Anti-cancer drugs site of action and uses in different diseases , their origin and action in cell cycle,specific places where these drugs acts

1. MECHANISM OF ACTION OF
ANTICANCER DRUGS
NADIR SHAH

2. What is cancer?
• Defined as the uncontrolled growth of cells coupled with malignant
behaviour, invasion and metastasis.
• Interaction between genetic and environmental factors, causing
mutations in oncogenes and tumour suppressor genes.

4. HISTORY
• The era of cancer chemotherapy began in the 1940s with the first use
of nitrogen mustards and folic acid antagonist drugs.
• Mustard gas was used as a chemical warfare agent during World War
I and was discovered a potent suppressor of hematopoiesis
• December 1942, several people with advanced lymphomas were given
the drug by vein, their improvement, although temporary, was
remarkable

5. • The first chemotherapy drug to be developed from this line of research
was mustine
• The term was coined in the early 1900s by Paul Ehrlich as meaning
any use of chemicals to treat any disease (chemo +therapy),

6. CELL CYCLE
1. G1: the growth phase in which the cell increases in size and prepares to copy
DNA
2. S (Synthesis): which allows doubling of the chromosomal material
3. G2: a further growth phase before cell division
4. M (Mitosis): where the chromosomes separate and the cell divides.

11. ALKYLATING AGENTS
• Include, nitrogen mustards (melphalan and chlorambucil) and
oxazaphosphorines (cyclophosphamide and ifosfamide).
• Covalently linked an alkyl group (R-CH2) to nucleic acids or proteins.
• Form bridges between a single strand or two separate strands of DNA
• Interfering with the action of the enzymes involved in DNA
replication.

13. HEAVY METALS
• Include, platinum agents (carboplatin,
cisplatin and oxaliplatin).
• Cisplatin is an organic heavy metal
complex.
• This causes intra- and inter-strand DNA
cross-links, resulting in inhibition of DNA,
RNA and protein synthesis.

14. ANTIMETABOLITES
•Bear a structural similarity to naturally occurring substances such as
vitamins, nucleosides or amino acids.
• Compete with the natural substrate for the active site on an essential
enzyme or receptor.
• Some are incorporated directly into DNA or RNA.

15. Folic acid antagonists
• Methotrexate competitively inhibits dihydrofolate reductase, which is
responsible for the formation of tetrahydrofolate from dihydrofolate
• This is essential for the generation of coenzymes that are involved in
synthesis of purines, thymidylate, methionine and glycine
• Thymidine monophosphate essential for DNA and RNA synthesis.

17. Pyrimidine analogues
• Resemble pyrimidine molecules and
work by either inhibiting the synthesis of
nucleic acids e.g. fluorouracil
• By inhibiting enzymes involved in DNA
synthesis (e.g. cytarabine, which inhibits
DNA polymerase)
• By incorporated into DNA (e.g.
gemcitabine), interfering with DNA
synthesis and resulting in cell death.

18. Purine analogues
• 6 mercaptopurine (6MP) and thioguanine
are derivatives of adenine and guanine
respectively.
• A sulphur group replaces the keto group on
carbon-6 in these compounds.
• Inhibit nucleotide biosynthesis by direct
incorporation into DNA.

19. CYTOTOXIC ANTIBIOTICS
• Anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin)
• intercalate with DNA and affect the topoisomerase II enzyme -
interfere with replication.
• Actinomycin D intercalates between guanine and cytosine base pairs-
interferes with the transcription of DNA

20. • Bleomycin consists of a mixture of glycopeptides that cause DNA
fragmentation.
• Mitomycin C inhibits DNA synthesis by cross-linking DNA, acting
like an alkylating agent.

21. SPINDLE POISONS
1. Vinca alkaloids
• vincristine and vinblastine- mitotic
spindle poisons.
• Bind to tubulin- inhibits assembly of
the spindle during metaphase-
inhibiting mitosis
2. Taxoids
• Paclitaxel (Taxol) and docetaxel
(Taxotere) promote assembly of
microtubules and inhibits their
disassembly.

23. TOPOISOMERASE INHIBITORS
• Responsible for altering the 3D structure of DNA by
cleaving/unwinding/rejoining reaction
• Involved in DNA replication, chromatid segregation and transcription
• The drugs are phase-specific and prevent cells from entering mitosis
from G2

24. • There are two broad classes:
1. Topoisomerase I inhibitors (e.g. irinotecan and topetecan).
These bind to the enzyme-DNA complex, stabilizing it and preventing
DNA replication.
2. Topoisomerase II inhibitors (e.g. etoposide). These stabilize the
complex between topoisomerase II and DNA that causes strand breaks
and ultimately inhibits DNA replication.

25. CHEMOTHERAPY IN HEAD
AND NECK CANCER
• Chemotherapy is regularly employed in the management of head and
neck cancer.
• It has not changed the cure rates of locally advanced cancer.
• However, allowed improved organ preservation when combined with
radiotherapy and has led to a reduction in rates of distant metastases.

26. CHOICE OF CHEMOTHERAPY
IN HEAD AND NECK CANCER
• The single agents active in head and neck cancer, with response rates
between 15% and 40%,
• Include methotrexate, cisplatin, carboplatin, fluorouracil,
ifosfamide , bleomycin, paclitaxel, and docetaxel.
• Cisplatin is one of the most active drugs against squamous head and
neck cancer.

27. CHEMOTHERAPY STRATEGIES
1.Combination chemotherapy
Combinations of cytotoxic agents are widely- more effective than single
agents.
 Possible explanations for this include:
 exposure to agents with different mechanisms of action and non-
overlapping toxicities
 reduction in the development of drug resistance
 the ability to use combinations of drugs that may be synergistic.
 Combination chemotherapy in head and neck cancers usually includes
cisplatin.

28. 2.Adjuvant chemotherapy
• Administration of chemotherapy after curative surgery or radiotherapy,
in patients considered to be at high risk of relapse.
• The intention is to eradicate micrometastatic disease.

29. 3.Neoadjuvant chemotherapy
(induction chemotherapy)
• Neoadjuvant, or induction chemotherapy, is the use of chemotherapy
prior to definitive surgery or radiotherapy.
• To reduce the tumour bulk before definitive treatment
• Hence improve local and distant control of the disease.
• This will also achieve greater organ preservation and overall survival.

30. 4.Concurrent chemoradiation (CRT)
• Synchronous use of chemotherapy and radiotherapy.
• The rationale- is that chemotherapy can sensitize tumours to
radiotherapy by inhibiting tumour repopulation,
• preferentially killing hypoxic cells, inhibiting the repair of sublethal
radiation damage, sterilizing micrometastatic disease outside of the
radiation fields and decreasing the tumour mass,
• Which leads to improved blood supply and enhance drug delivery

31. NOVEL THERAPIES
• Over the last years interest has focused on the role of novel agents
with more targeted mechanisms of action
• Agents that able to manipulate the immune system to provide tumour
control (immunotherapy)
• Targeted therapy aims to specifically act on a well-defined target or
biologic pathway that, when inactivated, causes regression or
destruction of the malignant process
• It includes monoclonal antibodies or targeted small molecules.

32. Monoclonal antibodies
• can be derived from a variety of sources:
• Murine – mouse antibodies
• Chimeric – part mouse/part human antibodies
• Humanized – engineered to be mostly human
• Human – fully human antibodies.
• Murine monoclonal antibodies may themselves induce an immune
response that limits repeated administration.
• Humanized and, to a lesser extent, chimeric antibodies are less
immunogenic and can be given repeatedly

33. Proposed mechanisms of action of monoclonal antibodies as anticancer
agents are-
• Induction of apoptosis
• Blocking of the receptors needed for cell proliferation/ function
• Antibody dependent cellular cytotoxicity (ADCC, conjugating the
‘killer cell’ to the tumour cell)
• Complement-mediated cellular cytotoxicity (fixation of complement
leading to cytotoxicity).

34. A desirable target for MAbs would have the
following properties:
• Wide distribution on tumour cells
• High level of expression
• Bound to tumour, allowing cell lysis
• Absent from normal tissues
• Trigger activation of complement on MAb binding
• Remains unchanged following antibody binding to ensure it remains
visible to the immune system
• Antibodies have also been used as vectors for the delivery of drugs
and radiopharmaceuticals to a target of tumour cells.

35. Monoclonal antibodies against EGFR
• An example of a monoclonal antibody developed against EGFR is the
chimeric IgG antibody cetuximab
• which has the binding affinity equal to that of the natural ligand
• Can effectively block the effect of epidermal growth factor

36. Targeted small molecules against EGFR
• Gefitinib (Iressa) and erlotinib (Tarceva) are orally active epidermal
growth factor receptor tyrosine kinase inhibitors (EGFR-TKI)
• Block the EGFR signalling cascade, thereby inhibiting the growth,
proliferation and survival of many solid tumours.

37. Inhibitors of angiogenesis
• Angiogenesis is the process of new blood vessel formation,
• Triggered by hypoxia and regulated by numerous stimulators and
inhibitors.
• It is vital for cancer development.
• A tumour cannot exceed beyond 2–3 mm3 without inducing a
vascular supply.
• New vessels develop on the edge of the tumour and then migrate into
the tumour.

38. Vascular endothelial growth factor receptor
• VEGF is a cytokine released in response to hypoxia and is an
important stimulator of angiogenesis
• It binds to two structurally related transmembrane receptors present on
endothelial cells
• associated with a higher tumour proliferation rate and worse survival

39. Monoclonal antibodies against VEGFR
• Bevacizumab (Avastin) is a humanized murine monoclonal antibody
targeting VEGF
• It is the first anti-angiogenic drug to have induced a survival
advantage in cancer therapy.
• Currently clinical trials are exploring the feasibility and the therapeutic
potential of a combination of bevacizumab and EGFR-targeted drugs.

40. Toxic effects of anticancer drugs

41. THANK YOU!