II- Antimetabolites

1. II- Antimetabolites

2. II- ANTIMETABOLITES(Structural Analogues) • Antimetabolites are structurallyrelated to normal cellularcomponents • 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

6. DFR • Inhibition of dihydrofolate reductase (DFR)

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

8. 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. Leucovorinrescue 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 dihydrofolatereductase enzyme -- lower affinity for MTX Increase in dihydrofolatereductase enzyme concentration in the cell

13. II- ANTIMETABOLITES • They inhibit the synthesis purine or pyrimidinenucleotide 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: • 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 thymidylatesynthetase • Inhibition of thymidylatesynthetaseleads to suppression of the formation of thymidine nucleotides. This results in inhibition of DNA synthesis through “Thymidine-less death”

18. 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 • Acream 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 Vincaalkaloids • Both drugs are cell cycle-specific (CCS) because they block mitosis in metaphase

25. Therapeutic uses • 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 VinBlastine Myelo-supression Peripheral neuropathy: Depressed deep tendon reflex, paresthesia, foot drop Vincristine NOT myelosuppressant

27. 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 Dactinomycinis 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 • Itintercalates, 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 Minor Groove D

33. Therapeutic Uses • 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

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 • Dactinomycinsensitizes to radiation; inflammation at sites of prior radiation therapy may occur

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

36. binding to cell membranesto 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 severealopecia at standard dosage *** • Stomatitis and GIT disturbances • Increased skin pigmentation • Doxorubicin causes bone marrowdepressionwhich 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 failuredue 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: ametal-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-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 leukemiain combination with vincristine and prednisone • Adverse effects: Hypersensitivity reactions, liver affection and pancreatitis

49. Hydroxyurea Hydroxyureais 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