Académique Documents
Professionnel Documents
Culture Documents
Fakultas Kedokteran
Universitas Sumatera
Utara
24 November 2012, KBK SM-7, FK USU
Modalities of
Chemotherapy
Curative
Total irradication of cancer cells; possible?
The concept of log kill
If 109 cells present, and drug kills 99.999%, then 0.001%
left------- still 10.000 cells left alive
This is a 5-log kill
Palliative
Alleviation of symptoms
Avoidance of life-threatening toxicity
Prevention
Tamoxifen, ASA, folic acid, sunscreen, lead suits?
Fakultas Kedokteran
Universitas Sumatera
Utara
GF
Alkylating Agents
Platinum Compounds
Antibiotics
Principles of chemotherapy
Classification of cytotoxic agents
Alkylating
Agents
AntiMetabolites
Mitotic
Inhibitors
Antibiotics
Others
Busulfan
Cytosine
Etoposide
Bleomycin
L-asparaginase
Carmustine
Arabinoside
Teniposide
Dactinomycin
Hydroxyurea
Chlorambucil
Floxuridine
Vinblastine
Daunorubicin
Procarbazine
Cisplatin
Fluorouracil
Vincristine
Doxorubicin
Cyclophospha
mide
Mercaptopurine
Vindesine
Mitomycin-C
Ifosfamide
Methotreaxate
Taxoids
Mitoxantrone
Melphalan
Plicamycin
Principles
of chemotherapy
Aim of combination
therapy
INCREASED EFFICACY
ACTIVITY
Different mechanisms of action
Different mechanisms of resistance
SAFETY
Compatible side effects
Principles of chemotherapy
Side effects of chemotherapy
Alopecia
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Sterility
Renal failure
Myalgia
Myelosuppression
Neuropathy
Phlebitis
Specific Toxicities
Pulmonary fibrosis, fevers, skin
hardening and blisters, anaphylaxis.
Cisplatin
Mesna ( mercaptoethanesulfonate)
Drug Resistance
De novo Resistance
Acquired Resistance
Multidrug Resistance (MDR)
De novo resistance:
De novo resistance can be de novo genetic
(i.e. the cells are initially inherently resistant),
or can arise because drugs are unable to
reach the target cells because of permeability
barriers such as the blood-brain barrier
Drug Resistance
Acquired Resistance:
Drug Resistance
Multidrug Resistance (MDR):
P-glycoprotein transports many naturally occurring drugs
out of neoplastic cells, and its induction may lead to
multidrug resistance.
=Inhibited by verapamil,diltiazem,
amiodarone,quinidine,ketoconazole,eritromisin
As scientific understanding of the mechanisms of drug
resistance increases, new treatments may be developed
to counteract resistance.
Alkylating agents
o Formation of trapping
agents
o Changes in target
enzymes or receptors
Alkylating agents
o Decreased activation of
prodrugs
o Formation of druginactivating enzymes.
o Decreased drug
accumulation via increase
in P-gp transporters.
6-mercaptopurine, 5fluorouracil.
Etoposide, gonadal
hormones, methotrexate,
vincristine, vinblastine.
COMBINATION THERAPY
o Reduces resistance to drugs
o Increased effectiveness
o Access to sanctuary sites e.g. lungs, CSF.
o Each hospital has its own regiments
o Combinations selected to avoid overlapping
toxicity but:
o Causes spectrum of adverse effects but
minimises risk of lethal effects.
PRODRUGS
1. Cyclophosphamide 4Hydroxyphosphamide
2. Procarbazne dacarbazine
3. Merkaptopurine 6-merkaptopurine
ribozophosphate
4. Tioquann
6-tioquann-ribzophosphate
5. Fluorouracil 5-fluoro-deoxy- uracil
monophosphate
6. Mitomycin (only at the hypoxic tissue of
tumors)
7. Doxorubicin idarubicin
CYTOTOXIC DRUGS
A. Alkylating Agents
1. Mechanisms of action : The alkylating
agents are CCNS drugs.
a. They interact covalently with DNA bases,
especially at the N-7 position of guanine.
b. Nucleic acid functions are disrupted due
to cross-linking, abnormal base pairing,
and DNA strand breakage.
ALKYLATING AGENTS
Cyclophosphamide, Ifosphamide, Chlorambucil, Nitrosoureas
Cell- cycle-nonspecific drugs
combine with DNA of both malignant and normal cells and
thus damage not only malignant cells but also dividing
normal cells (the bone marrow and the GIT)
mechanisms: the alkyl groupings (ethyleneimine ions and
positively charged carbonium ions) are highly reactive, so
that combine with susceptible groups in cells and in tissue
fluids (SH, PO4)
The alkylating action on DNA leads to abnormal base
pairing or intra and interstrand links with DNA molecule
M e c h a n is m o f in tr a m o le c u la r b r id g in g o f D N A b y a lk y la tin g a g e n ts .
D N A
A lk y la tin g
agent
i.e .
A
C
A
C
G
T
=
=
=
=
a d e n in e
c y to s in e
g u a n in e
th y m id in e
Cyclophosphamide
an inactive prodrug
can be given orally
is activated by the CYP450 in liver as well as in
tumors.
with time, the active metabolite and also acrolein
are formed. The latter compound is responsible for
bladder toxicity (chemical hemorrhagic cystitis).
a wide spectrum antitumor and immunosuppressive
activity used as a part of combination therapy
regimens to treat lymphoma, breast cancer, bladder
cancer, ovarian cancer and various children
malignancies
T o x i c i t i e s:
bone marrow depression, granulocytopenia,
x
thrombocytopenia.
urotoxicity appears with chronic therapy M e s n a (2-mercaptoethanesulfonate sodium)
protects the urinary tract against the irritant effects
by supplying sulfhydryl groups to form a stable
thioether with acrolein. Mesna is given by IV
injection or po
The nitrosoureas:
Carmustine and Lomustine are potent bone marrow
toxins. Hepatotoxicity and nephrotoxicity.
Broad spectrum of activity (solid tumors, in particular
brain tumors).
B. Antimetabolites
1. Mechanisms of action : Antimetabolites are CCS
drugs.
a. They are structurally similar to endogenous
compounds.
b. Anticancer and immunosuppressive actions result
from interference with the metabolic functions of
folic acid, purines, and pyrimidines.
2. Methotrexate (MTX) is an analog of folic acid that
inhibits dihydrofolate reductase and other
enzymes in folic acid metabolism.
a. It is used (orally and intravenously) in acute
leukemias, breast cancers, and non-Hodgkins and
T-cell lymphomas.
b. Folinic acid (leucovorin) is used to reverse MTX
toxicities and full hydration is needed to prevent
crystalluria.
Topoisomerase Inhibitors
o Topoisomerase I inhibitor
Topotecan
Irinotecan
Camptotheca
accuminate
Camptothecin analog
o Topoisomerase II inhibitor
Etoposide
Anthracyclins:
Doxorubicin
Idarubicin
Epirubicin
Daunorubicin
Podophyllum
peltatum
Camptothecin-Mechanism
Antimicrotubule Agent
o Vinka alkaloid: prevent microtubule
formation
Vincristine
Vindesine
Vinblastine
Vinorelbine
Structure of Microtubule
()
Treadmilling:
net growth at one end and
net shortening at the other
end
Dynamic instability:
the plus end switch
spontaneously between slow
growth and rapid shortening
()
Vincristine (Oncovin)
potent vesicant (heat)
Mechanism: inhibit
,
microtubule assembly &
block mitosis
Metabolism: liver
Toxicity: neurotoxicity by a
peripheral, symmetric
sensorymotor, and
Dose capping: 1.4mg/m2
autonomic polyneuropathy,
Up to 2mg (due to toxicity)
phlebitis, alopecia
PPO 7th edition
Paclitaxel
Taxus brevifolia
D. Antibiotics
1. Bleomycin:
is a glycopeptide mixture (CCS) that alters
nucleic acid functions via free radical
formation.
a. It is used in regimens for Hodgkins and other
lymphomas and squamous cell and testicular
cancers.
b. Pulmonary toxicity, skin thickening, and by
hypersensitivity reactions are distinctive.
PLATINUM COMPOUNDS
Cisplatin (cis-diaminedichlorplatinum) is an inorganic
platinum complex.
mechanism of action: DNA synthesis by formation
of intra-and interstrand cross-links with DNA molecule.
Adverse effects, toxicity:
severe vomiting
nephrotoxicity is dose-related
(acute distal tubular necrosis).
Prevention: the patients is fully hydrated by IV infusion
combined with manitol and furosemide.
hypomagnesemia
ototoxicity develops in up to 30%.
Peripheral neuropathy can be disabling.
myelosuppression
Cisplatin
is the most effective single agent in testicular
x
teratomas, but is usually given in combination with
other cytotoxic drugs.
Cisplatin has been used with some success in head
and neck
and bladder cancers -IV .
Carboplatin
is less toxic (renal toxicity or ototoxicity),
neuropathy is rare and vomiting although common,
is less severe than after cisplatin.
Oxaliplatin
Progestogens: = megesteron,
= medroxy-progesteron acetate:
Indication:
-adenocarcinoma of the body of the uterus
- in advanced breast cancer,
- carcinoma of the kidney.
G l u c o c o r t i c o s t e r o i d s:
= are cytotoxic to lymphoid cells
= are usedwith combination with other cytotoxic
agents in treating:
lymphomas, myeloma and
to induce a remission in acute lymphoblastic
leukemia.
Hormone
a n t a g o n i s t s:
Anti-estrogens:
tamoxifen - in breast tissue competes with
Anti-androgens:
flutamide is used in prostate tumors
Adrenal hormone synthesis inhibitors: inh
sex hormone synthesis. Aminoglutethimide.
Aminoglutethimide
inhibits adrenal synthesis of estrogens,
glucocorticoids and mineralocorticoids
by inhibition of the enzyme producing
their common precursorpregnandione
Pharmacokinetics:
polymorphic acetylation to an inactive N-acetyl
metabolite. Fast acetylators - slow acetylators.
Adverse effects:
dizziness, lethargy are common on starting
treatment
but decline during chronic dosing
(probably due to enzyme induction).
Usage:
A. is effective in about 30% of postmenopausal
patients
with best effects on skin and breast disease.
The response of bone metastases is also good.
Anticancer Drugs
o Alkylating Agent
o Antimetabolite
o Antibiotics
o Alkaloid
o Hormones
o Otherscis-platinumcarboplatinlobaplatin
Alkylating Agents
o One of the frightening developments of World War I was
the introduction of chemical warfare. These compounds
were known as the nitrogen mustard gases. The nitrogen
mustards were observed to inhibit cell growth, especially
of bone marrow. Shortly after the war, these compounds
were investigated and shown to inhibit the growth of
cancer cells.
Alkylating Agents
Mechanism of Action
o Nitrogen mustards inhibit cell reproduction by binding
irreversibly with the nucleic acids (DNA). The specific
type of chemical bonding involved is alkylation. After
alkylation, DNA is unable to replicate and therefore can
no longer synthesize proteins and other essential cell
metabolites. Consequently, cell reproduction is
inhibited and the cell eventually dies from the inability
to maintain its metabolic functions.
Cyclophosphamide, Chlormethine,
Chlorambucil, Sarcolysine
Nithrosoureas
Carmustine Lomustine
Ethyeneammonium or Aziridines
Thiotepa triethylene melamine
Alkysulfonates Busulfan
Alkylating AgentsMustine
o Mustine must be injected intravenously because
it is highly reactive. It disappears very rapidly
from the blood, the activity of Mustine lasts only
a few minutes.
o The main indication for Mustine is in treatment of
Hodgkins disease and lymphomas, but it may
also be useful in other malignancies.
Alkylating Agents
Cyclophosphamide
Cyclophosphamide can also be given orally.
Indications
Adverse Effects:
myelosuppression,
and
Alkylating AgentsNitrosoureas
Carmustine, Lomustine, Semustine
Pharmacokinetics:
Nitrosoureas are highly lipophilic and reach
cerebrospinal fluid concentrations that are
about 30% of plasma concentrations.
Indications:
Because of their excellent CNS penetration,
carmustine and lomustine have been used to
treat brain tumors.
Alkylating Agents
Phenylalanine Nitrogen Mustard
o Melphalan is a nitrogen mustard that is primarily
used to treat multiple myeloma (plasma cell
myeloma), breast cancer, and ovarian cancer.
Alkylating Agents
Alkysulfonates
Busulfan [Myleran]
Indications:
Busulfan is administered orally to treat chroic
granulocytic leukemia and other myeloproliferative
disorders.
Adverse Effects:
Busulfan produces advers effects related to
myelosuppression. It only occasionally produces
nausea and vomitting. In high doses, it produces a rare
but sometimes fatal pulmonary fibrosis, busulfan lung.
Alkylating AgentsThiotepa
Thiotepa is converted rapidly by liver mixedfunction oxidases to its active metabolite
triethylenephosphoramide (TEPA); it is active in
bladder cancer.
Antimetabolites
General Characteristics
Antimetabolites are S phase-specific
drugs that are structural analogues of
essential metabolites and that interfere
with DNA synthesis.
Myelosuppression is the dose-limiting
toxicity for all drugs in this class.
Classification of Antimetabolites
Folic acid Antagonists: MTX
Purine Antagonists: 6MP
6TG
Pyrimidine Antagonists 5FU
araC
HU
Antimetabolites
Folic Acid Antagonist
Methotrexate MTX
Mechanism of Action
Antimetabolites
Folic Acid Antagonist
Methotrexate MTX
Indications
o The use of MTX in the treatment of choriocarinoma, a
trophoblastic tumor, was the first demonstration of
curative chemotherapy.
o It is especially effective for treating acute lymphocytic
leukemia and for treating the meningeal metastases of a
wide range of tumors.
Antimetabolites
Folic Acid Antagonist
Methotrexate MTX
Adverse Effects
Antimetabolites
Purine Antagonists
6-Mercapapurine 6-MP
The drugs are believed to act similarly to inhibit purine
base synthesis, although their exact mechanisms of action
are still uncertain.
Indications:
Mercaptopurine is used primarily for the maintenance of
remission in patients with acute lymphocytic leukemia and
is given in combination with MTX for this purpose.
Adverse Effects:
Well tolerate.
Myelosuppression is generally mild with thioguanine.Longterm mercaptopurine use may cause hepatotoxicity.
Antimetabolites
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Mechanism of Action
Fluorouracil is an analogue of thymine in which the methyl
group is replaced by a fluorine atom. It has two active
metabolites: 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits
thymidylate synthetases and prevents the synthesis of
thymidine, a major building block of DNA. 5-FdUTP is
incorporated into RNA by RNA polymerase and interferes
with RNA function.
Antimetabolites
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Indications
Fluorouracil is exclusively used to treat solid
tumors, especially breast, colorectal, and gastric
tumors and squamous cell tumors of the head
and neck.
Antimetabolites
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Adverse Effects
Fluorouracil may cause nausea and vomiting,
myelosuppression, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.
With fluorouracil, myelosuppression is more problematic
after bolus injections, whereas mucosal damage is doselimiting with continuous infusions.
Antimetabolites
Pyrimidine Antagonists
Cytarabine
Indications
Cytarabine has a narrow clinical spectrum and is primarily
used in combination with daunorubicin or thioguanine for
the treatment of acute nonlymphocytic leukemia.
Adverse Effects:
High doses of cytarabine can damage the liver, heart, and
other organs.
Antibiotics
Classification of Antibiotics:
o Adriamycin (Anthracyaline Antibiotics)
o Mitomycin C
o Bleomycin
o Actinomycin D
Antibiotics
Adriamycin and Daunorubicin
Properties:
o Adriamycin and Daunorubicin are tetracycline rings with the
sugar daunosamine. They are DNA intercalating agents that
block the synthesis of DNA and RNA.
o These agents are primarily toxic during the S phase of cell
cycle.
o These agents imparts a red tinge to the urine.
o Adramycin is used to treat acute leukemias, lymphoma, and
a number of solid tumors.
Antibiotics
Mitomycin C:
Mechanism:
Mitomycin C is an antineoplastic antibiotic that
alkylates DNA and thereby causes strand breakage
and inhibition of DNA synthesis.
Indications:
It is primarily used in combination with vinvristine as
salvage therapy for breast cancer.
Adverse Effects:
Mitomycin
produces
delays
and
prolonged
myelosuppression that preferentially affects platelets
and leukocytes.
Antibiotics
Actinomycin D:
o Actinomycin D intercalates DNA and thereby prevents
DNA transcription and messenger RNA synthesis.
o The drug is given intravenously, and its clinical use is
limited to the treatment of trophoblastic (gestational)
tumors and the treatment of pediatric tumors, such as
Wilms tumor and Ewings sarcoma.
Antibiotics
Bleomycin:
Mechanism:
o The drug has its greatest effect on neoplastic cell in
the G2 phase of the cell replication cycle.Although
bleomycin intercalates DNA, the major cytotoxicity is
believed to result from ironcatalyzed free radical
formation and DNA strand breakage.
Indications:
o It is useful in Hodgkins and non-Hodgkins
lymphomas, testicular cancer, and several other solid
tumors.
Adverse Effects:
o Bleomycin produces very little myelosuppression. The
most serious toxicities of Bleomycin are pulmonary
and mucocutaneous reactions.
Indications:
Vinblastine is used in combination with Bleomycin
and Cisplatin for metastatic testicular tumors.
Vincristine is used in combination with prednisone
to induce remission in childhood leukemia.
Vinorelbine is used to treat non-small-cell lung
cancer and breast cancer.
Platinum Compound
Cisplatin:
Mechanism of Action:
Cisplatin binds to guanine in DNA and RNA, and
the interaction is stabilized by hydrogen bonding.
The molecular mechanism of action is unwinding
and shortening of the DNA helix.
Platinum Compound
Cisplatin:
Indications:
Cisplatin has efficacy against a wide range of
neoplasms. It is given intravenously as a first-line drug
for testicular, ovarian, and bladder cancer, and it is also
useful in the treatment of melanoma and a number of
other soild tumors.
Adverse Effect:
Cisplatin produces relatively little myelosuppression but
can cause severe nausea, vomiting, and nephrotoxicity.
Platinum Compound
Carboplatin:
Indication:
Carboplatin has a similar spectrum of activity,
but it is approved only as a second-line drug for
ovarian cancer.
Hormones
Several types of hormone-dependent cancer (especially
breast, prostate, and endometrial cancer) respond to
treatment with their corresponding hormone antagonists.
Estrogen antagonists are primarily used in the treatment
of breast cancer, whereas androgen antagonists are
used in the treatment of prostate cancer. Corticosteroids
are particularly useful in treating lymphocytic leukemias
and lymphomas.
Hormones
Estrogens:
Estrogens inhibit the effects of endogenous androgens
and androgen-dependent metastatic prostatic
carcinoma. Diethylstilbestrol is usually the agent of
choice.
Cardiac and cerebrovascular complications and
carcinoma of the male breast are potential adverse
effects.
Hormones
Progenstins:
Progestins are useful in the management of endometrial
carcinoma and back-up therapy for metastatic hormonedependent breast cancer.
Hormones
Antiestrogen: Tamoxifen
Tamoxifen is the drug of choice in postmenopausal
women with or recovering from metastatic breast cancer.
It is most effective in patients who have estrogen
receptor-positive tumors.
Tamoxifen is also used as adjunvctive therapy to
oophorectomy to leuprolide or goserelin in
premenopausal women with estrogen receptor-positive
tumors.
Hormones
Androgens:
Androgen activity in breast cancer is similar to that of
estrogens, perhaps for the same mechanistic reasons.
Virilizing effects and hepatic toxicity make them
unacceptable to most patients.
Fluoxymesterone is the most widely used agent.
Danazol has use in hematology in aplastic anemia and
congenital anemias.
Hormones
Glucocorticoids:
o They are integral components of curative therapy for
acute lymphoblastic leukemia, non-Hodgkins lymphoma,
and Hodgkins disease.
o Glucocorticoids have essential roles in the prevention of
allergic reaction, emesis control, relief of intracranial
hypertension or spinal cord compression in neurologic
complications, and pain relief.
Immunomodulating Drugs
Immunosuppressive Agents:
o Act to suppress immune mechanisms and are used to
treat autoimmune diseases or to prevent graft rejection
following tissue transplantation.
o Ciclosporin, Tacrolimus, adrenocortical hormones,
antimetabolites, alkylating agent, antilymphocyte
globulin, Mycophenolate Mofetil
Immunomodulating Drugs
Immunopotentiator :
Enhance antitumor immunity and are used to treat
neoplastic disease.
Recombinant Interferons and Cytokines.
5-Fluorourasil
Principles of chemotherapy
Metotreksat
Daktinomisin
Daunorubisin
Doksorubisin
Mitramisin
Sint. Purin
L-Asparaginase
RIBONUKLEOTID
DEOKSORIBO
NUKLEOTID
DNA
RNA
transkripsi
Sint. Pirimidin
Bleomisin
Hidroksiurea
ENZIM
PROTEIN
translasi
MIKRO
TUBULI
Alkilator
Sitarabin
Alkaloid Vinka
Kolkisin
ACRONYMS
ABVD
CHOP
CMF
COP
FAC
FEC
o Drug Resistance
o Drug Toxicity
Drug Resistance
De novo Resistance
o Acquired Resistance
Drug Resistance
De novo resistance:
o
Drug Resistance
Acquired Resistance:
o Acquired drug resistance may result from genomic
mutations, such as the induction or deletion of enzymes
involved in drug inactivation or drug activation,
respectively.
Drug Resistance
Multidrug Resistance (MDR):
o P-glycoprotein transports many naturally occurring drugs
out of neoplastic cells, and its induction may lead to
multidrug resistance.
o As scientific understanding of the mechanisms of drug
resistance increases, new treatments may be developed
to counteract resistance.
Drug Toxicity
o The most common toxicities of antineoplastic drugs
result from inhibition of cell replication in the bone
marrow, gastrointestinal epithelium, and hair follicles.
Many antineoplastic drugs also stimulate the
chemoreceptor trigger zone in the medulla and thereby
elicit nausea and vomiting.