Cancer: a proliferative disease.

Cancer is classified on the basis of the

tissue from which it developed.
Secretory epithelia Protective cell
layers

Epithelial cells
>90 % of cancers (80% of cancer related
deaths)
1% of tumors
Bone, connective tissue cells, muscle
Central and peripheral nervous system cells
1% of cancers (2.5% cancer-related deaths)
Classes of Anticancer Drugs

Antimetabolites Ex: 5-Flurouracil

Gemcitabine

Antibiotics ex: Anthracyclines/ Doxorubicin

Alkylating agents ex: Cyclophosphamide

Microtubule inhibitors
ex: Paclitaxel
Vinca alkaloids

Others ex: Camptothecins

Etoposide
Platinum compounds
 ALKYLATING AGENTS

Mechanism of Action:
Alkylating drugs – transfer alkyl groups to guanine
resulting in the cross-linking of DNA bases

Alkylating agents belong to the group of “Nitrogen

Mustards”

The first nitrogen mustard drug was mustine (HN2)

(not in use anymore)
and other
alkylating
agents

It attaches the alkyl group to the guanines on opposite strands

at the number 7 nitrogen atom of the imidazole ring.
Cross-linked bases result in attempts at repair which can then
result in strandbreaks cell death
and mismatch repair mutation *

CELL CYCLE: Alkylating agents are effective in

both resting and cycling (more effective) cells.
WHY?
Prototype: Cyclophosphamide: Bis(chlorethyl)amine

Cyclophosphamide is metabolized by Cyt P450 first

to hydroxylated intermediates and then to the active
phosphoramide mustard

Wide application:
• lymphomas, leukemias, multiple myeloma
• neuroblastoma retinoblastoma
• lung breast ovary

Side effects:
• Nausea/ vomiting/ alopecia/ bone marrow
depression (myelosuppression)
• *secondary malignancies may appear years later

Resistance:
• increased repair activity
• decreased cell permeability
• glutathione-mediated reduction
 ANTIMETABOLITES

Mechanisms of action are based on the structures of the drugs

which are closely related to the normal molecules made by
the body and therefore interfere with normal processes.

2 Classes:

• Inhibiting the synthesis of purine and pyrimidine precursors

ex: methotrexate and 5-flurouracil

• directly competing with the normal molecules in

DNA or RNA synthesis ex: Gemcitabine
Antimetabolites interfere mainly with DNA and RNA synthesis

MTX, 5-FU

FH4 FH2
RNA/DNA)

MTX
High levels of
folinic acid can
rescue cells from
methotrexate
 Methotrexate (MTX):

Mechanism of action:
Folic acid is reduced by the enzyme Dihyodrofolate
Reductase (DHFR) to form FH4

MTX strongly inhibits DHFR

Since FH4 is a required cofactor for many molecules but
thymidine synthesis is the most effected.

The drug Leucovorin can be used to reverse the effects of

MTX
CELL CYCLE: MTX is only effective in cycling cells

Applications:

Used in combination with other drugs in some leukemias

Some lymphomas, breast cancers and head and neck
carcinomas

Resistance: amplification of DHFR, decreased influx of drug

 A uracil analogue

5-Fluoruracil

The F atom in 5-FU

interferes with conversion
of deoxyuridylate to
dUMP dTMP deoxythymidylate by
the thymidylate synthase
Thymidylate
synthase enzyme.
N5,N10-methylene-FH4 FH2 Administered with a
low level of Leucovorin
N,N-methylene-FH4
(folinic acid) in order
Used for DNA to insure the formation of a
synthesis 5-FU: thymidylate synthase:
folinic acid complex which
cannot then proceed with
methyl transfer
5-FU- a pyrimidine analog

Application: slow growing solid tumors (colorectal,

breast, ovarian, pancreatic, gastric carcinomas)

Cell cycle: blocks S phase

Resistance mechanisms:
-loss of ability to metabolize
5-FU or increased levels of thymidylate synthase.

Side effects:
- myelosuppression
- GI irritation (oral formulations)
- Stomatitis (inflammation in the mouth)
- hepatotoxicity
 Mechanism of action:

-competes with deoxycytidine

for the kinase
- incorporation into DNA
results in chain termination

Deoxycytidine pyrimidine analog

 DNA INTERCALATING DRUGS

Doxorubicin: antibiotics derived from Streptomyces peucetius

Mechanisms of action:
1- 4 ring structure- 2 of which are quinones which generate
reactive oxygen species which can create strand breaks
2- intercalation between bases resulting in uncoiling

S. peucetius
Doxorubicin:

Applications:

Leukemias, lymphomas, sarcomas, adenocarcinomas

Metabolism:

Hepatic metabolism (hepatotoxicity)

Side effects:

-Nausea and vomiting

-Alopecia
-Somatitis
-Cardiotoxicity- due to free radical peroxidation of
heart tissue
-bond marrow suppression (Myelosuppression)

Mechanisms of resistance:

-P-glycoprotein (Pgp-170) multidrug resistance

-altered topoisomerase II (see below)
The Pgp (P-glycoprotein) multidrug resistance
transporter protein
Bleomycin:

A copper chelating molecule that binds to DNA

(DNA-bleomycin-Fe2+)

Like Doxrubicin it undergoes oxidation to bleomycin-Fe3+

The freed electrons react with O2 to form superoxide
radicals causing DNA strand breaks.

Applications:

- Lymphoma and squamous cell cancers

- testicular and bladder cancers

Metabolism:

-Given IV and broken down by bleomycin hydrolase enzyme

Mechanism of resistance:
Increased hydrolase activity

Side effects:
- Hyperpigmentation, hyperkeratosis, rashes
- nausea and vomiting (targets dividing cells in gut)
An unusual reaction to bleomycin treatment
“flagellate hyperpigmentation”
During transcription and DNA replication, the DNA needs
to be unwound in order for the transcription/replication
machinery to gain access to the DNA so it can be copied
or replicate, respectively. Topoisomerases I and II are also
essential in the separation of daughter strands during
replication- nicking and resealing the the DNA helix so it
does not becomesupercoiled and tangled.

Doxorubicin

Video

Type II topoisomerase cuts both strands of one DNA double

helix, passes another unbroken DNA helix through it, and
then reseals the cut strand.
Drugs that target DNA unwinding enzymes
(Topoisomerases)

1) Anthracylines
2) Campothecins
3- Anthracyclines prevent the resealing step catalyzed by
Topoisomerase II resulting in double stranded breaks in the DNA
Type I topoisomerases cut one strand of double-stranded DNA
relax the strand, and reanneal the strands.
Camptothecins (Topotecan) bind to the Topo I:DNA
complex (cleavable complex) during the
intermediate step of the DNA relaxation process
resulting in a single or double stranded break

Camptotheca acuminate
Podophyllins : mechanism is similar to anthracylines-
Topo II inhibition

ie. Etoposide

Derived from Mandrake plant root

Drugs that inhibit microtubules

Inhibitors of microtubules prevent mitosis by interfering

with the mitotic spindle.
 1) Taxanes: paclitaxel (Taxol) (IV) and docetaxel (oral)

α&β
tubulin

Taxanes bind to β-tubulin

Video
Taxanes

Paclitaxel - bark of the Pacific Yew

A challenge to synthesize!!

Docetaxel –needles of the European

Yew
Tubulin depolymerization
cycle is necessary for
movement of the spindle
to separate chromosomes
2) Vinca alkaloids: vincristine and vinblastine

Derived from periwinkle

How do the Vinca alkaloids destabilize microtubules

Microtubule Inhibitors
Side effects:

Vinca alkaloids- neurotoxicity for both vincristine and

Vinblastine
Myelosuppression (reduced hematopoetic cells)- vincristine
only

Taxanes- myelosuppression, alopecia, neurotoxicity

Indications:

Vinca alkaloids- both hematalogic cancers

and solid epithelial carcinomas

Taxanes: metastatic ovarian and breast and

certain lung cancers

Mechanisms of resistance:

- β-tubulin mutations

- Drug efflux through the Pgp transporter (MDR-1)

which actively pumps drug out of the cell
 Video

Cisplatin, Oxaliplatin
Cisplatin:

Applications:
neurological cancers, epithelial cancers
(refractory to other treatments), melanoma, hematopoetic
cancers

Metabolism:

Directly eliminated through the kidneys

Toxicity:

Renal failure
Severe nausea and vomiting
Alopecia, ototoxicity, myelosuppression
Monoclonal antibody: Bevicazumab
 Bevicazumab

Metabolism:
-undergoes proteolysis

Applications:
-colorectal cancers, some breast cancers and
lung cancers

Side Effects:

-Gastrointestinal (GI) perforation

- destabilization of blood vessels leading to hemorrhage
-thrombosis (stroke)
-reduced wound healing