Pharm 3620

Human Pharmacology and Therapeutic Principles

Anticancer Drugs

Prof. Lina Dagnino

ldagnino@uwo.ca
 The Drugs
• Antimetabolites: Cell-cycle specific (mainly S-
phase)
– Methotrexate 
– 6-Mercaptopurine
– 5-Fluorouracil

Anti-metabolite drugs target DNA and/or molecules involved in DNA

replication, because tumour cells actively divide and, hence, need
to synthesize DNA
 6-Mercaptopurine
Mechanism of Action

• Very commonly used drug for

cancer and also other diseases
(e.g. inflammatory bowel disease,
and ALL)
6-MP) competes with hypoxanthine and guanine
for the enzyme HGPRTase and is itself
converted to thioinosinic acid (TIMP).

• Hypoxanthine analogue
• Hypoxanthine is necessary for … ?
 6-Mercaptopurine
Mechanisms of Action- Inhibition of purine synthesis
And/or incorporation into RNA or DNA, making it nonfunctional
• TIMP inhibits conversion of IMP into AMP. AMP is necessary to
produce ATP and nucleic acids

OH

Hypoxanthine

OH

Inosine monophosphate

GMP
 Pharmacokinetics of 6-MP

-Poor oral absorption

-Broad distribution (except CNS)
-First pass metabolism (liver)
-Metabolized to 6-methyl-MP by
TPMT
or thiouric acid (by xanthine oxidase)
-Excreted mainly by the kidney
 Pharmacogenomics and
Metabolism of 6-MP
6-MP is converted to methylated derivatives by TPMT
(Thiopurine-S-methyltransferase ) (Detoxification)
 Pharmacogenomics and 6-MP metabolism
There are several variant polymorphism forms of TPMT,
with different activity compared with the wild type form

•Variant forms are slow enzymes

•The polymorphisms can be identified
by sequencing the patient’s DNA
•The DNA is prepared from blood
samples
 Effects or TPMT polymorphisms on the pharmacogenetics of 6-MP
toxicity
wt=wild type v= variant or TPMT-deficient

6-MP is a drug which should be used following the principles

of “personalized medicine”

Active thioguanine nucleotide measured

Adjusted doses for

“slow: metabolizers

Cheok et al. Nature Reviews Cancer 6, 117–129 (February 2006) | doi:10.1038/nrc1800

 More on Metabolism of 6-MP
6-MP is converted to thiouric acid by
Xanthine oxidase
 6-MP DRUG INTERACTIONS

-6-MP is a substrate of hepatic

xanthine oxidase, which converts
it into thiouric acid

-Allopurinol is a drug used to treat

hyperuricemia and gout

-Allopurinol inhibits xanthine oxidase

-What could happen to 6-MP levels

in a patient that takes allopurinol? and
How would that problem be addressed?

Figure 39.11 (still)

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 6-MP ADVERSE EFFECTS

-Bone marrow depression

-(Anemia, immunosuppression)

-Anorexia, vomiting, nausea, diarrhea

-  sensitivity to UV radiation and skin

cancer in chronic users

Figure 39.11 (still)

Chapter 39 MENU >

 5-FLUOROURACIL (5-FU)

-F in place of H interferes with

synthesis of dTMP

-Very useful for solid tumors

(colon, pancreas)

-5-FU is a prodrug. Its metabolite

5-FdUMP inhibits dTMP production

Figure 39.12 (still)

Chapter 39 MENU >

 5-FLUOROURACIL (5-FU)

-5-FU is catabolized by DPD (dihydropyrimidine dehydrogenase) to FDHU both in

tumors and in the liver

-DPD is rate-limiting for catabolism, converting 5-FU to 5-fluorodihydrouracil

(FDHU). About 80% of 5-FU is catabolized to FDHU in liver – important for
toxicity

- 15 DPD polymorphic enzymes. Polymorphisms give rise to enzymes with differing

activities. 5% of people have almost no activity, but the rest can be highly variable
(difficult to personalize doses with this segment of the population)

-Current recommendations: Genotype to identify variants with low or no activity

before initiating chemotherapy, to avoid toxicity
Figure 39.12 (still)

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 PHARMACOKINETICS

- IV for solid tumors: Colon, pancreatic,

stomach, breast tumors. Topical forskin
tumors (high GI tract toxicity)

-Broad tissue distribution

-Metabolized in liver, lung and kidney

-Excreted as metabolites by kidneys

or lungs

-Dosage should be adjusted according

to metabolic enzyme activity levels if
possible
(especially DPD activity)

Figure 39.13 (still)

Chapter 39 MENU >

 ANTI-CANCER ANTIBIOTICS

-Different from the antibacterial antibiotics

-Mechanism of action: Disruption of DNA. Not cell-cycle specific (i.e. they
are toxic in any phase of the cell cycle)
-Anthracycline antibiotics (doxorubicin)
-Bleomycin
 DOXORUBICIN

-One of the most important anti-

cancer drugs
-For sarcomas, breast and lung
carcinomas, ALL and lymphomas
-Limiting toxicity: Heart (due to
Free radicals
cell damage from free radicals)
-Transient bone marrow
suppression, alopecia, GI tract
problems

Figure 39.18 (still)

Chapter 39 MENU >

 PHARMACOKINETICS OF DOXORUBICIN

- IV administration, as it is deactivated in the GI tract

-Care to avoid extravasation, as it produces tissue

necrosis

-Binding to plasma proteins and extensive hepatic

metabolism

Figure 39.19 (still)

Chapter 39 MENU >

 ALKYLATING AGENTS

-They covalently modify DNA at any phase of the cell cycle. They substitute
alkyl groups for H atoms on DNA, which can cross-link DNA chains.
-Most toxic in S-phase, and to rapidly dividing cells. They inhibit DNA
transcription into RNA and, subsequently, protein synthesis
-They are carcinogenic, mutagenic and teratogenic
-Secondary tumors (e.g. leukemias) may arise following treatment
-Prototype drugs: Mechlorethamine (nitrogen mustard) and
cyclophosphamide

Figure 39.21 (still)

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 ALKYLATING AGENTS : CYCLOPHOSPHAMIDE

-Prodrug. Active species generated by

hydroxylation (P450-mediated), followed by
formation of phosphoramide mustard
-Broad spectrum (lymphoma to breast
carcinoma)
-VERY important for autoimmune disorders
(e.g. rheumatoid arthritis)

Figure 39.22 (still)

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 Reminder:

Many types of drugs are

used because
there are
many types of
Cancer

Figure 39.1 (still)

Chapter 39 MENU >

 Microtubule inhibitors
- During mitosis, the two copies of DNA replicated during S-phase migrate to
opposite ends of the dividing cell
-This redistribution of chromosomes is regulated by microtubules
- Microtubule inhibitors alter the equilibrium between polymerized and
depolymerized tubulin
 VINCA ALKALOIDS: VINCRISTINE AND VINBLASTINE

Obtained from the periwinkle (VINCA)

-For Acute Lymphocitic Leukemia,

Wilm’s Tumour, lymphomas, testicular
and lung cancer
-Cell cycle-specific
-They directly bind to tubulin AND
PREVENT TUBULIN POLYMERIZATION
-Resistance via P-glycoprotein
- IV administration
-Hepatic metabolism and biliary/fecal
excretion
-Hyperuricemia due to oxidation of
purines from DNA. Treated with
allopurinol

Figure 39.26 (still)

Chapter 39 MENU >

 Paclitaxel (Taxol)

-Extracted from the needles of the Pacific yew

-Good for ovarian and metastatic breast cancer
-Cell-cycle specific drug (M phase)
-Resistance mediated by P-glycoprotein

Figure 39.27 (still)

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 Paclitaxel (Taxol)
Mechanisms of action and Pharmacokinetics
-Taxol binds to beta-tubulin and
stabilizes microtubules,
preventing their depolymerization
-This induces cell death
-Common for breast tumors
- IV administration
-Broad distribution
-No CNS penetration
-Hepatic metabolism
-Biliary excretion

- Adverse effects: Neutropenia leading to increased infections. Alopecia and

hypersensitivity; peripheral neurophaties due to opening of ion channels on
neurons (non-specific effects)
Figure 39.27 (still)

Chapter 39 MENU >

 CISPLATIN AND CARBOPLATIN

-Mechanism of Action: Covalent binding to DNA and inter- or intrastrand cross-links

(cisplatin-DNA adducts)-
-Inhibition of DNA and RNA synthesis
-Non cell-cycle specific, but greater toxicity in G1 and S-phases
 -For testicular, ovarian, lung, bladder
carcinoma
-IP administration for ovarian tumours
-Dose-limiting toxicity: Kidney
- Hypomagnesemia, hypocalcemia, ototoxicity,
mild bone marrow suppression

Figure 39.31 (still)

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 TOPOISOMERASE INHIBITORS

-Every cell has about 2 m of DNA, which need to be unbundled during replication
-Topoisomerases I and II catalyze DNA unwinding
-Topo II cleaves both DNA strands, passes a second duplex through
the break, and then repairs the broken strands

http://www.youtube.com/watch?v=EYGrElVyHnU
 ETOPOSIDE

-Plant alkaloid that binds DNA/Topo II and inhibits Topo II

-It results in DNA double strand breaks, because it prevents the resealing of the
DNA strand break

Figure 39.33 (still)

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 ETOPOSIDE

-Cell cycle arrest in G2 phase, followed by apoptosis

-Used for testicular cancer and small cell lung carcinoma
-Limiting tissue toxicity: Bone marrow suppression
-Adverse reactions: Potential for leukemia development