Professional Documents
Culture Documents
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.
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
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,
Production metalloproteinases
Angiogenesis
Metastasis
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.
Non-Specific
Cyclophosphamide
Chlorambucil
Ciplastin
Actinomycin-D
L-asparaginase
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)
(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
Natural
1. Antibiotics
Actinomycin D
Doxorubicin
Daunorubicin
Belomycin
Mitomycin C
2. Vinca alkaloids
Vincristine
Vinblastine
Vinolrelbine
3. Taxanes
Paclitaxel
docetaxel
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
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
A/E
1. Nausea
Most widely in
colorectal cancer
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
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)
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)
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
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
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)
1. Prostate CA
2. Benign
prostatic
hyperplasia
(finasteride:
non-steroidal
inhibitor of testosterone
reductase)
1. Metastatic
prostate CA
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)
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