Introduction

Chemotherapy (often abbreviated to chemo and

sometimes CTX or CTx) is a category of cancer
treatment that uses one or more anti-cancer drugs
as part of a standardized chemotherapy regimen.

 Chemotherapy may be given with a curative intent

or it may aim to prolong life or to treat symptoms i.e
best supportive care, (palliative chemotherapy).
 Introduction

Data from the US estimates a life-time probability of

25%.
Overall 5-year survival is 68%.

Multidisciplinary approaches can cure up to 50% of

all cancers but chemotherapy alone can cure only
about 10–15% of all cancer patients.
 Chemotherapy ctd

Curative treatment reduces tumor mass below

1gram/ 1 bilion cells.
Steep dose-response curves for both therapeutic and
toxic effects
The log-kill hypothesis or fractional kill is the basis
of continued therapy.
Dosage is based on body surface area
 Balancing toxicity

At high doses the percentage of normal and cancer

cells killed is very similar.
For this reason, doses are chosen where anti-tumour
activity exceeds normal cell death
Narrow therapeutic index
 Combination drug therapy

Challenges of chemotherapy include resistance,

adverse events, toxicity and mutagenesis
COMBINATION
Full doses or reduced doses
Advantages include efficacy, low toxicity, broad
spectrum, prevent/delay resistance
Forms protocols with acronyms
 Definitions

PHASES OF CHEMOTHERAPY

-Induction

-Consolidation

- Intensification

-CNS treatment/prophylaxis..Sanctuaries

-Maintenance
 Definitions ctd

Neoadjuvant chemotherapy
refers to the use of chemotherapy before surgery.
Aim is down-staging
Determines chemo-sensitivity
 Chemotherapy

Adjuvant chemotherapy.
Use of chemotherapy after surgical excision
Reduce the incidence of both local and systemic
recurrence and to improve the overall survival of
patients.
Indications.. breast cancer, colon cancer, gastric
cancer, non-small cell lung cancer, Wilms' tumor,
anaplastic astrocytoma, and osteogenic sarcoma.
CLASSIFICATION OF ANTI-CANCER DRUGS
 1. Classification Based on cell-cycle

 Cell cycle–specific (CCS)

drugs
 Cell cycle–nonspecific
(CCNS) drugs can sterilize
tumor cells whether they are
cycling or resting in the G0
compartment. CCNS drugs
can kill both G0 and cycling
cells (although cycling cells
are more sensitive).
 CELL CY CLE SPECIFIC DRUGS

S phase–dependent M-Phase dependent

Antimetabolites Vinca alkaloids

Vinblastine Capecitabine,
Hydroxyurea Doxorubicin
Etoposide Podophyllatoxins
Paclitaxel Gemcitabine
Irinotecan Taxanes
Thioguanine Mercaptopurine
 Cycle specific drugs continued

G1 –Phase dependent G2-Phase dependent

Asparaginase Bleomycin
Corticosteroids Procarbazine
Mitoxantrone
Topotecan
 Cells

Note; Reduction of tumor burden through surgery,

or radiation or cell-cycle non-specific drugs can
promote non-proliferating cells into active
proliferation and make them sensitive to cell-cycle
specific drugs.
Clssification based on structure
and MOA
 1. Alkylating agents

Originally derived from mustard gas used in WW1.

Bis(chloroethyl)amines (Nitrogen mustards) eg

cyclophosphamide, mechlorethamine, melphalan, and
chlorambucil.
Ethyleneimines (Aziridines) eg Thiotepa and busulfan and
mytomycin

Nitrosoureas eg carmustine (BCNU), lomustine (CCNU), and

semustine (methyl-CCNU) and streptozotocin
Tetrazines include , mitozolamide and temozolamide.
 Mechanism of Action

As a class, the alkylating agents exert their cytotoxic

effects via transfer of their alkyl groups to various
cellular constituents such as DNA, RNA and
proteins.
Covalent alkylations of DNA causes apoptosis during
division or repair.
 Cancer cells

Replicating cells are most susceptible to these drugs.

Thus, although alkylating agents are not cell cycle
specific, cells are most susceptible to alkylation in
late G1 and S phases of the cell cycle and express
blockage in G2.
 Resistance

The mechanism of acquired resistance to alkylating

agents may involve increased capability to repair
DNA lesions, decreased transport of the alkylating
drug into the cell, and increased production of
glutathione and glutathione-associated proteins,
which are needed to conjugate the alkylating agent,
or increased glutathione S-transferase activity, which
catalyzes the conjugation.
 Alkylating agents ctd

The adverse effects usually associated with alkylating

agents are generally dose-related and occur primarily
in rapidly growing tissues such as bone marrow, the
gastrointestinal tract, and the reproductive system.
Nausea and vomiting.
Direct vesicant effects.
 Carcinogenic especially acute myelogenous
leukemia.
Mutagenic
 Nitrosoureas

The nitrosoureas are highly lipid-soluble and are

able to cross the blood-brain barrier, making them
useful in the treatment of brain tumors.
 Nonclassic Alkylating Agents

Procarbazine most carcinogenic alkylating agent.

Hexamethylmelamine
Bendamustine; Used for CLL and indolent NHL
 Platinum Analogs

Cisplatin,Carboplatin, and Oxaliplatin.

In addition to targeting DNA, the platinum analogs

have also been shown to bind to both cytoplasmic
and nuclear proteins,
 2. Antimetabolites

Impair DNA and RNA synthesis by Inhibiting purine

or pyrimidine nucleotide precursors or incopoaration
into DNA causing apoptosis

Resemble either nucleobases ( purines or pyrimidines)

or nucleosides(nucleotides without phosphate group)
Maximal effects in S-phase

Cell cycle specific

 Antimetabolites ctd

1. ANTIFOLATES
Methotrexate a folic acid analog that binds with high
affinity to the active catalytic site of dihydrofolate
reductase (DHFR), inhibiting synthesis of
tetrahydrofolate (THF), inhibiting synthesis of
Adenine,Guanine,Thymidine and the amino acids
serine and methionine.
S-phase specific
 Methotraxate

Administered by the intravenous, intrathecal, or oral

route. However, oral bioavailability is saturable and
erratic at doses greater than 25 mg/m2.
Care must also be taken when MTX is used in the
presence of drugs such as aspirin, penicillin,
cephalosporins, and nonsteroidal anti-inflammatory
agents, as they inhibit the renal excretion of MTX.
Hydration and alkalinization of urine prevents renal
toxicity
 Methotraxate

The biologic effects of MTX can be reversed by

administration of the reduced folate leucovorin (5-
formyltetrahydrofolate) or by L-leucovorin, which is
the active enantiomer.
Leucovorin rescue is used in conjunction with high-
dose MTX therapy to rescue normal cells from undue
toxicity, and it has also been used in cases of
accidental drug overdose.
 Pemetrexed and Pralatraxate

Pemetrexed is a pyrrolopyrimidine antifolate analog

which inhibits thymidylate synthase in addition to
DHFR. Mainly used in non-small cell lung ca
Pralatraxate is a newer DHFR, 2nd-line for T-cell
lymphoma.
Folic acid and vitamin B12 supplements reduce
hematologic and GIT toxicities of both drugs
 2. FLUOROPYRIMIDINES

1. 5-Fluorouracil
forms 3 metabolites; 5-fluoro-2'-deoxyuridine-5'-
monophosphate (FdUMP) inhibits thymidylate synthase
and 5,10-methylenetetrahydrofolate, therefore inhibiting
de novo synthesis of thymidylate. This results in inhibition
of DNA synthesis through "thymineless death.”
5-fluorouridine-5'-triphosphate (FUTP) is incorporated
into RNA, where it interferes with RNA processing and
mRNA translation.
And 5-fluorodeoxyuridine-5'-triphosphate (FdUTP) can be
incorporated into cellular DNA, resulting in inhibition of
DNA synthesis and function.
 Capecitabine

Capecitabine is pro-drug of 5-fluorouracil.

Given orally.
 3. DEOXYCYTIDINE ANALOGS

1. Cytarabine
An S phase-specific antimetabolite Ara-CTP
competitively inhibits DNA polymerase-α and DNA
polymerase-β, thereby resulting in blockade of DNA
synthesis and DNA repair, respectively.
Ara-CTP is also incorporated into RNA and DNA.
 Gemcitabine

2. Gemcitabine is a fluorine-substituted deoxycytidine

analog with 3 MOA.
Inhibits ribonucleotide reductase through gemcitabine
diphosphate, which reduces the level of
deoxyribonucleoside triphosphates required for DNA
synthesis.
Inhibits DNA polymerase through gemcitabine
triphosphate of thereby resulting in blockade of DNA
synthesis and DNA repair.
Incorporated into DNA through gemcitabine triphosphate,
leading to inhibition of DNA synthesis and function
 4. PURINE ANALOGS

1. 6-Mercaptopurine (6-MP) and Azathioprine

which is used as an immunosuppressant.
Activated by addition of ribosephosphate catalyzed
by Hypoxanthine-guanine
phosphoribosyltransferase.
The nucleotide (6-MP ribosephosphate)is
incorporated into both RNA and DNA.
Or inhibits de novo purine synthesis
 6-MP

6-MP is converted to an inactive metabolite (6-

thiouric acid) by an oxidation reaction catalyzed by
xanthine oxidase
 Fludarabine

Fludarabine(5’phosphate of 2-fluoroadenine
arabinoside)
The diphosphate metabolite inhibits ribonucleotide
reductase, leading to inhibition of essential
deoxyribonucleotide triphosphates.
The triphosphate metabolite inhibits DNA
polymerase and can also be directly incorporated
into DNA
Finally, fludarabine induces apoptosis in susceptible
cells. A potent immunosuppressant!
 Cladribine

Cladribine (2-chlorodeoxyadenosine)
is a purine nucleoside analog. Resembles
Fludarabine
Causes DNA chain termination
Inhibits ribonucleotide reductase
No cross-resistance with fludarabine
 3. Microtubule inhibitors

1. VINCA ALKALOIDS
Vinblastine Vincristine, Vinorelbine
Inhibit tubulin polymerization, which disrupts
assembly of microtubules, an important part of the
cytoskeleton and the mitotic spindle.
Results in mitotic arrest in metaphase.
Metabolized by the liver P450 system
 Taxanes

2. TAXANES
Paclitaxel is an alkaloid ester. Binds to
microtubules with enhancement of tubulin
polymerization and results in inhibition of mitosis
and cell division. Metabolized extensively by the
liver P450 system
Abraxane is A novel albumin-bound paclitaxel
formulation
 Taxanes

Docetaxel is a semisynthetic taxane.

Ixabepilone is not a taxane but binds directly to β-
tubulin subunits on microtubules, leading to
inhibition of normal microtubule dynamics. Of note,
this agent continues to have activity in drug-resistant
tumors that overexpress P-glycoprotein or tubulin
mutations.
 4. Cytotoxic Antibiotics

All of the anticancer antibiotics now being used in

clinical practice are products of various strains of the
soil microbe Streptomyces. These include the
anthracyclines, bleomycin, and mitomycin.
 Cytotoxic antibiotics ctd

ANTHRACYCLINES
Doxorubicin, daunorubicin, idarubicin, epirubicin,
and mitoxantrone.
(1) inhibition of topoisomerase II; (2) high-affinity
binding to DNA through intercalation, with
consequent blockade of the synthesis of DNA and
RNA, and DNA strand scission; (3) generation of
semiquinone free radicals and oxygen free radicals
through an iron-dependent, enzyme-mediated
reductive process; and (4) binding to cellular
membranes to alter fluidity and ion transport.
 Antibiotics

Mitomycin C It undergoes metabolic activation

through an enzyme-mediated reduction to generate
an alkylating agent that cross-links DNA
 Antibiotics

Bleomycin
is a small peptide that contains a DNA-binding
region and an iron-binding domain at opposite ends
of the molecule. It acts by binding to DNA, which
results in single-strand and double-strand breaks
following free radical formation, and inhibition of
DNA biosynthesis. The fragmentation of DNA is due
to oxidation of a DNA-bleomycin-Fe(II) complex and
leads to chromosomal aberrations. Its a cell cycle-
specific drug that causes accumulation of cells in the
G2 phase of the cell cycle.
 5. Tyrosine Kinase Inhibitors

Imatinib, Dasatinib, Nilotinib, Erlotinib, Sorafenib

and Sunitib

Imatinib is an inhibitor of the tyrosine kinase

domain of the Bcr-Abl oncoprotein and prevents
phosphorylation of the kinase substrate by ATP. It
also inhibits other receptor tyrosine kinases for
platelet-derived growth factor receptor (PDGFR),
stem cell factor, and c-kit.
 TKs

Imatinib, dasatinib, and nilotinib are all metabolized

in the liver, mainly by the CYP3A4 liver microsomal
enzyme.
Patients should avoid grapefruit products and the
use of St. John's wort.
Gefitinib and erlotinib are small molecule
inhibitors of the tyrosine kinase domain associated
with the EGFR.
 TKs

Sorafenib is a small molecule that inhibits multiple

receptor tyrosine kinases (RTKs), especially VEGF-
R2 and VEGF-R3, platelet-derived growth factorβ-
(PDGFR- β), and raf kinase.
Sunitinib is similar to sorafenib in that it inhibits
multiple RTKs, although the specific types are
somewhat different. They include PDGFR-α and
PDGFR-β, VEGFR-R1, VEGF-R2, VEGF-R3, and c-
kit.
 6. Steroid hormones/antagonists

Steroids: Prednisone,Dexamethasone, Estrogens,

Megacestrol acetate
Estrogen receptor antagonists.Tamoxifen,Raloxifene
Estrogen Aromatase inhibitors:
Anastrazole,Letrozole, Exemestane, Fulvestrant
GNRH analogues Goserelin, Leuprolide, Triptorelin
Testosterone receptor antagonists:Bicalutamide,
Nilutamide,Flutamide,
 7. Topoisomerase inhibitors

1.CAMPTOTHECINS
Topotecan and irinotecan are natural products
derived from the Camptotheca acuminata tree.
They inhibit topoisomerase I, the key enzyme
responsible for cutting and religating single DNA
strands.
 Topoisomerase inhibitors

2. EPIPODOPHYLLOTOXINS
Etoposide (and teniposide), extracted from the
mayapple root (Podophyllum peltatum).
Inhibits topoisomerase II, which results in DNA
damage through strand breakage induced by the
formation of a ternary complex of drug, DNA, and
enzyme.
 8. Monoclonal antibodies

Cetuximab is a chimeric monoclonal antibody

directed against the extracellular domain of the
EGFR.
Panitumumab is a fully human monoclonal
antibody directed against the EGFR and works
through inhibition of the EGFR signaling pathway.
 Monoclonal antibodies ctd

Bevacizumab is a recombinant humanized

monoclonal antibody that targets all forms of VEGF-
A. It binds to and prevents VEGF-A from interacting
with the target VEGF receptors.
Trastuzumab
 IMMUNE-CHECK POINT INHIBITORS

Are monoclonal antibodies.

Difine “immune checkpoint”
Produce response beyond treatment
Includes CTLA-4 and PD-1/PD-L1/2
The first immune-checkpoint inhibitor approved by
the US Food and Drug Administration (FDA) was
ipilimumab, a fully human immunoglobulin (Ig) G1
monoclonal antibody (mAb) that blocks cytotoxic T-
lymphocyte antigen (CTLA)-4 for the treatment of
metastatic melanoma in 2011.
 Programmed cell death pathway

The interaction between PD-1 and its ligands PD-L1

and PD-L2 reduces T-lymphocyte function .
 PD-1 signaling inhibits T-cell activation, leading to
reduced proliferation, cytokine production, and T-
cell cytolysis.
 PD-1/PD-L1/2 ctd

Programmed cell death receptor (PD-1) is an

immunoinhibitory receptor that belongs
to the CD28 family and is expressed on T cells, B
cells, monocytes, natural killer cells, and many
tumor-infiltrating lymphocytes (TILs).
It is activated by the two ligands; PD-L1 and PD –L2.
Certain tumors over-express this receptor as an
immune-evasion mechanism
 PD-1 Inhibitors

Nivolumab is a fully human IgG4 monoclonal

antibody against PD-1. Approved for treatment of
melanoma, squamous cell lung cancer, and Hodgkin
lympoma.
Pembrolizumab is a highly selective, humanized
IgG4-kappa monoclonal antibody with activity
against PD-1.Approved for the treatment of
ipilumumab-refratory melanoma.
 PD-L1 Inhibitors

 MPDL-3280A, an anti-PD-L1 monoclonal antibody

is approved for the treatment of bladder cancer and
non-small cell lung cancer.
 9. Others

Asparaginase (L-asparagine amidohydrolase) is an enzyme isolated

from Escherichi coli.
Retinoic Acid Derivatives eg Tretinoin (all-trans-retinoic acid)
There are three generations of retinoids:
First generation retinoids: which include retinol, retinal, tretinoin (
retinoic acid, Retin-A), isotretinoin, and alitretinoin.
Second generation retinoids: which include etretinate and its metabolite
acitretin.
Third generation retinoids: which include tazarotene, bexarotene and
Adapalene.
Fourth generation : retinoids derived from pyranones as the fourth
generation. One such compound is Seletinoid G

Arsenic trioxide (As2O3) causes apoptosis, used in AML

 BSA CALCULATOR

The calculator can be found under “calculators” on the Data

Management Center’s Web page,
https://www.fstrf.org/apps/cfmx/apps/common/Portal/index.
cfm
.
