Basic Pharmacology of anticancer drugs

AY1415
R&D, 7th edition, chpt 55

Dr. Orla P. Barry

Dept. of Pharmacology and Therapeutics,
Rm. 3.89, WGB.
Email: o.barry@ucc.ie
 Types of Anti-cancer drugs
 1. Alkylating agents

 2. Anti-metabolites

BNF shows the number of

cytotoxic drugs available  3. Plant alkaloids
to-date as 86
 4. Antibiotics

 5. Topoisomerase inhibitors

 6. Hormones

 7. Immune-modulating agents

 8. Receptor and non-receptor tyrosine kinase inhibitors

 1. ALKYLATING
.
AGENTS
 Work on all phases of the cell cycle, active against chronic leukemias,
non-Hodgkin’s lymphoma, Hodgkin’s disease, multiple myeloma.

 Nitrogen mustards
(e.g. Cyclophosphamide, Chlorambucil, Estramustine,
Ifosfamide, Melphalan)
 Nitrosoureas
(e.g. Carmustine, Lomustine)
 Alkyl sulfonates
(e.g. Busulphan)

 Triazenes
(e.g. Dacarbazine)
The effects of bifunctional
 Ethylenimines alkylating agents on DNA
(e.g. Thiotepa) R&D, Fig 55.3, pg 678

 Platinum compounds
(e.g Cisplatin and Carboplatin)
 1. ALKYLATING AGENTS
 M.O.A.

bind covalently to nucleophilic substances.

formation of carbonium ion.
monofunctional and bifuntional alkylation,
intra- and interchain cross linking
N7 of guanine, also N1 and N3 of adenine and
N3 of cytosine
1. Attachment of alkyl groups to DNA bases

2. DNA damage in the form of cross-bridges

3. Mispairing of the nucleotides leading to

mutations
 End Result
interference with transcription and replication
An example of alkylating and cross-linking
 >>cell-cycle arrest>>DNA repair and apoptosis.
of DNA by a nitrogen mustard
R&D, Fig 55.4, pg 679
 2. ANTIMETABOLITES
 Work during the S phase of the cell cycle, active against leukemias,breast,
ovary, and GI tumours.
 Antifolates
(e.g. methotrexate)

 Purine analogs
(e.g. 6-mercaptopurine (6-MP)
6-thioguanine (6-TG)
pentostatin
fludarabine
cladrabine

 Pyrimidine analogs
(e.g. 5-Fluorouracil (5-FU)
Cytarabine
Gemcitabine)
 2. ANTIMETABOLITES
 Antifolates
H
(e.g. Hmethotrexate)
N N N H2N N N H
 M.O.A. 2
H2 H O
H
O
N CH
N C N C N CHC OH
N N
H 2C O H
N
methotrexate (folate antagonist) H2C C OH
CH2

essential for nucleotide synthesis

one-carbon group transfer DHFR DHFR

high affinity to DHFR

inhibits FH2 reduction FOLATE DIHYDROFOLATE TETRAHYDROFOLATE
depletion of FH4 F
MTX
FH 2
MTX
FH4

FH 4-CH 2
 End Result
Inhibits DNA synthesis
DTMP DUMP
deoxythymidine monophosphate deoxyuridine monophosphate

H 2N N N
H2 O O
H
N C N C N CHC OH
N O
CH3 H 2C
NH2 H2C C OH

methotrexate
 2. ANTIMETABOLITES
 Purine analogs
(e.g. 6-mercaptopurine, 6-thioguanine, pentostatin)
 M.O.A.
 6-mercaptopurine (analog of hypoxanthine)
 6-thioguanine (analog of guanine)

 Converted to fraudulent nucleotides

 Inhibit first step in “de novo” purine synthesis

 End Result inhibits DNA/RNA synthesis

 pentostatin – M.O.A. inhibits adenosine deaminase

catalyzes adenosine to inosine

 End Result Interferes with purine metabolism and cell

proliferation
 2. ANTIMETABOLITES
 Pyrimidine analogs
(e.g. 5-Fluorouracil)

 M.O.A.
5-fluorouracil (analogue of uracil)
must first be converted to the nucleotide
to form - 5‘FdUMP (5-fluoro-2‘-deoxyuridine
5‘- phosphate)
rect inhibitor of thymidylate synthetase
the key enzyme in thymidylate synthesis
(methotrexate in contrast is an indirect
inhibitor of this enzyme through inhibition
of DHFR)

Simplified diagram of action of

 End Result methotrexate and fluorouracil on
thymidylate synthesis
 inhibits DNA synthesis R&D, Fig 55.3, pg 680
 3. PLANT ALKALOIDS
 Work during the M phase of the cell cycle, active against metastatic testicular
cancer, lymphomas, Kaposi’s sarcoma, breast cancer and neuroblastoma.

 Vinca alkaloids
(e.g. vincristine, vinblastine and vindesine)

 Taxanes
(e.g. paclitaxel, docetaxel)
 3. PLANT ALKALOIDS
 M.O.A.
Vinca alkaloids
 Bind to tubulin >> prevention of
spindle formation

 End Result
 arrest in metaphase

 M.O.A.
Taxanes
 Bind to microtubules – antagonises
microtubule disassembly
Schematic representation of the different
 End Result actions of Vinca alkaloids and taxanes on
 arrest in metaphase tubulin/microtubule dynamics. Vinca alkaloids
block polymerization of tubulins and promote
depolymerization, whereas taxanes block
microtubule depolymerization.
 4. ANTIBIOTICS
Anthracyclines e.g. Doxorubicin, daunorubicin, idarubicin
Other related compounds e.g. Bleomycin, dactinomycin, mitomycin, procarbazine
 M.O.A.
Intercalation between DNA bases
DNA strand breakage
Inhibition of Topoisomerase II

 End Result
 Inhibition of DNA synthesis

 Doxorubicin
 Binds to and stabilises DNA-topoisomerase II complex
 Dactinomycin
 Intercalation between DNA bases
 Mitomycin
 Bifunctional alkylating agent
 5. Topoisomerase Inhibitors
 Topoisomerase I inhibitors
e.g. Etoposide
Irinotecan
Topotecan

 Topoisomerase II inhibitors
e.g. Etoposide
Doxorubicin
Amsacrine
 M.O.A. Mitoxantrone

 impairing the ability of topoisomerase to religate DNA

 enhancing the forward rate of DNA cleavage

End Result

 Inhibition of DNA synthesis

 6. HORMONES
 Hormone therapy

 used in three situations

 secondary or adjuvant therapy (slow down the spread of cancer cells that
have escaped)
 palliative (ease pain caused by the spread of cancer)
 neoadjuvant therapy (shrink the tumour before a procedure to reduce the
likelihood of spread)

 How hormone therapy works:

 Decrease hormones in the body

 Change the cancer’s ability to use hormones
 6. HORMONES
Gonadotropins: Luteinizing and Follicle Stimulating Hormones

Recall..........
 6. HORMONES
 1.Sex hormones Breast, Prostate, Ovarian, Uterine cancers
 anti-estrogens
 tamoxifen and fulvestrant
(breast, ovarian, melanoma)
 M.O.A. Tamoxifen
competitive partial antagonist of estrogen receptor (tissue selective
antagonist or agonist activity)
suppresses serum levels of IGF-1 and upregulates TGF production
M.O.A. Fulvestrant – antagonist of estrogen receptor
 anti-androgens
 Flutamide, bicalutamide (non-steroidal) for prostate cancer
 Cyproterone acetate (steroidal) for prostate cancer
 M.O.A. Compete with testosterone (and DHT) for binding to androgen
receptors in the prostate gland
 aromatase inhibitors
exemestane (steroidal irreversible aromatase inhibitor)
anastrozole and letrozole (nonsteroidal reversible aromatase
inhibitor)
used for treatment of advanced estrogen or progesterone receptor positive
non-tamoxifen responsive breast cancer
 M.O.A. – Inhibition of estrogen production from androgens
 6. HORMONES

Anti-oestrogen
Anti-oestrogen
 6. HORMONES
 LHRH (GnRH) analogs (agonists)
 leuprolide for prostate cancer
 goserelin for breast and prostate cancer
 triptorelin for ovarian and prostate cancer
 M.O.A. – Stimulate the pituitary’s GnRH receptors thus inducing negative
feedback inhibition and ultimately reducing LH and testosterone
 LHRH (GnRH) antagonists
 abarelix, degarelix for prostate cancer (devoid of any agonist effect on the
GnRH receptor - no initial “flare-up” or surge)
M.O.A. – Reduce levels of LH (and FSH) and thus testosterone
 Corticosteroids - acute leukemia, myeloma, lymphomas, and
other haematological cancers
 Prednisone
 Dexamethasone
 Prednisolone
 Hydrocortisone
 M.O.A. – Reduction of ACTH secretion and subsequent adrenal steroid
production (inhibition of lymphocyte proliferation)
 6. HORMONES
Summary of hormone therapy targets in breast cancer
Aromatase inhibitors block estrogen
synthesis and decresase the ligand
concentration. Antiestrogens bind to Partial agonist
the estrogen receptor (ER) and act
either as partial agonists (tamoxifen) Anti-estrogens (tamoxifen)
or initiate a cascade of ER degradation
(fluvestrant). Antagonist
(fulvestrant)

Estrogen synthesis E
E-ERα
Nucleus
Estrogen synthesis E

Cytoplasm
Aromatase inhibitors
 6. HORMONES
 TNBC (Triple Negative Breast Cancer)
HER2
7%-20%, aggressive nature,
poor prognosis

 ER- ER
 PR-
 HER2- PR

 Hormonal Therapy X Targeted Therapies (in development)

 Trastuzumab X Anti-VEGF
Anti-EGFR
 Cytotoxic Chemotherapy  Multi-tyrosine kinase inhibitors
 Doxorubicin mTOR inhibitors
 Taxanes IGF-1R
Hsp 90 inhibition
7. IMMUNE-MODULATING AGENTS

Pictures taken from the HSE website to

promote the HPV vaccine

http://www.hse.ie/eng/health/child/immunisation/hcpinfo/conference/hpv4.pdf
7. IMMUNE-MODULATING AGENTS
 Vaccines
 2 types
 Prophylactic vaccines e.g. HPV
Gardasil (Merck and Co.) HPV-16, -18, -31, -6, -11
Cervarix (GlaxoSmithKline) HPV-16, -18, -31, -33, -35

 Therapeutic vaccines e.g. 1) Cell based vaccines

2) TAAs (Tumour associated Ags)
3) Peptide vaccines

 Cytokines  HPV
 GM-CSF
 IL-2  Cervical
 IL-12  Anus
 Penis
 Immunotherapies that overcome tolerance
 Vulva
 T-reg cell depletion
 Vagina
 Targeted T-cell therapies
 Head and neck
                       
7. IMMUNE-MODULATING AGENTS
                       
      
Sciencewww.sciencemag.org
Major milestones in the historical path of the development of vaccinology and vaccine design.

Approved as a treatment for

mCRPC by the FDA in 2010

prostatic acid phosphatase (PAP).

2013 2nd therapeutic

vaccine
Ipilimumab
Delany I et al. EMBO Mol Med.
doi:10.1002/emmm.201403876 
©2014 by European Molecular Biology Organization
 7. IMMUNE-MODULATING AGENTS
Ipilimumab

Drug: Ipilimumab is a recombinant,fully human, monoclonal antibody targeted at

cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
Studied: hormone-refractory PCa, mRCC, NSCLC
Used: Malignant Melanoma

Mechanism of action
Ipilimumab
8. Receptor and non-receptor tyrosine
kinase (TK) modulators

The mechanism of action of

anticancer monoclonal
antibodies and protein
kinase inhibitors
R&D, Fig 55.8, pg 685

Downloaded from: StudentConsult (on 8 September 2011 03:58 PM)

© 2005 Elsevier
8. Receptor and non-receptor tyrosine
kinase (TK) modulators
 Strategies to target TKs in Cancer Therapy
 1. Small molecule inhibitors that interfere with the binding of ATP
 Imatinib mesylate (Gleevec) (BCR-ABL)
 Lapatinib (Tykerb) (ErbB1 and ErbB2)
 Canertinib
 Gefitinib (Iressa) (ErbB1)
 Erlotinib (Tarceva) (ErbB1)

 2. MoAbs against receptor TKs or their ligands

 Trastuzumab (Herceptin) (ErbB2, also known as Her2)

 Cetuximab (Erbitux) (ErbB1)
 Panitumumab (Vectibix) (ErbB1)
 Bevacizumab (Avastin) (VEFG-A)
 8. Receptor and non-receptor tyrosine kinase (TK) modulators
BCR-ABL – Translocation between human chromosomes
9 and 22 t(9q34;22q11)
Treatment - Imatininb (Gleevec) – 1st generation drug
- Nilotinib (2nd generation drug)
- Dasatinib (3rd generation drug)

Schematic diagram of the translocation that creates the Philadelphia chromosome. The ABL and BCR
genes reside on the long arms of chromosomes 9 and 22, respectively. As a result of the (9;22) translocation, a
BCR-ABL gene is formed on the derivative chromosome 22 (Philadelphia chromosome).
 8. Receptor and non-receptor tyrosine kinase (TK) modulators
BCR-ABL – Translocation between human chromosomes
9 and 22 t(9q34;22q11)
Treatment - Imatininb mesylate (Gleevec)

Mechanism of action of imatinib. (A) The constitutively active BCR-ABL tyrosine

kinase functions by transferring phosphate from ATP to tyrosine residues on various
substrates to cause excess proliferation of myeloid cells characteristic of CML. (B)
Imatinib blocks the binding of ATP to the BCR-ABL tyrosine kinase, thus inhibiting
kinase activity.
 8. Receptor and non-receptor tyrosine kinase (TK) modulators

ErbB ligands
EGF
TNF
EGFR Signaling network
EGFR/
ErbB ErbB1 ErbB2 ErbB3 ErbB4
EGFR Her2/new
receptors

Tumour cell TK TK

STATS MAPKs PI(3)K PLC

Migration Cell division Modulation of apoptosis Adhesion Differentiation

% EGFR
Tumour type expression

● NSCLC ● 40-80
Four members HER1 (EGFR, ErbB1) ● Head and neck ● 80-100
HER2 (ErbB2) ● Colorectal
● Gastric
● 25-100
● 33-81
HER3 (ErbB3) ● Pancreatic ● 30-50
● Ovarian ● 35-70
HER4 (ErbB4) ● Breast ● 15-37
● Prostate ● 40-90
● Glioma ● 40-92