prognosis
Drug regime:
1. Initial Rx:
vincristine +
predinisone +
other agents
(induce
remission)
2. Circulating

Clinical implications
Lymphoma
Hodgkins
Adequate
stage
important:
o Stage I & II:
combination
chemothera
peutic
agents +
radiation
therapy
o Stage III &

Multiple myeloma
Tumor in BM &
surrounding
bone
Rx:
o Combination of
alkylating
agent
mephalan +
intermittent
high dose
prednisone
(effective)

Breast Ca
Stage I & II: LN status
indicates risk occult distant
micrometastases
Rx:
o Post op systemic cytotoic
agents: CMF
(cyclophosphamidemethotrexate-fluoroucil /
FAC (fluorouraciladriamycincyclophophamide)
prolong survival

efficacy
Adjuvant chemotherapy for
micrometastasis: multimodality
therapy
1. Effective chemotherapy as
adjuvant initial Rx w/ other
method (surgery & radiation)
2. Only systemic therapy can
adequately attack micro
metastases
3. Effect of therapy: Prolong dsfree & overall all survival in
patient w/ osteogenic sarcoma,
rhabdomyosarcoma/ breast CA,
Hodgkins Ds
4. Breast CA: curative rate
5. Regiment at least 3 drugs
useful combination result are
superior to single agents

leukemic cell
often migrate
to sanctuary
sites (brain, &
testes)
prophylactic
Rx
3. CNS leukemia:
intrathecal
methotrexate
prophylactically
(major mech of
relapse)

IV: DVBD, 4
cycles
Initial Rx:
o MOPP
o After
remission
induction w/
6 courses
50 % free of
signs for 2
years, 50 %
w/ complete
remission
cured

Thalidiomide:
refractory /
relapsed ds
alone /
combine w/
dexamethason
e

Tamoxifen: useful for post


menopausal after
multiagent chemo given
given for 5 years after
surgery followed by
aromatase inhibitor
(anastrazole)
Stage III & IV: palliation
Rx:
o Combination therapy
prolong survival & relief
symptoms
o Oophorectomy / use
tamoxifen (ER / PR +ve)
o