1. II- Antimetabolites

2. II- ANTIMETABOLITES (Structural Analogues)
Antimetabolites are structurally related to normal cellular components
MOA: block one or more of the metabolic pathways involved in DNA synthesis
Most antimetabolites interfere with nucleic acid synthesis (nucleotide synthesis)

3. II- ANTIMETABOLITES
They inhibit the synthesis purine or pyrimidine nucleotide or by competing with them in DNA or RNA synthesis
Their maximal cytotoxic effects are S-phase and are therefore cell-cycle specific drugs (CCS)

4. Examples of Antimetabolites
Folic acid Antagonists:
Methotrexate (MTX)
Purines antagonists:
Mercaptopurine (6-MP)
Pyrimidines antagonists:
Fluorouracil (5-FU)

5. Folic Acid
Folic acid is needed for the synthesis of the  thymidine, required for DNA synthesis
Also, folate is essential for the synthesis of purine nucleotides which in turn are essential for DNA synthesis and cell division
Methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis.[7] The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

6. Inhibition of dihydrofolate reductase (DFR)

7. A. Folic Acid Antagonists Methotrexate (MTX)
MTX is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase
This enzyme converts folic acid to its active, coenzyme form (FH4); tetrahydrofolic acid
Methotrexate has a higher affinity than Folate for dihydrofolate reductase and thus inhibits the enzyme = depleting intracellular FH4

8. MTX is cytotoxic during the S-phase of the cell cycle.
Lack of this cofactor (FH4) interrupts the synthesis of thymidine, purine nucleotides
Thereby interfering with the formation of DNA, RNA, and protein leading to cell death
 MTX is cytotoxic during the S-phase of the cell cycle.
MTX has a greater toxic effect on rapidly dividing cells (GIT, oral mucosa, BM)

9. Therapeutic Uses
Methotrexate, is effective against acute leukemia, choriocarcinoma, non Hodgkin’s lymphoma in children, breast cancer and head & neck carcinoma
To induce abortion with misoprostol
It is effective against certain inflammatory diseases, such as:
Rheumatoid arthritis
Severe psoriasis

10. Adverse Effects Depression of the bone marrow
Damage to the epithelium of the GIT; stomatitis, nausea, vomiting and diarrhea
Erythema, rash, urticaria, alopecia
High doses of MTX may cause renal damage (crystalluria) so it is important to keep the urine alkaline + hydration
Intrathecal administration lead to meningeal irritation, stiff neck, headache
Hepatic and pulmonary toxicity

11. Leucovorin rescue
Large doses of MTX must be followed by 'rescue' with folinic acid (a form of FH4)
Rescue normal cells by Leucovorin =folinic acid
Folinic acid bypasses the blocked enzyme and replenish the folate pool

12. Tumor resistance to MTX
Decreased drug transport into the cell
Altered dihydrofolate reductase enzyme -- lower affinity for MTX
Increase in dihydrofolate reductase enzyme concentration in the cell

13. II- ANTIMETABOLITES
They inhibit the synthesis purine or pyrimidine nucleotide or by competing with them in DNA or RNA synthesis
Their maximal cytotoxic effects are S-phase and are therefore cell-cycle specific drugs (CCS)

14. B. Purine Antagonists
6-Mercaptopurine impairs the synthesis of purine nucleotide
After oral administration, 6-mercaptopurine undergoes first-pass metabolism, inactivated by xanthine oxidase in the liver
Clinical uses:   For remission induction and maintenance therapy of acute lymphatic leukemia.

15. MOA of 6-mercaptopurine
6-MP is activated inside cell
6-MP by Hypoxanthine Guanine Phospho-Ribosyl Transferase
(HGPRTase) Thiol inosine monophosphate
Toxic nucleotide (TIMP)
E needed for
purine synthesis 
TIMP
Incorporated into DNA
“Non functional”
Tumor cell death

16. Adverse effects: Drug interaction: Principal toxicity is BM depression
N & V, diarrhea
Hepatotoxicity
Drug interaction:
Allupurinol; is used to inhibit xanthine oxidase, to prevent hyperuricemia associated with tumor cell lysis, inhibits the breakdown of 6-MP and increases 6-MP effects, toxicity so dose of 6-MP must be reduced by at least 25%

17. C. Pyrimidine antagonists
Fluorouracil (5-FU)
It is converted to the corresponding deoxynocleotide (5-FdUMP) which inhibits thymidylate synthetase
Inhibition of thymidylate synthetase leads to suppression of the formation of thymidine nucleotides. This results in inhibition of DNA synthesis through “Thymidine-less death”

18. Cytotoxic effects on both RNA and DNA
MOA of Fluorouracil
5FU  5-FdUMP
inhibits Thymidylate synthetase
 synthesis of  thymidine nucleotide   DNA synthesis
Cytotoxic effects on both RNA and DNA
Thymidine-less death

19. Therapeutic Uses
Fluorouracil is used primarily in the treatment of slowly growing solid tumors such as colorectal cancer, cancer of breast, ovary, pancreas
A cream incorporating fluorouracil is used topically for treating skin cancers

20. Toxic Effects:
It may lead to nausea, vomiting, anorexia, diarrhea and alopecia
Severe ulceration of the oral and gastrointestinal mucosa
Bone marrow depression

21. Microtubule inhibitors

22. Microtubules Inhibitors
Mitototic spindle is formed during cell division

23. Microtubules Inhibitors
CCS
Vinca alkaloids
Vinblastine
Vincristine
Taxanes
Paclitaxel
Podophyllotoxins
Etoposide

24. Vinblastine and Vincristine
Belongs to Vinca alkaloids
Both drugs are cell cycle-specific (CCS) because they block mitosis in metaphase

25. Therapeutic uses Adverse Effects:
Vinblastine is used in testicular carcinoma, Hodgkin’s disease
Vincristine is used in the treatment of acute leukemia in children, Wilm’s tumor, and Hodgkin’s and non-Hodgkin’s lymphomas
Adverse Effects:
Common adverse effects for both drugs include cellulitis or phlebitis if the drugs extravasate during injection
Nausea, vomiting, diarrhea, and alopecia

26. Toxicity of Vinblastine & Vincristine
Myelo-supression
Peripheral neuropathy: Depressed deep tendon reflex, paresthesia,
foot drop
Vincristine
NOT myelosuppressant

27. Side effects; neutropenia ‼, peripheral neuropathy
Taxanes
Paclitaxel (Taxol) shows good activity against metastatic breast cancer and advanced ovarian cancer
Side effects; neutropenia ‼, peripheral neuropathy
Filgrastim ( granulocyte colony stimulating factor)

28. IV. Cytotoxic Antibiotics

29. Substances of microbial origin that prevent mammalian cell division
Some antibiotics that affect DNA in both microbial and mammalian cells can be used in cancer chemotherapy

30. Cytotoxic Antibiotics (Antitumor Antibiotics)
Dactinomycin (Actinomycin D)
Doxorubicin (Adriamycin)
Bleomycin
As a rule, they should not be given together with radiotherapy, as the cumulative toxicity is very high

31. Dactinomycin (Actinomycin D)
Dactinomycin was the first antibiotic used in cancer chemotherapy
It affects cells in all phases of the cell-cycle i.e. CCNS
Dactinomycin is given intravenously, it remains unchanged and is concentrated in the liver and excreted in bile
It does not cross the BBB

32. Mechanism of action of Dactinomycin
It intercalates, in the minor groove of DNA, between adjacent guanine-cytosine pairs thus preventing transcription
(through an effect on topoisomerase II
that essentially unwinds the DNA helix for replication) D D
Minor Groove

33. Therapeutic Uses Adverse Effects:
It is mainly used for treating paediatric cancers
with other drugs in the treatment of Wilm’s tumor, gestational choriocarcinoma
Adverse Effects:
Extravasation during injection produces severe irritation and cellulitis
(leucopenia and thrombocytopenia)

34. Adverse Effects (cont.)
Bone marrow depression is the major dose-limiting toxicity
(leucopenia and thrombocytopenia)
Nausea, vomiting, diarrhea, oral ulcers alopecia and skin eruptions may also be noted
Dactinomycin sensitizes to radiation; inflammation at sites of prior radiation therapy may occur

35. Doxorubicin (Adriamycin)
Doxorubicin (Adriamycin) is the most commonly used member of the anthracycline antibiotics, given IV
Mechanism of Cytotoxic Action:
Doxorubicin exerts its cytotoxic actions through 3 mechanisms:
1. intercalates in the DNA, to stabilize the DNA-topoisomerase II complex thus halting replication

36. binding to cell membranes to alter fluidity and ion transport
generation of oxygen free radicals (hydrogen peroxide) through interaction with molecular oxygen
This action may be responsible for cardiac toxicity (dysrhythmias and heart failure)
The heart is devoid of superoxide dismutase (SOD) which protects tissues against oxygen free radicals

37. Clinical indications of Doxorubicin
One of the most important and widely used anti- cancer drug, used in combination with other agents in treatment of sarcomas and cancer of breast, lung , ovary and thyroid gland
It is useful also in acute lymphoblastic leukemia, and lymphomas

38. Adverse Effects: Extravasation causes tissue necrosis
The drug may lead to severe alopecia at standard dosage ***
Stomatitis and GIT disturbances
Increased skin pigmentation
Doxorubicin causes bone marrow depression which is of short duration, with rapid recovery
The drug has dark red color and leads to red color of the urine

39. Adverse Effects (cont.)
Doxorubicin cause cumulative, dose- dependent cardiac toxicity, leading to dysrhythmias cardiomyopathy and heart failure due to generation of free radicals and lipid peroxidation
Dexrazoxane , an iron chelator , decrease the formation of superoxide radicals is used to protect against the cardiotoxicity of the drug

40. Bleomycin: a metal-chelating antibiotic
DNA- bleomycin-Fe2+ complex
intercalate between
base pair Fe
DNA- bleomycin-Fe3+ B
The liberated electrons react with oxygen
Generate free radicals
(superoxide, hydroxyl radicals) Fe B
DNA strands fragmentation

41. Clinical uses of Bleomycin
Bleomycin is most effective in the G2 phase of the cell cycle and mitosis, but it is also active against non-dividing cells (i.e. cells in the G0 phase)
CCNS
It is used to treat germline cancer
Testicular carcinoma
Hodgkin’s lymphoma

42. Adverse effects of Bleomycin
Pulmonary fibrosis
Skin toxicity: Alopecia , blisters and hyperkeratosis
Hypersensitivity reactions; fever, chills,…
It is not a myelosuppressant

43. Pulmonary & skin toxicity ‼
Hydrolase ( bleomycin inactivating enzyme) is deficient in the lung and skin .

44. V. Miscellaneous Anticancer Agents

45. V- Miscellaneous Agents
L-Asparaginase
Hydroxyurea
Mitotane
Retenoic acid derivatives
Interferon

46. L- Asparaginase
Asparagine is amino acid required for protein synthesis
Most normal cells can synthesize asparagine
Neoplastic cells require an external source of asparagine (from the plasma) because of their limited capacity to make sufficient asparagine to support growth

47. L-Asparginase is derived from bacteria
L-Asparaginase
L-asparaginase
Asparagine aspartic acid
+Ammonia
L-Asparginase is derived from bacteria
L-asparaginase hydrolyzes serum asparagine and thus deprives the tumor cells of this nutrient required for protein synthesis
Most normal cells can synthesize asparagine and thus are less susceptible to the action of asparaginase

48. Theraputic uses:
L-asparginase is used to treat childhood acute lymphocytic leukemia in combination with vincristine and prednisone
Adverse effects: Hypersensitivity reactions, liver affection and pancreatitis

49. Hydroxyurea Hydroxyurea is an analog of urea.
MOA: blocks the incorporation of the thymidine nucleotide into the DNA strand.
used in chronic myeloid leukemia
administered orally.

50. Miscellaneous Agents Mitotane Reduces excessive steroid secretion
used for Adrenal carcinoma
Retenoic acid derivatives
Remissions -- acute leukemia

51. Drug combinations

52. The administration of combinations of drugs in the treatment of cancer produces better results than a single drug
A combination of drugs with different toxic effects and affecting different biochemical pathways has higher anti-tumor activity without additive toxicity
Therapy is given intermittently to allow recovery of normal tissue i.e. bone marrow and immune system that has been affected by the drugs

53. Examples of drug combinations
Acute lymphocytic leukemia: vincristine, methotrexate and 6-mercaptopurine
Advanced breast cancer : Doxorubicin, cyclophosphamide with or without flurouracil
Non-Hodgkin's lymphomas: Cyclophosphamide, doxorubicin, vincristine