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Antineoplastic AB

Prepared by:
Bashayer Al- Balkhi
Layla Al-Blowi
Alanoud Al-Homoud
Amal Al-Subaity
Zeina Al-Abdulkareem

Supervised by:
Dr. Qadria AL-Deab
Dr. Areej Altaweel
Introduction to cancer
Our bodies are made up of millions of tiny
cells. Most of our cells divide and multiply
from time to time - when an old cell is worn
out or damaged, a new cell is formed to
replace it. Each cell contains genes (made up
from DNA). The proteins inside the gene
control when the cell should divide and
multiply.

If the gene is damaged or
altered, the cell becomes
abnormal. This abnormal
cell can then divide and
multiply, without knowing
when to stop. When a
group of abnormal cells
clump together and grow,
a tumour forms.
There are two types of tumours:
- Benign tumours are not cancerous, and will
not invade or spread to other parts of the
body.
- malignant tumours are the real cancers. They
can grow very quickly, invade nearby tissues
and organs, and cause damage. They may
even spread to other parts of the body and
cause secondary tumours (metastases).

There are two broad categories of cancers:
- Carcinomas: cancers that develop in the
surface linings of organs.
- Sarcomas: cancers that appear in the cells of
solid tissues, such as muscles, bones and
blood vessels.
 Carcinomas are the most common.

Types of cancer
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There are about 200 different types of cancer.
Some types are more serious than others,
some are more easily treated, and others
have better survival rates.
They include: bladder, breast, colon, rectal,
kidney (renal cell) cancer, leukaemia, lung,
pancreatic, prostate, melanoma, and thyroid
cancer.
Symptoms
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unexplained lumps and swellings,
tiredness,
weight loss,
poor appetite,
night sweats,
fever, and
anaemia.
Causes
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Hereditary.
Smoking.
Diet.
Environmental factors such as UV light from
the sun.
Diagnosis
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X-ray.
Ultrasound.
Computerised tomography (CT or CAT)
scan.
Magnetic resonance imaging (MRI) scan.
Positron emission tomography scan (PET).
Once the problem area is found, blood and
tissue samples (biopsy) will be taken for
analysis and testing to determine if, or how
far, the cancer has spread in the body (this is
called staging).
Prevention
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Stop smoking.
Eat a healthy diet.
Reduce alcohol intake.
Use protection from the harmful effects of the
sun.
Treatment
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Surgery: the main treatment for most solid tumours,
especially when the cancer is in the early stages and has not
spread to other areas of the body.
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Radiotherapy: aims to destroy the cancerous cells with
radiation from X-rays.
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Chemotherapy: Different drug combinations are given
depending on the type of cancer. The drugs are given either by
mouth, or more commonly by IV, to try and kill cancer cells or
stop them from spreading.
Chemotherapy
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Depending on which drug combination given,
there may be some side effects, such as
sickness, diarrhoea, hair loss and mouth
sores.
The majority of chemotherapeutic drugs can
be divided in to: alkylating agents,
antimetabolites, mitotic inhibitors,
antineoplastic antibiotics, hormonal agents,
and miscellaneous antineoplastic agents.
Antineoplastic antibiotic
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A type of anticancer drug that blocks cell
growth by interfering with DNA.
The antineoplastic antibiotics are products of
Streptomyces.
The important drugs in this group include,
actinomycin D (dactinomycin), doxorubicin,
mitoxantrone, and bleomycin. Drugs less
commonly used include daunorubicin,
mithramycin, and mitomycin.
Doxorubicin
Drug Description

Doxorubicin is an anthracycline glycoside
antineoplastic antibiotic produced by
Streptomyces peucetius var. caesius.
Structure and SAR
Daunorubicin:
R. = OCH3, R2 = H
Doxorubicin:
R. = OCH3, R2 = OH
ldarubicin:
R. = H, R2 = OH
Carminomycin:
R. = OH, R2 = H

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The anthracycline antibiotics have
tetracycline ring structures with an unusual
sugar, daunosamine, attached by glycosidic
linkage.
Cytotoxic agents of this class all have
quinone and hydro quinone moieties on adj
acent rings that permit them to function as
electron-accepting and donating agents.

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Although there are marked differences in the
clinical use of daunorubicin and doxorubicin,
their chemical structure differ only by a single
hydroxyl group on C-14
The anthracyclinones differ from each other
in the number and location of the phenolic
hydroxyl groups, the degree of oxidation of
the two-carbon side chain at the position 9,
and the presence of a carboxylic acid ester at
position 10
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Doxorubicin binds to nucleic acids,
presumably by specific intercalation of the
planar anthracycline nucleus with the DNA
double helix. The anthracycline ring is
lipophilic, but the saturated end of the ring
system contains abundant hydroxyl groups
adjacent to the amino sugar, producing a
hydrophilic center. The molecule is
amphoteric, containing acidic functions in the
ring phenolic groups and a basic function in
the sugar amino group. It binds to cell
membranes as well as plasma proteins.
Mechanism of action
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Doxorubicin binds directly to DNA via intercalation
between base pairs on the DNA helix.
Doxorubicin also inhibits DNA repair by inhibiting
topoisomerase II. These actions result in the
blockade of DNA and RNA synthesis and
fragmentation of DNA.
Doxorubicin is also a powerful iron-chelator. The
iron-doxorubicin complex can bind DNA and cell
membranes producing free radicals that immediately
cleave DNA and cell membranes.
Doxorubicin appears to be active in all phases of the
cell cycle and although maximally cytotoxic in S
phase, it is not cell cycle-phase specific.
Mechanism of Resistance:
1- One mechanism for adriamycin resistance,
impaired cellular drug uptake, may
experimentally be overcome by concomitant
amphoteracin B (Fungizone) injection in
some adriamycin-resistant patients.
2- Acceleration of the efflux, P-glycoprotein,
synthesized in high quantity as a result of
gene amplification.
3- Increased GSH peroxidase activity.
4- Decreased activity of topoisomerase II.
Spectrum & uses

In experimental animal systems, Adriamycin
has wide spectrum of activity in both solid
tumors such as sarcomas, carcinomas,
melanomas as well as transplantable and
viral induced leukemia lymphomas.
Uses
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Carcinomas-Doxorubicin: breast carcinoma, ovarian
carcinoma , thyroid carcinoma endometrial carcinoma,
testicular carcinoma , lung carcinoma
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Sarcomas-Doxorubicin: Ewing's sarcoma,
osteosarcoma, rhabdomyosarcomas
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Hematologic Cancers-Doxorubicin: acute leukemia,
multiple myeloma , Hodgkin's disease, non-Hodgkin's
lymphoma
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The most often reported combination, AdOAP, includes
Adriamycin with vincristine (Oncovin), cytarabine (ARAC), and prednisone.
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For resistant Hodgkin's and non-Hodgkin's
lymphoma the combination CHOP has
demonstrated activity and combines
Adriamycin (hydroxyl daunorubicin) with
cyclophosphamide, Oncovin, and prednisone.
Rout of administration: administered IV
Dosage Form: injection, powder, lyophilized,
for solution.
Pharmacokinetics
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Absorption: Oral: poor <50%
Metabolism: Primarily hepatic to
doxorubicinol (active) - then to inactive
aglycones, conjugated sulfates and
glucoronides
Excretion: feces 40-50% as unchanged
drug, urine 3-10% as metabolites.
Drug Interaction
AGENT EFFECT
MECHANISM
MANAGEMENT
barbiturates
(phenobarbital)
delayed,
moderate
possible;
decreased
pharmacologica
l effects of
doxorubicin
doxorubicin
metabolism
increased by
barbiturates via
CYP3A4 induction
monitor therapy
calcium
channel
blockers
(e.g:
verapamil)
doxorubicininduced
cardiotoxicity
may be
increased
additive toxicity
monitor cardiac function
throughout treatment
Cyclophosphamide
doxorubicininduced
cardiotoxicity may
be increased
additional
myocardial cell
damage
caution, but
combination
regime is
commonly used
digoxin
tablets
delayed, moderate,
suspected;
decreased
pharmacological
effects of digoxin
digoxin
absorption
decreased by
antineoplastic
agents due to
alteration of
intestinal mucosa
monitor for
decreased
effect of digoxin
quinolones
(e.g.,
ciprofloxacin)
delayed, moderate,
possible; the
antimicrobial effect
of quinolones may
be decreased
quinolone
absorption
decreased by
antineoplastic
agents due to
alteration of
intestinal mucosa
monitor
therapy
stavudine
decreased
pharmacologica
l effects of
stavudine
stavudine
avoid
metabolism to
concomitant
active drug is
use
decreased by
doxorubicin due
to inhibition of
phosphorylation
streptozocin
greatly
enhanced
leukopenia and
thrombocytope
nia
doxorubicin half caution
life possibly
prolonged
Doxorubicin (Adriamycin) has been found to be
physically incompatible with the following drugs
1. Fluorouracil (5-FU).
2. Dexamethasone
3. Hydrocortisone sodium phosphate
4. Aminophylline
5. Cephalothin sodium (Keflin)
6. Sodium heparin
Side effects
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Cardiovascular:
Acute: arrhythmias, heart block, pericarditismyocarditis, facial flushing
GIT: acute nausea and vomiting, mucositis,
ulceration, necrosis of the colon, anorexia and
diarrhea, stomatitis, esophagitis.
Genitourinary: discoloration of urine (red)
Hematologic: myelosuppression, leucopenia, dose
limiting toxicity.
Endocrine & metabolic: hyperuricemia
Dactinomycin
Introduction

Common trade name : Cosmegen.

Dactinomycin is a drug used to treat many
kinds of cancer .

It is a derivative of streptomyces parvulus.
Structure-Activity Relationship
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The planar phenoxazone
actinocin, which is responsible
for the yellow-red colour of the
compounds.
The differences among
naturally occurring
actinomycins are confined to
the peptide side chains, and
the variations are in the
structure of the constituent
amino acids.
By varying the amino acid
content of the growth medium,
it is possible to alter the types
of actinomycins produced and
the biological activity of the
molecule .
Mechanism of Action

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The planar phenoxazone ring intercalates
between adjacent guanine-cytosine base
pairs of DNA .
The summation of these interactions provides
great stability to the dactinomycin-DNA
complex, and, as a result of the binding of
dactinomycin, the transcription of DNA by
RNA polymerase is blocked.
Mechanism of resistance

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Resistance is due to an increased efflux of
the antibiotic from the cell via P-glycoprotein.
DNA repair may be also play a role .
Uses
Ewings sarcoma
 Rhabdomyosarcoma
 Wilms tumor
Less frequent uses :
 Germ cell tumours
 Melanoma
 Testicular cancer
 Uterine cancer

Dosage
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The dose intensity per 2-wk cycle for adults
and children should not exceed 15
mcg/kg/day or 400 to 600 mcg/m 2 /day for 5
days.
Pharmacokinetic
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administered by parentral injection .
Excreted both in bile and in the urine and
disappears from plasma with a terminal halflife of 36 hours.
Metabolism is minimal.
Does not cross the blood-brain barrier.
Drug interaction
AGENT
EFFECT
MECHANISM MANAGEME
NT
Halogenate
d inhalation
anesthetics
(e.g,
enflurane ,
halothane )
Increased
hepatotoxicity
additive
caution
Side effect
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nausea and vomiting
loss of appetite
abdominal pain
diarrhea
difficulty swallowing
thinned or brittle hair
skin irritation
Contraindication
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If you are allergic to any ingredient in this
medicine.
If you have chickenpox , or shingles (herpes
zoster infection), or if you have had either of
these infections recently.
Warnings

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Dactinomycin is extremely corrosive to soft
tissue. If extravasation occurs during IV use,
severe damage to soft tissues will occur.
Avoid use in pregnancy ( teratogenic ) and
avoided in breast feeding.
Mitomycin
Introduction
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The mitomycins are a family of aziridine-containing
natural products isolated from Streptomyces
lavendulae.
use as a chemotherapeutic agent by virtue of its
anti-tumor antibiotic activity.
Brand Names:
Mutamycin®
Index Terms:
Mitomycin-C, Mitomycin-X, MTC, NSC-26980.
Strucrure & SAR
1.
2.
3.
at least three reactive
center of compound have
been identified:
Cl carbon of mitosane
ring.
Quinone ring structure,
which can undergo one or
two electron reduction
Urethane groups that can
open to form an alkylating
site at CI0.
Mechanism of action
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After intracellular enzymatic reduction of quinon and loss of
the methoxy group, mitomycin becomes a bi-functional or trifunctional alkylating agent; it can also be activated
nonenzymatically. The drug inhibits DNA synthesis and cross links DNA at N6 position of adenine and at the O6 and N2
position of guanine. In addition, single-strand breakage of
DNA is caused by reduced mitomycin; this can be prevented
by free radical scavengers.
Mitomycin is derived from Streptomyces caespitosus and has
antineoplastic activity similar to that of the alkylating agents.
Mitomycin selectively inhibits the synthesis of DNA by causing
cross-linking, degrades preformed DNA, and causes nuclear
lysis and formation of giant cells. At high concentrations,
cellular RNA and protein synthesis may also be suppressed.
Mitomycin is cell cycle phase-nonspecific, although it has its
maximum effect in late G- and early S-phases.
Mechanism of resistance
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Resistance has been ascribed to deficient
activation, intracellular inactivation of the
reduced quinine, and P-glycoproteinmediated drug efflux.
Even if we give combination of therapy this
protein is capable of causing rapid efflux of
multi-drug resistance (MRD). MRD type
drugs, thus protecting the cells from damage
by preventing these drugs from reaching their
intracellular target.
Uses & spectrum
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Primary uses: Anal cancer,
Bladder cancer (intravesical),
Colon cancer, Gastric cancer,
Head and neck cancer,
Primary unknown cancer,
Pseudomyxoma peritonei.

Other uses: Breast cancer,
Cervical cancer, Conjunctival
melanoma (topical), Lung
cancer, non-small cell, Ocular
surface squamous neoplasia
(topical), Pancreatic cancer,
Primary acquired melanosis
with atypia (topical).
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Compatible: bleomycin,
doxorubicin, cyclophosphamide,
fluorouracil, furosemide,
methotrexate…etc.
Incompatible: Aztreonam,
cefepime, etoposide phosphate,
filgrastim, gemcitabine…etc.
Dosage:
Single agent therapy: I.V.: 20
mg/m2 every 6-8 weeks.
 Combination therapy: I.V.: 10
mg/m2 every 6-8 weeks.
Administration:
Administer slow I.V. push or by
slow (15-30 minute) infusion via a
freely-running dextrose or saline
infusion. Consider using a central
venous catheter.
Pharmacokinetic:
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Distribution: Vd: 22 L/m2;
high drug concentrations
found in kidney, tongue,
muscle, heart, and lung
tissue; probably not
distributed into the CNS
Metabolism: Hepatic
Half-life elimination: 23-78
minutes; Terminal: 50
minutes
Excretion: Urine (<10% as
unchanged drug), with
elevated serum
concentrations.
Drug interaction:
Agent: vinca alkaloids.
Effect: shortness of breath
and broncho-spasm have
been reported in patients
receiving vinca alkaloids in
combination with or after
mitomycin.
Mechanism: unknown.
Management: may be
managed with
bronchodilators, steroids
and/or oxygen
Side effect
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Cardiovascular: CHF
Central nervous system:
Fever
Dermatologic: Alopecia,
nail
banding/discoloration
Gastrointestinal: Nausea,
vomiting and anorexia
Hematologic: Anemia,
myelosuppression
1 to 10%:
 Dermatologic: Rash
 Gastrointestinal: Stomatitis
 Neuromuscular: Paresthesia
 Renal: Creatinine increased
 Respiratory: Interstitial
pneumonitis, infiltrates,
dyspnea, cough.
 <1%: Malaise, pruritus,
extravasation reactions,
hemolytic uremic syndrome,
renal failure, bladder
fibrosis/contraction
(intravesical administration).
Precaution
 Before taking this drug, tell your doctor:

If you are pregnant, or breastfeeding. This drug may cause birth defects
if either the male or female, cause sterility.

If you have any of the following medical problems: chickenpox or gout,
heart disease, kidney stones, liver disease, or other forms of cancer.

While you are being treated with mitomycin, and after you stop
treatment, do not have any immunizations (vaccinations) without your
doctor’s okay.

Mitomycin can lower your blood counts. Your doctor will check your
blood counts before and after each treatment.

Mitomycin is given intravenously. If the drug accidentally leaks out of
the vein where it is given, it may damage the tissue and cause scarring.

Hair loss is temporary, and your hair will grow back after treatment.

Mitomycin can cause severe nausea and vomiting
Contraindication
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Hypersensitivity to mitomycin or any
component of the formulation;
thrombocytopenia;
coagulation disorders,
increased bleeding tendency;
pregnancy.
Bleomycin
Introduction

Is a glycosylated peptide antibiotic produced by the
bacterium Streptomyces verticillus.

When used as an anti-cancer agent, the
chemotherapeutical forms are primarily bleomycin
A2 and B2 .

Common trade name: Blenoxane ®
Structure
The bleomycin are water-soluble, basic glycopeptides. It forms
equimolar complexes with metal ions
SAR
1-The bleomycins are family of basic gycopeptides that differ
from one another in their terminal alkylamine group .
2-The toxic effects and antitumor spectrum are probably
modified by changes in the terminal alkylamine moiety .
3-The bleomycin Cu(π) complex has no antitumor activity .
4-The active form contain Fe(π) with complex formation through
the nitrogen moiety in :
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β-aminoalanine
Propionamide
Β-hydroxyl-histidine
Mannose
Mechanism of action

The cytotoxic action results from their ability to cause
oxidative damage to the deoxyribose of the thymidylate

and other nucleotides leading to single- and double-stranded
breaks in DNA . This action results in inhibition of DNA
synthesis .

It is believed that bleomycin chelates metal ions producing a
pseudoenzyme that reacts with oxygen to produce superoxide
and hydroxide free radicals that cleave DNA.

In addition, these complexes also mediate lipid peroxidation
and oxidation of other cellular molecules.
Resistance

Although the mechanisms of resistance have
not been elucidated, experimental systems
have implicated increased levels of
bleomycin hydrolase ( or deaminase ) ,
glutathione-S-transferase, and possibly,
increased efflux of drug. DNA repair also may
contribute .
Spectrum & uses
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Hodgkin’s Disease It is used with doxorubicin, vinblastine,
and dacarbazine.
Testicular Cancer bleomycin, cisplatin, and etoposide .
Pleural Effusions It is used by intracavitary injection as a
sclerosing agent . bleomycin has been suggested as a
suitable alternative to tetracycline .
Head and Neck Cancer In a patients receiving bleomycin,
cisplatin,
methotrexate, and vincristine for head and neck cancer had
higher rates of
complete response.
Cervical Cancer combination chemotherapy regimens :
bleomycin, cisplatin, and ifosfamide with mesna.
AIDS-related Kaposi’s Sarcoma combination chemotherapy
with the drug (e.g., bleomycin, doxorubicin, and a vinca
alkaloid
Side effect
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Rash
Fever
Chills
Scarring and stiffening of the lungs causing
breathlessness
Flushing of the skin due to widening of the small
blood vessels Loss of appetite
Inflammation of the lining of the mouth Inflammation
of the lungs
Renal toxicity
Precaution & Contraindication

Contraindicated in: patients who have a history of hypersensitivity
reaction to bleomycin.

Use with caution in patients: with compromised pulmonary
function & compromised renal function .

Carcinogenicity
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Mutagenicity
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Fertility
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Pregnancy: FDA Pregnancy Category D.

Breastfeeding
Pharmacokinetics

Absorption :
It is not significantly absorbed from the GI tract and the drug
must be administered parenterally.

Distribution :
The drug is distributed mainly into the skin, lungs, kidneys and
peritoneum, Concentrations of the drug in tumor cells of the skin
and lungs are higher than those in hematopoietic tissue.

Elimination :
the terminal half-life of the drug is inversely related to creatinine
clearance.
In patients with normal renal function, 60–70% of a
parenterally administered dose is excreted in the urine as active
drug.
Drug interaction
AGENT
cisplatin
digoxin
phenytoin
vincristine
EFFECT
may increase risk of
bleomycin toxicity .
may decrease digoxin levels .
may decrease phenytoin
levels .
sequential administration of
vincristine given before
bleomycin may improve
bleomycin efficacy
Conclusion
Doxorubic
in
M.O.A Binds to
DNA
Inhibit
DNA &
RNA
synthesis
Dactinomycin
Prevent
transcription
Bleo-mycin Mitomycin
Degradate
the
preformed
DNA
Bifunctional
Alkylating
agent
& may also
Degradate
DNA
Through
Generation of
Free radical
R.O.A
IV infusion
Parentrally
(IV,IM,
intralesional
)
Side
effect
*Cardiac
*Myelodamage
suppression
*Local
necrosis
*Hair loss
*Myleosuppression
Parentrally
IV
*Allergic
reaction
*Hyperpyrexia
*Pulmonary
fibrosis
*Myelosuppression
*Kidney
damage
Indication
* breast
carcinoma
*Hodgkin's
disease
* nonHodgkin's
lymphoma
*Wilms
tumor
*Hodgkin's
disease
*Rhabdom *Testicular
yosarcoma Cancer
*Pleural
Effusions
*Anal
cancer
*Bladder
cancer
References
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Charles F. Lacy, Lora L. Armstrong, Morton P.
Goldman, Leonard L. Lance. Drug Information
Handbook International, 12th edition.
David S. Fischer, M. Tish Koobf, Henry J. Durivage.
The Cancer Chemotherapy Handbook, 5th edition.
Joel G. Hardmen, Lee E. Limbird. Consultant editor:
Alfred Goodman Gilman.Goodman & Gilman's The
Pharmacological Basis of Therapeutics, 10th edition.
http://www.nhsdirect.nhs.uk/articles/article.aspx
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The Pharmacological Basis of Tberapeutics. Goodman and Gilman,
tenth edition, 2001.
Drug information hand book, 2007.
British national formulary, 1989.
http://en.wikipedia.org/wiki/Mitomycin
http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Mitomy
cin.htm
http://www.cancer.org/docroot/CDG/content/CDG_mitomycin.asp
MedlinePlus Drug Information Dactinomycin.htm
Dactinomycin facts and comparsions at Drugs_com.htm
Complete Dactinomycin information from Drugs_com.htm