This document discusses principles of chemotherapy used in ENT (ear, nose, and throat) cancers. It covers cell cycle phases, tumor biology principles like cell signaling and oncogenes. It describes different classes of chemotherapy drugs like alkylating agents, antimetabolites, cytotoxic antibiotics, spindle poisons, and monoclonal antibodies. It discusses strategies like combination chemotherapy and neoadjuvant chemotherapy. The key points are that chemotherapy targets rapidly dividing cancer cells, different drug classes have varying mechanisms of action and toxicities, and combining drugs may be more effective than single agents to reduce resistance.

1. CHEMOTHERAPY IN ENT
MODERATOR-DR.SATHYAKI
PRESENTER-DR.RAZAL

2. PRINCIPLES OF CHEMOTHERAPY
◦ Chemotherapies are targeted at the process of cell division, but
the cancer cells are more likely to be replicating than a normal
cells.
◦ Their action is not specific and are associated with significant
toxicity.
◦ Only 10% of cancers are genetically inherited, rest are
environmental.

3. CELL CYCLE
◦ Uncontrolled cell division is a result of interference in the normal
balance of the cell cycle.
◦ The cell cycle is divided into 5 phase
PRINCIPLES OF TUMOR BIOLOGY

4. CELL CYCLE
◦ G0- Gap 0 or resting phase (Non Proliferative Stage)
◦ G1- Gap 1 ,during which the cell increases in size and prepare to copy
DNA
◦ S Phase (Synthetic phase)-Involving DNA synthesis(doubling of
chromosomal material)
◦ G2-Gap 2 Post synthetic phase – during which DNA replication is
determined and errors are corrected.
◦ M Phase- Mitotic phase during which the replicated chromosomes are
separated into 2 nuclei for the 2 daughter cells
These daughter cells re-enter cell cycle or resting G0 phase.

5. Cell Signaling
◦ Cell respond via external signals called growth factors. These interact
with cell surface receptors that activates an internal signaling cascades
◦ Stimulating cell cycle and influencing the processes of cell division
migration, apoptosis.
Protoonceogenes
◦ Involved in controlling normal cell growth
Oncogenes
◦ Leads to inappropriate stimulations of cell cycle and excessive cell
growth.
CELL CYCLE

6. CELL DEATH
Two main types of cell death
◦ Apoptosis-A regulated form of cell death.
◦ Necrosis-it is caused by cell injury
Many anticancer drug act by inducing mutations in caner cells which
are not significant to cause cell death ,but which can be recognized
by the cell but triggering apoptosis.

7. FRACTIONAL CELL KILL HYPOTHESIS
AND DRUG DOSING
◦ Theoretically the administration of successive dose of
chemotherapy will result in a fixed reduction of caner cells with
each cycle.
◦ A gap is given between cycles to recover the normal tissues.
◦ Clinical response of antitumor therapy are defied by tumor size
tumor products.

8. CLASSIFICATION
◦PHASE SPECIFIC
◦MECHANISM

9. PHASE SPECIFIC/CYCLE ACTIVE
◦It kills proliferating cells only during a specific part or parts of the
cell cycle.
◦Antimetabolites, such as methotrexate, are more active against
S-phase cells
◦Vinca alkaloids are more M-phase specific (inhibiting spindle
formation)
◦Vinblastine can arrest cells in mitosis.

10. CELL CYCLE-NONSPECIFIC
◦The drugs like alkylating agents and platinum derivatives, have
an equal effect on tumour and normal cells whether they are in
the proliferating or resting phase.
◦The greater the dose of the drug, the greater the fractional to
cell kill.

11. ACCORDING TO MECHANISM
◦ ALKYLATING AGENTS
◦ Produced by covalently linking an alkyl group to a chemical species in
nucleic acid or proteins.
◦ They forms a bridge between a one or two strands of DNA, interfering
action of enzyme involved in DNA replication
◦ They damages mostly during S phase.
◦ Immunosuppressant action
◦ RADIOMIMETIC DRUGS

12. ALKYLATING AGENTS
Nitrogen Mustards
Melphalan
◦ Multiple Myeloma, Ovarian cancer
◦ Can be given Oral,IV infusion, Intraperitoneal
◦ S/E-vasculitis, skin rash, anemia, arrhythmia , hepatic toxicity, renal
failure
◦ It is a carcinogenic (Mutations)
◦ Dose-.25mg/kg(2mg tablet)

13. Chlorambucil
◦ Slow,short acting agent usually act on lymphoid tissues.
◦ CLL,Hodgkin's disease,non-Hodgkin's lymphoma, breast, ovarian
and testicular cancer
◦ It has an immunosuppressant Property.
◦ Dose-0.1 - 0.2 mg/kg /2mg tablets
ALKYLATING AGENTS

14. Oxazaphosphorenes
Cyclophosphamide
◦ Pro drug-Hydroxy phoshamide
◦ Also an immunosuppressant
◦ S/E Alopecia, Cystitis
◦ Dose-2-3mg/kg/day,Oral (50 mg tab,100-200mg iv prep)
◦ MESNA(Prevent Hemorrhagic cystitis)
Ifosfamide (isophosphamide )
◦ Has longer half life and dose dependent
◦ Used in Head and neck CA, breast and bladder cancer
ALKYLATING AGENTS

15. ALKYLATING AGENTS
ALKYL ALKANE SULPHONATES
◦ Busulphan
◦ Highly selective for Myeloid elements
◦ S/E Pulmonary Fibrosis, Sterility
◦ Dose 2-6 mg/kg/day
NITROSUREAS
◦ Carmustin
◦ Highly lipid soluble
◦ They cross blood brain barrier-effective in Brain tumors, meningeal leukemia
◦ S/E CNS depression, Bone marrow suppression ,renal damage.
◦ Dose 100-130 mg/dl

16. Tetrazines
◦ Dacarbazine
◦ it has inhibitory action in RNA synthesis and protein synthesis.
◦ Indication-malignant melanoma,Hodgkins disease.
◦ S/E Nausea vomiting.
◦ 3.5mg/kg/day.
ALKYLATING AGENTS

17. HEAVY METALS
Platinum Agents
◦ Heavy metal complex
◦ Chloride ions from the molecule cross link with the DNA strands, resulting in
the inhibition of DNA,RNA and protein synthesis.
◦ Cisplatin
◦ Carboplatin
◦ Oxaliplatin
Carboplatin is bounded with a organic carboxylic group. This leads to
increased water solubility and slower hydrolysis. So less neurotoxic
and nephrotoxic

18. ◦ Compounds that bear a structural similarity to naturally occuring
substance such as Vitamins, amino acids .
◦ They compete with natural substrate for the active site on an
essential enzyme or receptors. Some incorporate directly into DNA
or RNA.
◦ Phase specific –During S phase of cycle.
◦ Efficacy is greater over prolonged period of time.
ANTI METABOLITES

19. ANTI METABOLITES
There are 3 class,
◦ Folic Acid Antagonists
◦ Pyrimidine Analogues
◦ Purine Analogues.

20. FOLIC ACID ANTAGONISTS
Methotrexate
◦ Inhibits dihydrofolate reductase which is essential for DNA and RNA synthesis.
◦ Cytotoxic action, Immunosuppression, Anti-inflammatory .
◦ Squamous cell ca, ALL
◦ S/E Megaloblasic anemia,Thrombocytopenia,alopecia,Stomatits
◦ Prep/Dose-Oral,Intravenous,intrathecal-2.5 to 5 mg per day.
Pemetrexed
Pralatrexate

21. PYRIMIDINE ANALOGUES
These drugs resemble pyrimidine molecules and inhibiting the synthesis of
nucleic acid
5-FLUOROURACIL
◦ Resembles pyrimidine molecule and it inhibits synthesis of nucleic acid.
ARABINE
◦ Inhibiting enzymes involved in DNA synthesis
CYTARABINE
◦ Inhibits DNA polymerase
GEMCITABINE
◦ Interfering DNA synthesis and causes cell death

22. PURINE ANALOGUES
◦ Analogues of the natural purine bases and nucleotides
◦ It inhibit nucleotide biosynthesis by direct incorporation into DNA.
6-MERCAPITOPURINE
◦ Used in childhood Acute leukemia
FLUDARABINE
◦ Hodgkin's Lymphoma
◦ Chronic lymphocytic leukemia
CLADRIBINE
◦ High specificity for lymphoid cells

23. CYOTOXIC ANTIBIOTICS
They are produced from bacterial and fungal cultures (Streptomyces species).
Anthracyclines (doxorubicin, daunorubicin)
◦ Intercalate with DNA and affect the topoiosmerase enzyme.
Actinomycin D
◦ intercalates between guanine and cytosine base pairs.
Bleomycin
◦ consists of a mixture of glycopeptides that cause DNA agmentation.
Mitomycin C
◦ inhibits DNA synthesis by cross-linking DNA, acting like an alkating agent.

24. SPINDLE POISONS
VINCA ALKALOIDS
Vincristine and Vinblastine that are extracted from the Periwinkle plant
◦ They are mitotic spindle poisons that act by binding to tubulin, the building block of
the microtubules.
◦ Thus they inhibit mitosis.
TAXOIDS
Paclitaxel (Taxol) is a drug derived from the bark of the pacific yew (Taxus
brevifolia).
◦ It promotes assembly of microtubules and inhibits their disassembly.

25. TOPOISOMERASE INHIBITORS
◦ Topoisomerases are responsible for altering the structure of DNA
by a cleaving/unwinding/rejoining reaction
◦ Phase specific-Prevent cells from entering mitosis.
◦ They are involved in DNA replication, chromatid segregation and
transcription.
◦ Camptothecin, derived from Camptotheca acuminata
◦ Binds to the enzyme-DNA complex, stabilizing it and preventing DNA
replication.

26. MONOCLONAL ANTIBODIES
Mono clonal antibodies can be derived from
◦ Murine: mouse antibodies
◦ Chimeric: part mouse/part human antibodies
◦ Humanized: engineered to be mostly human
◦ Human: Fully Human antibodies
Rituximab-Non Hodgkin Lymphoma
Alemtuzumab-Leukemia.

27. MOA
◦ Direct effect
◦ Induces apoptosis
◦ Inhibition of signaling through receptors
◦ Indirect Effect
◦ Antibody dependent cellular toxicity
◦ Complement mediated cytotoxicity
MONOCLONAL ANTIBODIES

28. LIMITATIONS OF CYTOTOXIC AGENTS
◦ Cytotoxics predominantly act rapidly dividing cells so do not
specifically target cancer cells in the resting phase.
◦ The most adverse effects include bone marrow suppression,
alopecia, mucositis, nausea and vomiting.

29. CHEMOTHERAPY STRATEGIES
Combination chemotherapy
◦ Combinations of cytotoxic agents are widely used for many cancers and may be
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
◦ Cisplatin + 5 FU – oral cavity, oropharynx, nasopharynx, hypopharynx, larynx ca.
NeoAdjuvant chemotherapy
◦ NeoAdjuvant or induction chemotherapy is the use of chemotherapy before
definitive surgery or radiotherapy in patients with locally advanced disease.
◦ The intention of this strategy is to improve local and distant control of the
disease

30. THANK YOU