This PPT covers Drug therapy for Cancer which includes classification of anticancer drugs, and pharmacotharapy of cytotoxic drugs.

1. PREPARED BY: JEGAN.S.NADAR
ANTICANCER
DRUGS

2. ANTICANCER DRUGS
● The anticancer drugs either kill cancer cells or modify their growth.
● The attack is generally directed toward DNA or against metabolic sites essential to
cell replication, for example, the availability of purines and pyrimidines, which are
the building blocks for DNA or RNA synthesis
● Ideally, these anticancer drugs should interfere only with cellular processes that are
unique to malignant cells.
● But, most currently available anticancer drugs do not specifically recognize
neoplastic cells but, rather, affect all kinds of proliferating cells, both normal and
abnormal.
JEGAN

3. CLASSIFICATION
A. Cytotoxic drugs
B. Targeted drugs
C. Hormonal drugs
JEGAN

4. CYTOTOXIC DRUGS
1. Alkylating agents
2. Platinum coordination complex,
3. Antimetabolites
4. Microtubule damaging agents
5. Topoisomerase-2 inhibitors
6. Topoisomerase-1 inhibitors
7. Antibiotics
8. Miscellaneous JEGAN

5. TARGETED DRUGS
1. Tyrosine protein- kinase inhibitors
2. EGF receptor inhibitors
3. Angiogenesis inhibitors
4. Proteasome inhibitor
5. Unarmed, monoclonal antibody
JEGAN

6. HORMONAL DRUGS
1. Glucocorticoids and others
2. Estrogens
3. Selective estrogen receptor modulators
4. Selective estrogen receptor down regulators
5. Aromatase inhibitors
6. Antiandrogen
7. 5-α reductase inhibitor
8. GnRH analogues
9. Progestins JEGAN

7. JEGAN

8. JEGAN

9. JEGAN

10. ALKYLATING AGENTS
JEGAN

11. ALKYLATING AGENTS
● Alkylating agents exert their cytotoxic effects by covalently binding to
nucleophilic groups on various cell constituents.
● Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to
the tumor cells.
● These compounds produce highly reactive carbonium ion intermediates
which transfer alkyl groups to cellular macromolecules by forming covalent
bonds
JEGAN

12. CYCLOPHOSPHAMIDE AND IFOSFAMIDE
● Cyclophosphamide is the most commonly used alkylating agent.
● Both cyclophosphamide and ifosfamide are first biotransformed to hydroxylated
intermediates primarily in the liver by the CYP450 system
● The hydroxylated intermediates then undergo breakdown to form the active
compounds, phosphoramide mustard and acrolein.
● Reaction of the phosphoramide mustard with DNA is considered to be the
cytotoxic step.
● The parent drug and its metabolites are primarily excreted in urine. JEGAN

13. JEGAN

14. ● Cyclophosphamide is available in oral or IV preparations, whereas
ifosfamide is IV only
● Cyclophosphamide is metabolized in the liver to active and inactive
metabolites, and minimal amounts are excreted in the urine as unchanged
drug
● Common side effects are
● Hemorrhagic cystitis, which can lead to fibrosis of the bladder
● Neurotoxicity
JEGAN

15. NITROSOUREAS- CARMUSTINE AND LOMUSTINE
● Because of their ability to penetrate the CNS, the nitrosoureas are primarily
employed in the treatment of brain tumors.
● The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication
and, eventually, RNA and protein synthesis.
● Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily
on cells that are actively dividing.
● Therefore, nondividing cells can escape death if DNA repair occurs.
● Nitrosoureas also inhibit several key enzymatic processes by carbamoylation of
amino acids in proteins in the targeted cells.
JEGAN

16. ● These are highly lipid soluble alkylating agents with a wide range of
antitumour activity.
● They cross blood-brain barrier—are effective in meningeal leukaemias and
brain cancer.
● Nausea, vomiting are common and cns effects also occur.
● Bone marrow depression is peculiarly delayed, taking nearly 6 weeks to
develop.
● Renal damage can occur
JEGAN

17. TRIAZINE-DACARBAZINE
● Dacarbazine is an alkylating agent that must undergo biotransformation to an
active metabolite, methyltriazenoimidazole carboxamide (MTIC).
● This metabolite is responsible for the drug’s activity as an alkylating agent by
forming methylcarbonium ions that can attack the nucleophilic groups in the
DNA molecule.
● Thus, similar to other alkylating agents, the cytotoxic action of dacarbazine has
been attributed to the ability of its metabolite to methylate DNA
● Dacarbazine has found use in the treatment of melanoma and Hodgkin
lymphoma.
JEGAN

18. MICROTUBULE INHIBITORS
JEGAN

19. MICROTUBULE INHIBITORS
● The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton)
that is essential for the movements of structures occurring in the cytoplasm
of all eukaryotic cells.
● The mitotic spindle consists of chromatin plus a system of microtubules
composed of the protein tubulin.
● The mitotic spindle is essential for the equal partitioning of DNA into the
two daughter cells that are formed when a eukaryotic cell divides
JEGAN

20. VINCRISTINE AND VINBLASTINE
 Vincristine (VX) and vinblastine (VBL) are structurally related compounds
derived from the periwinkle plant, Vinca rosea
 These are mitotic inhibitors, bind to microtubular protein—‘tubulin’, prevent
its polymerization and assembly of microtubules, cause disruption of mitotic
spindle and interfere with cytoskeletal function.
 The chromosomes fail to move apart during mitosis: metaphase arrest occurs.
 They are cell cycle specific and act in the mitotic phase.
JEGAN

21. JEGAN

22. JEGAN

23. ● VX and VBL have certain toxicities in common.
● These include phlebitis or cellulitis, if the drugs extravasate during
● injection, as well as nausea, vomiting, diarrhea, and alopecia.
● However, the adverse effects of VX and VBL are not identical.
● VBL is a more potent myelosuppressant than VX
● Peripheral neuropathy (paresthesias, loss of reflexes, foot drop, and ataxia)
is associated with VX.
● Constipation is more frequently encountered with VX.
JEGAN

24. PLATINUM COORDINATION COMPLEXES
JEGAN

25. CISPLATIN
● It is hydrolysed intracellularly to produce a highly reactive moiety which
causes cross linking of DNA.
● The favoured site is N7 of guanine residue.
● It can also react with –SH groups of cytoplasmic and nuclear proteins
● Effects resemble those of alkylating agents and radiation.
● It is bound to plasma proteins, penetrates tissues and is slowly excreted
unchanged in urine with a t½ of about 72 hrs.
● Negligible amounts enter brain
JEGAN

26. JEGAN

27. ● Cisplatin is very effective in metastatic testicular and ovarian carcinoma.
● It is widely used in many other solid tumours like lung, bladder,
esophageal, gastric, hepatic, head and neck carcinomas.
● Cisplatin is a highly emetic drug.
● Antiemetics are routinely administered before infusing it.
● The most important toxicity is renal impairment
● Tinnitus, deafness, sensory neuropathy and hyperuricaemia are other
problems.
JEGAN

28. ANTIMETABOLITES
JEGAN

29. ANTIMETABOLITES
 Antimetabolites 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.
 Their maximal cytotoxic effects are in S-phase and are, therefore, cell cycle
specific
JEGAN

30. FOLATE ANTAGONIST-METHOTREXATE (Mtx)
 The vitamin folic acid plays a central role in a variety of metabolic reactions involving the
transfer of one-carbon units and is essential for cell replication
 This folic acid analogue is one of the oldest and highly efficacious antineoplastic drugs
 It acts by inhibiting dihydrofolate reductase (DHFRase)—blocking the conversion of
dihydrofolic acid (DHFA) to tetrahydrofolic acid (THFA).
 Utilizing the folate carrier it enters into cells and is transformed to more active polyglutamate
form
 Tetrahydrofolic acid is an essential coenzyme required for one carbon transfer reactions in de
novo purine synthesis and amino acid interconversions.
JEGAN

31. JEGAN

32.  Methotrexate has cell cycle specific action—kills cells in S phase
 In addition to DHFRase it inhibits thymidylate synthase as well so that
DNA synthesis is primarily affected.
 However, synthesis of RNA and protein also suffers.
 It exerts major toxicity on bone marrow—low doses given repeatedly cause
megaloblastic anaemia, but high doses produce pancytopenia.
 It has prominent immunosuppressant property useful in rheumatoid
arthritis, psoriasis and many other antoimmune disorders
JEGAN

33. Purine antagonists-6-Mercaptopurine
These are highly effective antineoplasticdrugs. After synthesis in the body to the
corresponding monoribonucleotides, they inhibit the conversion of inosine
monophosphate to adenine and guanine nucleotides that are the building blocks
for RNA and DNA.
There is also feedback inhibition of de novo purine synthesis.
They also get incorporated into RNA and DNA which are dysfunctional.
JEGAN

34. JEGAN

35. Pyrimidine antagonists-Fluorouracil (5-FU)
Fluorouracil (5-FU) is converted in the body to the corresponding nucleotide 5-
fluoro-2-deoxyuridine monophosphate, which forms a covalent ternary complex with
tymidylate synthase (TS) resulting in irreversible inhibition of TS.
Consequently conversion of deoxyuridilic acid to deoxythymidylic acid is blocked.
Selective failure of DNA synthesis occurs due to non-availability of thymidylate.
5-FU itself gets incorporated into RNA, interferes with RNA synthesis and function
contributing to its cytotoxicity.
Even resting cells are affected, though rapidly multiplying ones are more susceptible.
JEGAN

36. JEGAN

37. ANTIBIOTICS
JEGAN

38. Actinomycin D (Dactinomycin)
● It is a very potent antineoplastic drug, highly efficacious in Wilms’ tumour and
childhood rhabdomyosarcoma
● In addition to blocking RNA transcription (due to interference with template
function of DNA) dactinomycin causes single strand breaks in DNA.
● Prominent adverse effects are vomiting, stomatitis, diarrhoea, erythema and
desquamation of skin, alopecia and bone marrow depression
JEGAN

39. JEGAN

40. EGF receptor inhibitors
JEGAN

41. Gefitinib
● Gefitinib is a synthetic compound that penetrates cells, binds to the tyrosine
kinase domain of the EGF receptor (also Erbβ 1 , or HER1) and prevents
phosphorylation of regulatory proteins.
● Gefitinib has been found effective in selected patients of non-small cell lung
cancer which has EGFR activating mutation
● Gefitinib monotherapy has been used for locally advanced or metastatic
lung cancers after cisplatin and docetaxal have failed.
JEGAN

42. JEGAN

43. Angiogenesis inhibitors
JEGAN

44. Bevacizumab
● Angiogenesis (proliferation of new blood vessels) is essential for growth
and metastasis of cancers.
● Bevacizumab is a humanized monoclonal antibody that binds VEGF-A and
hinders its access to the VEGF receptor, interrupting angiogenic signalling.
● Combined with 5-FU, bevacizumab is used in metastatic colorectal cancer.
JEGAN

45. JEGAN

46. Unarmed monoclonal antibodies
JEGAN

47. Unarmed monoclonal antibodies
● Monoclonal antibodies (MAbs) are sourced from hybridomas created by fusing a
continuously proliferating cell line from mouse myeloma with antibody producing B
lymphocytes sensitized to produce antibody against a particular antigen.
● This hybridoma is then cloned so that the single species antibody is obtained in large
quantity. Separate hybridomas are created for each antibody.
● Chimerized MAbs are produced by substituting major portion with human IgG
molecule for the mouse antibody. These MAbs are part human-part mouse.
● Totally human MAbs are called humanized MAbs.
JEGAN

48. JEGAN

49. Thank You