Understand the pathogenesis and drug therapy of cancer

1. ANTICANCER DRUGS
TAHIR ALBASHIR (BSc. Pharm)
APRIL, 2021

2. ANTICANCER DRUGS

3. CANCER
• Cancer is characterised by uncontrolled
multiplication and spread of abnormal forms of the
body’s own cells.
• It is the second most common cause of death in the
developed nations (cardiovascular disease has the
dubious distinction of heading that table) and one in
three people will be diagnosed with cancer during
their lifetime.

4. CANCER…
• Cancer arises as a result of a series of genetic
and epigenetic changes, the main genetic
lesions being:
– inactivation of tumour suppressor genes
– the activation of oncogenes (mutation of the
normal genes controlling cell division and other
processes).

5. CANCER…
• Cancer cells have four characteristics that
distinguish them from normal cells:
– uncontrolled proliferation
– loss of function because of lack of capacity to
differentiate
– invasiveness
– the ability to metastasise.

6. CANCER…
• Cancer cells have uncontrolled proliferation often
because of changes in:
– growth factors and/or their receptors
– intracellular signalling pathways, particularly those controlling
the cell cycle and apoptosis
– telomerase expression.
• Proliferation may be supported by tumour-related
angiogenesis.

7. ANTICANCER DRUGS
• Most anticancer drugs are antiproliferative –
most damage DNA and thereby initiate
apoptosis.
• Their main target is cell division as such, they
affect all rapidly dividing normal tissues, and
therefore are likely to produce, to a greater or
lesser extent, the following general toxic
effects:

8. ANTICANCER DRUGS…
• Bone marrow toxicity (myelosuppression)
• Impaired wound healing
• Loss of hair (alopecia)
• Damage to gastrointestinal epithelium (including oral mucous
membranes)
• Depression of growth in children
• Sterility
• Teratogenicity
• Carcinogenicity – because many cytotoxic drugs are mutagens.

9. ANTICANCER DRUGS…
• The main anticancer drugs can be divided into the following
general categories:
• Cytotoxic drugs. These include:
 Alkylating agents
 Antimetabolites
 Cytotoxic antibiotics
 Plant derivatives
• Hormones/hormones antagonists
• Protein kinase inhibitors
• Monoclonal antibodies

10. ALKYLATING AGENTS AND
RELATED COMPOUNDS
• Alkylating agents have groups that form covalent bonds
with cell substituents; a carbonium ion is the reactive
intermediate.
• MOA: Intrastrand cross-linking of DNA
• This causes defective replication and chain breakage.
• Their principal effect occurs during DNA synthesis and
the resulting damage triggers apoptosis.
• Unwanted effects include myelosuppression, sterility and
risk of non-lymphocytic leukaemia.

11. • Nitrogen mustards:
Bendramustine, chlorambucil, cyclophosphamide,
estramustine, ifosfamide, melphalan
• Nitrosoureas:
Carmustine, lomustine
• Platinum compounds:
Carboplatin, cisplatin, oxaliplatin
• Other
Busulfan, dacarbazine, hydroxycarbamide,
mitobronitol, procarbazine treosulfan, thiotepa,
temozolimide

12. ANTIMETABOLITES
• Antimetabolites block or subvert pathways of DNA
synthesis.
• They are structurally related to normal compounds
that exist within the cell
• They generally interfere with the availability of
normal purine or pyrimidine nucleotide precursors,
either by inhibiting their synthesis or by competing
with them in DNA or RNA synthesis.

13. Folate antagonists
Methotrexate
Pyrimidine analogues
Azacitidine, capecitabine, cytarabine, decitabine,
fluorouracil gemcitabine
Purine analogues
Cladibrine, clofarabrine, fludarabine,
mercaptopurine, nelarabine, pentostatin, tioguanine

14. CYTOTOXIC ANTIBIOTICS
• This is a widely used group of drugs that mainly produce
their effects through direct action on DNA.
• As a rule, they should not be given together with
radiotherapy, as the cumulative burden of toxicity is very
high.
• MOA: Multiple effects on DNA/RNA synthesis and
topisomerase action
• Include: Daunorubicin, Doxorubicin, Epirubicin,
Idarubicin, Bleomycin, Dactinomycin, Mitomycin

15. PLANT DERIVATIVES
• These are naturally occurring plant products with potent
cytotoxic effects and have a use as anticancer drugs.
• Taxanes
Cabazitaxel, docetaxel, paclitaxel
• Vinca alkaloids
Vinblastine, vincristine
• Campothecins
Irinotecan, topotecan
• Other: Etoposide

16. HORMONES
• Tumors that are steroid hormone sensitive may be either
 hormone responsive, in which the tumor regresses following treatment
with a specific hormone
 hormone dependent, in which removal of a hormonal stimulus causes
tumor regression; or
 both.
• These drugs act as physiological agonists, antagonists or hormone
synthesis inhibitors to disrupt hormone-dependent tumour growth
• They are not cytotoxic, but modify the growth of hormone-
dependent tumours.
• All hormones are only palliative.

17. • Hormones/analogues
• Glucocorticoids
Prednisolone, Dexamethasone
• Oestrogens
Diethylstilbestrol, ethinyloestradiol
• Progestogens
Megestrol, norehisterone, medroxyprogesterone
• Gonadotrophin-releasing hormone analogues
Goserelin, buserelin, leuprorelin and triptorelin
• Somatostatin analogues
Octreotide, lanreotide

18. Hormone Antagonists
• Antioestrogens
Tamoxifen, toremifene, fulvestrant
• Aromatase inhibitors
Anastrozole, letrozole and exemestane
• Antiandrogens
Flutamide, cyproterone and bicalutamide

19. MONOCLONAL ANTIBODIES AND
PROTEIN KINASE INHIBITORS
• Many tumours overexpress growth factor receptors that therefore
stimulate cell proliferation and tumour growth.
• This can be inhibited by:
– monoclonal antibodies, which bind to the extracellular domain
of the EGF receptor, the oncogenic receptor HER2 receptor, or
which neutralise the growth factors themselves
– protein kinase inhibitors, which prevent downstream signalling
triggered by growth factors by inhibiting specific oncogenic
kinases or by inhibiting specific receptor tyrosine kinases or
several receptor-associated kinases
• Some monoclonals act directly on lymphocyte cell surface proteins
to cause lysis (e.g. rituximab), thereby preventing proliferation.

20. • Monoclonal antibodies
Bevacizumab, cetuximab, rituximab, trastuzumab
• Tyrosine kinase inhibitors
Dasatinib, imatinib, nilotinib, sorafenib, erlotinib,
sunitinib

21. THANK YOU