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I. Alkylating Agents & Related Compounds

I. Alkylating Agents & Related Compounds. Alkylating agents used in cancer chemotherapy include a diverse group of chemicals that have in common the capacity to contribute alkyl groups to DNA (alkylation of DNA) Alkylating agents are CCNS , proliferating cells are more sensitive to the drugs.

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I. Alkylating Agents & Related Compounds

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  1. I. Alkylating Agents & Related Compounds

  2. Alkylating agents used in cancer chemotherapy include a diverse group of chemicals that have in common the capacity to contribute alkyl groups to DNA(alkylation of DNA) • Alkylating agents are CCNS, proliferating cells are more sensitive to the drugs

  3. Alkylating agents are used in combination with other agents to treat lymphatic and solid tumors • Alkylating agents are mutagenic, and carcinogenic (may lead to acute leukemia) • Resistance may occur during treatment with alkylating agents

  4. Major classes of alkylatingagents Nitrogen mustards Nitrosoureas Carmustine Lomustine Streptozocin Cyclophosphamide Mechlorethamine Chlorambucil Melphalan Alkyl sulfonates Related agents Busulfan Platinium analogues; Cisplatin, Carboplatin, Oxaliplatin Thiazines; Dacarbazine

  5. MOA of alkylating agent Cross Intrastrand

  6. Alkylating agentsform covalent bonds between alkyl groups of the drug and N-7 of guanine bases of DNA Intrastrandand crosslinking of DNA interferes with transcription, stops replication of DNA (Inhibit cell division) DNA is unable to replicate

  7. 1.Nitrogen mustards Nitrogen mustards are related to the 'mustard gas' used during the first world war and caused severe myelosuppression

  8. Cyclophosphamide • Cyclophosphamide is the most commonly used alkylating agent • Cyclophosphamide is a prodrug, well absorbed orally • It is usually given orally or by IV or IM • Activated by the liver microsomal cytochrome P 450 to the cytotoxic metabolites; phosphoramide mustard and acrolein • Reaction of phosphoramidemustard with DNA is the cytotoxic step • Causes myelosuppression (especially lymphocytes)

  9. Hemorrhagic Cystitis Cyclophosphamide Metabolism

  10. Clinical uses of Cyclophoshamide Hodgkin disease & other lymphomas Ovarian cancer Breast Cancer (CMF) Cyclophoshamide, methotrexate & fluorouracil Lung cancer

  11. Other clinical uses of Cyclophoshamide • Cyclophosphamide is a potent immuno-suppressant drug used in: (a) control of organ rejection after transplantation (b) disorders associated with altered immune reactivity such as intractable rheumatoid arthritis

  12. Common adverse effects of Cyclophosphamide Alopecia, Nausea & Vomiting, diarrhea Amenorrhea, testicular atrophy & sterility. Bone marrow depression Carcinogenesis may appear years after therapy (acute leukemia)

  13. Adverse effects of Cyclophosphamide Characteristic toxicity: Hemorrhagic cystitis It is due to toxic metabolite “acrolein” in urine fibrosis of the bladder Prevented by: Proper hydration + IV of mercaptoethanesulfonate“MESNA”

  14. Sterile hemorrhagic cystitis due to chemical irritation produced by reactive metabolites of cyclophosphamide(acrolein) in urine • can be ameliorated by increasing fluid intake and administering compounds that are sulphydryl donors, e.g. NA-2-mercaptoethane sulfonate (MESNA) • MESNA neutralizes the toxinacrolein, forming a non-toxic compound.

  15. Chlorambucil • An alkylating agent used in treatment of chronic lymphocytic leukemia • Chlorambucil causes bone marrow depression and GITupset • Chlorambucil is mutagenic

  16. Melphalan • It is used to treat multiple myeloma and ovarian cancer • Oral or IV • Common side effects include: • N, V and oral ulceration • BM suppression, including • Decreased WBC countcausing increased risk of infection • Decreased platelet count causing increased risk of bleeding

  17. 2-Alkyl sulfonates Busulfan

  18. Busulfan • The main pharmacological action of busulfan is myelosuppression, • in low dosage granulocytesand platelets • in higher dosage red cells • Therapeutic uses: • Busulfanis the drug of choice in chronic granulocytic leukemia

  19. Busulfan • Adverse effects: • Myelosuppression • N, V and diarrhea • Carcinogenic • Characteristic toxicity: • Pulmonary fibrosis • Skin pigmentation • Adrenal insufficiency

  20. 3-Nitrosoureas include a nitroso (R-NO) group and a urea. Carmustine Lomustine Streptozocin

  21. Carmustineand Lomustine Use: Treatment of tumors of brain & meninges High lipid solubility cross the BBB They have a severe cumulative depressive effect on the BM that starts 3-6 weeks after initiation of treatment

  22. Streptozocin Use: Treatment of insulinoma Toxic to the β cells of islets of Langerhans

  23. Used in medical research to produce an animal model for Type 1 diabetes in large dose as well as Type 2 diabetes with multiple low doses.

  24. Platinum complexes Cisplatin Carboplatin Oxaliplatin

  25. Cisplatin Cisplatin is a water-soluble complex containing a central platinum atom alkylating agents : causing crosslinking of DNA, which triggers apoptosis(programmed cell death). It is a nephrotoxic, renal function is assessed by creatinine clearanceand strict regimens of hydration and diuresis must be initiated Cisplatinis one of the most emetogenic chemotherapy agents effective against testicular cancer

  26. CISPLATIN Cl NH3 Pt Cl NH3 Cisdiaminedichloroplatinum II, CDDP

  27. Mechanism of antitumour activity • Chloride atoms are replaced by water forming a positively charged hydrated species that form strong covalent bonds with electron rich atoms in nucleic acids and proteins resulting in: • DNA interstrand cross-links • DNA intrastrand cross-links • DNA-protein cross-link • Monofunctional and Bifunctional alkylation

  28. CISPLATIN Cl NH3 H20+ Pt Cl NH3 H20+ Cisdiaminedichloroplatinum II, CDDP

  29. CDDP-INDUCED ORGAN TOXICITY * * Neurotoxicity * Cardiomyopathy * Hepatotoxicity Nephrotoxicity

  30. CLINICAL TREATMENT OF CDDP-INDUCED NEPHROTOXICITY 1- Intensive hydration and diuresis. 2- Dosing according to kidney function. - BUN - Serum creatinine - Creatinine clearance 3- Avoiding concomitant use of other nephrotoxic drugs. 4- Employing New Analogues - Carboplatin - Oxaliplatin

  31. Broad-spectrum agents, fighting solid tumors: breast, ovarian, testicular, lung, bladder cancers Carboplatin 1. Much less N/V 2. Much less nephrotoxicity 3. Less risk of peripheral neuropathy , ototoxicity 4. It is more myelotoxic dose-limited toxicity blood cells decrease dramatically, sometimes as low as 10% of its usual production levels. Cisplatin 1. Severe N/V 2. Dose-related nephrotoxicity (Rx hydration, mannitol) 3. Neurotoxic; peripheral neuritis +Ototoxicity 4. Less Myelotoxic

  32. Oxaliplatin • A new member of this class with better pharmacological profile • Used in the treatment of colorectal cancer with other anticancer drugs.

  33. Dacarbazine • Belong to Thiazines • Is a prodrug, activated in the liver, and • the resulting compound is cleaved in the • target cell to release an alkylating • derivative • Treatment of melanomas • Common adverse effects: • Severe nausea & vomiting • Myelotoxicity • Hepatotoxicity

  34. Resistance to alkylating agents • Increased DNA repair • Decreased permeability of the drug • Increased conjugation with thiols (trapping agents)

  35. Thank you

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