CHEMOTHERAPEUTIC

DRUGS

dr. Putu Nita Cahyawati, MSc

Department of Pharmacology and Pharmacy, Faculty of Medicine and

Health Sciences, Warmadewa University
Goal of antineoplastic drugs therapy
Selective toxicity

Unique drugs targets

(peptidoglycan)

Selective inhibition of
similiar targets (DHFR)

Common targets
(thymidylate synthase)
Antineoplastic drug classes
DNA Damage Agents
Alkylating Agent
Classes of Alkylating Agents
• Interfere with DNA replication and gene
expression by ankylating the alkyl group
to DNA (the N-7 and O-6 atoms of
guanine bases)
• Alkylation is the transfer of an alkyl
group from one molecule to another.
• Alkylation of guanine can result in
miscoding through abnormal base pairing
with thymine or in depurination by
excision of guanine residues.
• The latter effect leads to DNA strand
breakage
M (mitosis)= cell divisoan
G1=active metabolism in the absence of
DNA syntesis
S (synthesis)= replication DNA
G2=prepare for mitosis
Cells are most susceptible to alkylation in
late G 1 and S phases of the cell cycle.
Cyclophosphamide
◦ Oral, im/iv (adding diluent)
◦ In combination: less toxic
◦ Highly toxic, low therapeutic index
◦ Carsinogenesis: bladder cancer
(acrolein, which is concentrated in the
urine)
The Platinum Drugs
Cisplatin, carboplatin, and oxalaplatin
They kill cells in a similar way with alkylating agentsCross-linking of DNA
cytotoxic action
Targeting nucleophilic center in guanine (N-7 and O-6), adenine (N-1 and N-3),
cytosine (N-3)
These drugs could be used at the maximum-tolerated dose

Cisplatin
IV infusion (6-8h)rapid inj (1-5min)nephrotoxicity
intraperitoneal
Pretreatment :antiemetic tx
In combination
CI:renal ds
Antitumor Antibiotics
Products of various strains of the
soil microbe Streptomyces.
Include the anthracyclines
(doxorubicin and daunorubicin),
bleomycin, and mitomycin.
Mechanism of action:
These antibiotics bind to DNA
through specific bases and block
the synthesis of RNA, DNA, or
bothcause DNA strand scission
and interfere with cell replication.
Free radicals mechanism
binding to cellular membranes to
alter fluidity and ion transport.
inhibition of topoisomerase II
 Inhibitor of DNA Syntesis and Integrity

1. Antimetabolites And Folate Pathway

Inhibitor

Inhibit the enzymes involved in nucleotide syntesis and

metabolism or are incorporated as analogues into DNAchain
termination or strand breaks

These drugas exert their effects during late G 1 and S phases of

the cell cycle when the cell are undergoing DNA replication
Classes of Antimetabolites and Folate Pathway
Inhibitor
Inhibitor of folate metabolism
inhibitor of dihyropteroate syntethase (unique target) sulfonamide
inhibitor of dihydrofolate reductase (similar)MTX, trimethoprim

Inhibitor of purine metabolism (Purine Antagonists)

6-mercaptopurine (6-MP), azatioprine (AZA)

Inhibitor of thymidylate syntetase

flourouracil (5-FU)

Inhibitor of ribonucleotide reductase

hydroxyurea

Nucleotide (purine&pyrimidine) analogues

thioguanide, fludarabine, cytarabine, cladibrine
 Purine Antagonists

ribonucleotide reductase

Nucleotide analogues

thymidylate syntetase
 2. Topoisomerase Inhibitors
CAMPTOTHECINS
Semisynthetic molecule derived from alkaloid extracts of Camptotheca plants
Target of actioninhibiting topoisomerase IDNA strand damage apoptosis
Topoisomerase Imodulates supercoling by complexing with DNA and nicking
one of its two strands
EPIPODOPHYLLOTOXINS
Semisynthetic molecule derived from alkaloid extracts of Podophyllum plants
Target of actioninhibiting topoisomerase IIDNA strand damageapoptosis

ANTHRACYCLINES
Natural antitumor antibiotics isolated from a species of the fungus Streptomyces
The cytotoxic action of anthracyclines:
a. inhibition of topoisomerase II
b. generation free radicals mechanism
c. binding to cellular membranes to alter fluidity and ion transport.
Inhibitor of Microtubule Functions
MICROTUBULE INHIBITORS
(Natural product cancer chemotherapy drugs)

VINCA ALKALOIDS
 Vinblastine, Vincristine
• Natural product originally isolated from Vinca rosea
• Bind to β-tubulin on a portion of the molecule that overlaps
with the GDP-binding domain
• Vinca alkaloid inhibit polymerization microtubule

TAXANES
Pactitaxel, Docetaxel
• Natural product originally isolated from the bark of the
western yew tree
• Bind to β-tubulin subunit of microtubules at a site distinct
from the vinca alkaloid binding site
• Taxanes promote microtubule (stabilizing) polymerization
and inhibit depolymerizationarrest cell in mitosis
apoptosis
MISCELLANEOUS ANTICANCER DRUGS
The anticancer drugs that do not fit traditional categories have
been approved for clinical use by the Food and Drug
Administration (FDA)
 THANK YOU
Refference
Golan, DE., Tashjian, AH., Armstrong, EJ., Armstrong, AW. 2012.
Principles of Pharmacology: The Pathophysiologic Basis of Drug
Therapy 3rd ed. Lippincott Williams & Wilkins. p 563-580.
Katzung, BG., Masters, SB., Trevor, AJ. 2012. Basic & Clinical
Pharmacology 12nd ed. The McGraw-Hill. p 949-975