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Anti-neoplastic Drugs

Anti-neoplastic Drugs. Prof. Dr. Yieldez Bassiouni. Introduction. Normal cells… The division of normal cells is precisely controlled. New cells are only formed for growth or to replace dead ones Balanced; cell birth=cell death

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Anti-neoplastic Drugs

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  1. Anti-neoplastic Drugs Prof. Dr. YieldezBassiouni

  2. Introduction

  3. Normal cells… • The division of normal cells is precisely controlled. New cells are only formed for growth or to replace dead ones • Balanced; cell birth=cell death • Regulation: intracellular chemical signalstell a cell when to start and stop dividing

  4. Cancer • Canceris one of the most common diseases in the developed world • 1 in 4 deaths are due to cancer • Cancer means uncontrolled growth of cells coupled with malignant behavior: invasion and metastasis

  5. What causes cancer? • Cancer arises as a result of: • inactivation of tumor suppressor genes • the activation of oncogenes (mutation of the normal genes controlling cell division and other processes) • Hereditary predisposition – Some families are more susceptible to getting certain cancers ( cancer is not inherited)

  6. The Development of Cancer Within every nucleus of the human body's 30 trillion cells exists DNA, the substance that contains the information needed to make and control every cell within the body

  7. This piece of DNA is an exact copy of the DNA from which it came. When the parent cell divided to create two cells, the cell's DNA also divided, creating two identical copies of the original DNA DNA of a normal cell

  8. Mutation of DNA • This section of DNA, one of the base pairs is different from the original • So, this DNA has suffered a mutation, either through mis-copying (when its parent cell divided), or through the damaging effects of exposure to radiation or a chemical carcinogen

  9. Carcinogens • Ionising radiation – X Rays, UV light • Chemicals – tar from cigarettes • Virus infection – papilloma virus can be responsible for cervical cancer

  10. Malignant cells… • Cancer cells have four characteristics that distinguish them from normal cells: • Grow more rapidly without control • Irregular shape; loss of function because of lack of capacity to differentiate • Invade surrounding cells • The ability to metastasize

  11. Benign and malignant growth • Benign neoplasms remain localized, and freely moveable, compress local tissue but do not invade • Malignant neoplasms metastasize to distant tissues through the lymph system and blood vessels. They also have an irregular shape, invade local tissue

  12. Main approaches to deal with cancer • Surgical excision • Irradiation • Anticancer Drugs • Immunotherapy • & Gene therapy

  13. Chemotherapy • Chemotherapy: the treatment of disease by chemical substances • Adjuvant Chemotherapy: The use of chemotherapy along with initial surgery, irradiation can increase the cure rate (i.e. in early stage breast cancer)

  14. What are the uses & goals of cancer chemotherapy Primary therapy: Treat tumors that cannot surgically excised : e.g. leukemias & lymphomas Adjuvant therapy: In combination with surgery or radiation therapy to treat solid tumors  prevent recurrence Palliative therapy: Inoperable solid tumors reduce size and retard growth reduce symptoms caused by tumor

  15. Major Classes of Anticancer Drugs • I. Cytoxic drugs • A. Alkylating agents • B. Antimetabolites • C. Plant alkaloids • D. Cytotoxic antibiotics • E. Miscellaneous agents • II. Hormones and hormones antagonists • III. Monoclonal antibodies

  16. Cytotoxic Drugs are therapeutic agents active on rapidly dividing cells intended for, but not limited to, treatment of cancer These drugs are known to be highly toxic to cells, mainly through their action on cell reproduction Many drugs cause DNA damage  initiates apoptosis "self programmed cell death"

  17. The Cell Cycle • G0: resting state • G1: synthesis of precursors, proteins etc.. needed for DNA synthesis • S: synthesis of DNA • G2: synthesis of cellular components required for mitosis • M: the cell divide

  18. Classification of Cytotoxic Drugs • According to chemical structure • According to mechanisms of anticancer action • According to the cell cycle or phase specificity of the drug

  19. Classification of Cytotoxic Drugs • According to chemical structure and resource of the drug: Alkylating Agents, Antimetabolites, Antibiotics, Plant Extracts

  20. Classification of Cytotoxic Drugs • According to their effect on the cell cycle: • Cell cycle nonspecific drugs (CCNS) • Cell cycle specific drugs (CCS)

  21. Cell cycle specific drugs • Cell cycle-Specific Drugs (CCS): • Exert their action during a specific phase of the cell cycle • Effective for high growth malignancies & Hematological malignancy • S Phase Specific Drug:Antimetabolites • M Phase Specific Drug: Vinca Alkaloids • G2 Phase Specific Drug:Bleomycin

  22. Cell cycle Non-specific drugs • Cell Cycle Nonspecific drugs (CCNS) • Act on cancer cells when they r traversing cell cycle and when they r resting • Alkylating agents • Platinum Compounds • Antibiotics

  23. Toxicity of Cytotoxic Drugs • Can affect normal cells undergoing • rapid proliferation Buccal mucosa & GIT Bone marrow Hair cells Gonads

  24. Common Toxicity of Cytotoxics GI Mucosa: Nausea, vomiting, stomatitis,oral ulceration, dysphagia and diarrhea Bone Marrow suppression, anemia, leukopenia, infection Hair: alopecia Gonadal Cells: Oligospermia and infertility in men. Menstrual irregularities and premature menopause in women

  25. Common Toxicity of Cytotoxics • In certain circumstances, may be carcinogenic (e.g. some alkylating agents) • If there is rapid cell destruction with extensive purine catabolism, urates may precipitate in the renal tubules causing kidney damage • All cytotoxic drugs produce severe nausea and vomiting

  26. I. Alkylating Agents & Related Compounds

  27. 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

  28. 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

  29. Major classes of alkylatingagents Nitrogen mustards Nitrosoureas Carmustine Lomustine Streptozocin Cyclophosphamide Chlorambucil Alkyl sulfonates Related agents Busulfan Platinium compounds; Cisplatin Thiazines; Dacarbazine

  30. MOA of alkylating agent Cross Intrastrand Guanine base of DNA is main target for alkylation

  31. Alkylating agentsform covalent bonds between alkyl groups of the drug and N-7 of guanine bases of DNA Intrastrandand crosslinking of DNA • This stops replication of DNA (Inhibit cell division) DNA is unable to replicate

  32. 1.Nitrogen mustards Nitrogen mustards are related to the 'mustard gas' used during the First World War

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

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

  35. 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

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

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

  38. 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. Sodium 2-mercaptoethane sulfonate (MESNA) • MESNA neutralizes the toxinacrolein, forming a non-toxic compound

  39. 2. Chlorambucil • An alkylating agent used in treatment of chronic lymphocytic leukemia • Chlorambucil causes BM depression ( anemia, neutropenia, thrombocytopenia) • GITupset • Chlorambucil is mutagenic

  40. 3. Melphalan • Used for treatment of multiple myeloma (collections of abnormal plasma cells accumulate in BM , interfere with the production of normal blood cells) • Common side effects include: N,Vand oral ulceration. • BM suppression, including WBC & increased risk of infection and platelet count causing increased risk of bleeding

  41. 2-Alkyl sulfonates Busulfan

  42. Busulfan • The main pharmacological action of busulfan is myelosuppression, depressing the formation of granulocytes and platelets in low dosage and red cells in higher dosage • Therapeutic uses: • Busulfanis the drug of choice in chronic granulocyticleukemia

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

  44. 3-Nitrosoureas Carmustine Lomustine Streptozocin

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

  46. Streptozocin • Uses: Treatment of insulinoma • in medical research to produce • an animal model for Type 1 diabetes can reduce the tumor size and reduce hypoglycemia due to  insulin secretion by insulinomas) Toxic to the β cells of pancreas

  47. Platinum complexes Cisplatin Carboplatin Oxaliplatin

  48. Cisplatin Cisplatin is contains a central platinum atom surrounded by two chlorine atoms and two ammonia groups It causes intrastrand, cross-linking of adjacent guanine molecules It is seriously nephrotoxic.Nephrotoxicity is a dose-limiting side effect. Creatinineclearance (a measure of renal function)  Strict regimens of hydration and diuresis must be initiated

  49. Used for 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 Cisplatin 1. Severe N/V 2. Dose-related nephrotoxicity (Rx hydration, mannitol) 3. Neurotoxic; peripheral neuritis + Ototoxicity 4. Hypersensitivity reactions 5. It has low myelotoxicity

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