Download Anticancer Drugs

Anticancer Drugs
Aims of Chemotherapy
1. Give palliative
a. Relieve of unpleasant symptoms of cancer
2. Induces remission
a. Control of the disease
b. Stop cancer
i. Enlargement
ii. Spreading
3. Cure
a. Eradication of all malignant cells
Classifications of Anticancer Drugs
Old Generation of Cytotoxic Drugs
1. Cycle phase specificity of the drugs classification
a. Cell Cycle Specific Agents (CCSA)
i. Drugs that act during a specific phase of cell cycle
ii. Effective against rapid growth of malignant cells
iii. Agents
1. S phase specific drug
a. Doxorubicin
2. M phase specific drug
a. Vinca alkaloids
i. Taxanes
3. G2 phase specific drug
a. Bleomycin
b. Cell Cycle Non-Specific Agents (CCNSA)
i. Active throughout cell cycle
ii. Active against all types of cancerous cells
iii. Agents
1. Alkylating agents
2. Antitumour antibiotics
3. Platinum compound
2. Chemical and origin of drugs classification
a. Alkalyting agent
i. Nitrogen mustard
1. Cyclophosphamide
ii. Platinum analogue
1. Cisplatin
iii. Alkyl sulfonate
1. Busulfan
b. Antimetabolites
i. Folate antagonist
1. Methotrexate (MTX)
ii. Pyrimidine analogue
1. 5-Fluorouracil (5-FU)
iii. Purine analogues
1. Azathioprine
2. 6-mercaptopurine (6-MP)
c. Plant Derivatives
i. Vinca alkaloid – Vinca rosea
1. Vincristine
ii. Taxoids – European yew
1. Paclitaxel
d. Antitumour Antibiotics
i. Doxorubicin
ii. Bleomycin
iii. Dactinomycin
New Generation of Anticancer Drugs
Anticancer Drugs Resistance Emergence
1. Hormones and Hormone Antagonists
a. Glucocorticoid
i. Use as supportive role in anticancer regimen
1. Prevention of allergic reaction
2. Emesis control
3. Relief neurologic complication
a. Intracranial hypertension
b. Spinal cord compression
4. Pain reliever
b. Estrogen and Antiestrogen
i. Tamoxifen
1. It is a partial agonist-antagonist of estrogen receptor
2. Binds to estrogen receptor on estrogen sensitive
tumor cells
a. Inhibits transcription of estrogen-responsive gene
c. Androgen and Antiandrogen
d. Progestogen
i. Progesteron
e. Gonadotrophin-releasing Hormone analogues
2. Monoclonal Antibodies
a. Rituximab
3. Interferons
4. Interlukin
1. Inherent Resistance
a. Native genetic resistance to anticancer drugs
i. Melanoma is resistant to almost all types of anticancer
drugs
2. Acquired Resistance
a. Due to mutation as result of prolonged administration of
anticancer drugs
b. Happens through few mechanisms
i. Membrane transport of anticancer drugs might be
depleted
ii. Bound to cytosolic glutathione (GSH) and being
inactivated through antioxidant mechanism
iii. Metabolized to inactive species though drug drug
interaction or CYP450 system
3. Multidrug Resistance
a. Resistance to several anticancer drugs
Major Adverse Effects of Anticancer Drugs
1. Inhibition of normal cell replication in the rapidly growth
tissue
a. GIT
i. Nausea
ii. Chemotherapy induced emesis
b. Bone marrow
i. Anemia
ii. Thrombocytopenia
iii. Immunosuppresion
c. Hair follicles
i. Allopecia
d. Gonads
i. Infertility
2. Stimulation of Chemoreceptor Trigger Zone (CTZ) in the area
of postrema at the lateral wall of the 4th ventricle of the
medulla and upper GIT
a. Eliciting massive nausea and vomiting
3. Massive cell destruction and excessive purine metabolism
a. Hyperuricemia
b. Secondary gout
c. Urate stone formation
4. DNA damages lead to
a. Mutagenesis
b. Carcinogenesis
c. Teratogenesis
Combined Cancer Chemotherapy
1. Supression of drug resistance
a. FEC regimen in breast cancer chemotherapy
2. Increased efficacy
a. CHOP (Cyclophosphamide, Hydroxydaunorubicin,
Ocovin, Prednisolone) + Rituximab in treatment of NonHodgkin Lymphoma
3. Reduced side effects
a. Prednisolone to reduce emesis
Mechanism of Actions of Anticancer Drugs
Agents
Nitrogen Mustard
Cyclophosphamide
Other Alkylating agent
worth of mentioning
1. Platinum analogue
a. Cisplatin
2. Alkyl sulfonates
a. Busulfan
Pharmacokinetics
Absorption
 Readily absorb in the
GIT mucosa
 Can be given either
orally or parenterally
Distribution
 Readily distributed in
the body
compartment
 Passes the BBB
Metabolism
 It is a prodrug
 Undergoes CYP450
metabolism into
active
Phosphoramide
mustard
Excretion
 Renal excretion
Alkylating Agents
Mechanism of Actions
1. It has a chemical that can bind covalently with
the DNA which leads to
a. DNA fragmentation
i. Due to recognition by the DNA
Polymerase repair system; the alkylated
DNA strands are fragmented and
consequently destroyed
b. Cross bridges formation
i. Two bases are linked together by an
alkylating agent that has 2 DNA binding
sites
ii. Cross bridges can be formed
1. Within a single DNA molecule
2. Two DNA molecules
c. Mispairing of Nucleotides
i. Mispairing between 2 noncomplimentary DNA molecules leading
to mutation
2. All of these pharmacological effects lead to
a. Prevention of DNA synthesis
b. RNA transcription
c. Resulting in DNA damage and cellular
apoptosis
Therapeutic Uses
Cancer treatment
1. Lymphomas
2. Breast cancer
Autoimmune diseases
1. Nephrotic syndrome
2. Rheumatid arthritis
Agents
Folate Antagonist
Methotrexate (MTX)
Pyrimidine Analogue
5-Fluorouracil (5-FU)

Analogue of Thymine in
which methyl group is
replaced by flourine
atom
Purine Analogues
1. Azathioprine – prodrug
2. 6-Mercaptpurine (6-MP)
– active metabolite
Pharmacokinetics
Antimetabolite
Mechanism of Actions
Therapeutic Uses
Absorption

70% well absorbed orally
Distribution

Rapid onset 4-6 weeks

Does not pass BBB
Metabolism

Metabolized into less active
hydoxylated metabolites
Excretion

90% excreted unchanged
though urine by
o
Filtration
o
Active secretion

Therefore requires dose
adjustment in pts with renal
impairment
MTX acts by
1. ↓direct inhibition towards cellular proliferation
2. Stimulates apoptosis in immune inflammatory cells
3. ↓chemotaxis of inflammatory cells
4. Inhibition in the synthesis of inflammatory cytokines
These are achieved through the
1. Irreversible inhibition of Dihydrofolate reductase (DHFR)
a. This enzyme requires for the conversion of Folic acid 
Dihydrofolate and Dihydrofolate  Tetrahydrofolate
2. Partially reversible inihibiton of Thymidylate synthetase
a. This enzyme requires for the conversion of Tetrahydrofolate 
Purine/Pyrimidine
3. Inhibition of Aminoimidazolecarboxamide Ribonucleotide
Transformylase (AICAR)
These steps are essential in the synthesis of DNA
Cancer treatment
1. Choriocarcinoma
2. Leukemias
3. Lymphomas
4. Breast cancer
Absorption

Readily absorb orally

Can be given
o
Orally
o
Topically
Distribution

Distributed across all body
compartments

Passes the BBB; therefore
penetrates the CNS
Metabolism

CYP450 metabolism
Excretion

Renal excretion in an
unchanged form
5-FU has 2 active metabolites which are
1. 5-fluoro-deoxyuridine monophosphate (5FdUMP)
a. Irreversible (suicide) inhibitor of Thymidylate
Synthase
b. Inhibition will lead to prevention in Thymidine
synthesis which is important as a building block of
DNA
2. 5-fluoro-uridine triphosphate (5-FUTP)
a. Incorporate into RNA by RNA polymerase
b. Leads to dysfunction of the RNA
Cancer treatment
1. Breast cancer
2. Colorectal cancer
3. Gastric tumors
4. Squamous cell tumours of
a. Head
b. Neck
Absorption
1. Readily absorb through
the GIT mucosa
Distribution
1. Doesn’t pass the BBB
Metabolism
1. Hepatic metabolism
Excretion
1. Renal excretion
1. Azathioprine is converted to 6-MP.
2. 6-MP is then converted into 6-Thioinosine-5monophosphate (TIMP)
3. TIMP inhibits enzyme that involves in the purine
metabolism
a. This will therefore inhibit the DNA and RNA synthesis
Cancer treatment
1. Acute lymphoblastic
leukemia
2. Lymphomas
3. Breast cancer
Drug drug Interaction
With Allopurinol – Xanthine Oxidase Inhibitor
Only if the cancer pts is having a Azathioprine or Mercaptopurine
regime;
1. Azathioprine  Mercaptopurine  Inactive metabolite
Conversion of mercaptopurine into inactive metabolite requires
xanthine oxidase, therefore inhibition of xanthine oxidase activity
will lead to ↑in mercaptopurine toxicity which is pancytopenia
Autoimmune Diseases
1. Rheumatoid arthritis
2. Psoriasis
3. Crohn’s disease
Autoimmune diseases
1. Rheumatoid arthritis
2. Crohn’s disease
Plant Derivatives
Mechanism of Actions
Agents
Vinca Alkaloid
Vincristine
Derived from Vinca rosea
Other Plant Derivatives
 Paclitaxel
o Derived from European
yew
1. Binds to tubulin and inhibits its polymerization into microtubule
2. This will prevent the formation of mitotic spindle during
metaphase in the M phase
3. It is also inhibits other celullar activities that involved microtubule
a. Phagocytosis
b. Chemotaxis
Agents
Pharmacokinetics
1. Doxorubicin
a. Streptomyces
peucetius
2. Dactinomycin
a. Actinomyces spp.
3. Bleomycin
a. Streptomyces
verticillus
Doxorubicin
Absorption
 Poorly absorb orally
as it is being
metabolised
extensively in the gut
Distribution
 Doesn’t cross the BBB
Metabolism
 Hepatic metabolism
Excretion
 Renal excretion leads
to red discoloration
of the urine
Side effects of
Doxorubicin
1. Cardiotoxicity
a. Cardiomayopathy
b. Congestive heart
failure
c. Cardiac
arrhythmias
Antitumour Antibiotic
Mechanism of Actions
1. Doxorubicin is known to interact with DNA by
intercalation and inhibition of macromolecular
biosynthesis.
2. This inhibits the progression of the enzyme
topoisomerase II,
a. which relaxes supercoils in DNA for
transcription.
b. Doxorubicin stabilizes the topoisomerase II
complex after it has broken the DNA chain for
replication, preventing the DNA double helix
from being resealed and thereby stopping
the process of replication.
Therapeutic Uses
Cancer treatment
 Acute lymphoblastic
leukemia
 Wilm’s tumour
 Lymphomas
Therapeutic Uses
Cancer treatment
1. Acute lymphocytic
leukemia
2. Lymphomas
3. Breast carcinomas
4. Lung carcinomas
5. Sarcomas