Antineoplastics Pharmacology III Practical Sessions Cairo University Faculty of Pharmacy Department of Pharmacology & Toxicology Pharmacology III Practical Sessions Antineoplastics

Cancer is a disorder of cell division (leading cause of death). Antineoplastics Pharma-III Practical What is Cancer ? Cancer is a disorder of cell division (leading cause of death). Cancers most commonly occur in: breast (♀) - prostate (♂) - lung - colon - rectum Common characteristics of neoplastic cells: - Persistent proliferation and Immortality -Dedifferentiation. - Invasive growth - Formation of metastasis -Sustained angiogenesis.

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-The abnormal behavior of cancer cells results from DNA alterations. Antineoplastics Pharma-III Practical Cancer Etiology -The abnormal behavior of cancer cells results from DNA alterations. Malignant transformation results from a combination of activation of oncogenes and inactivation of tumor suppressor genes. - These genetic alterations are caused by: Chemical carcinogens (cigarette smoking). Pathogens (hepatitis C virus, H. pylori). Radiation (X-rays). Hereditary factors. Drugs (estrogen).

Pathophysiology of cancer Chemicals, viruses, radiation,etc. Inherited mutations Acquired mutations Altered gene expression Proto-oncogenes to oncogenes. (Uncontrolled cell proliferation and dedifferentiation) Inactivation of tumor suppressor genes. (Decrease apoptosis) Development of primary tumor Invasiveness Angiogenesis Metastasis

Malignant transformation occur in three major stages: 1- initiation: DNA damage 2- promotion : multiplication 3- progression : growth and invasion

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Tumor staging Antineoplastics Pharma-III Practical Tumor staging Most commonly applied staging system for solid tumors is TNM (tumor-nodes-metastasis) classification where a numerical value is assigned to each letter to indicate size or disease extent. TNM system T: refers to the size of the primary tumor (0-4) e.g. T4 (large size tumor). N: refers to the extent of lymph nodes involvement (0-4) e.g. N0 (no lymph node disease). Nx(Lymph nodes not assessed). M: refers to the presence or absence of distant metastasis (0-1) e.g. M1 (distant metastasis). M0 ( No distant metastasis). Mx (distant metastasis not assessed). T2N1M0 (moderate size tumor with limited nodal disease and no distant metastases).

Cancer Grading: Tumor grade is the description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope. Gx: Grade cannot be assessed (undetermined grade) G1: Well differentiated (low grade) G2: Moderately differentiated (intermediate grade) G3: Poorly differentiated. G4: undifferentiated (high grade)

Cell Cycle Antineoplastics G1 = 40% S = 39% G2 = 19% M = 2% Pharma-III Practical Cell Cycle G1 = 40% S = 39% G2 = 19% M = 2% Checkpoints: P27: G1-S P53: G2-M Growth Fraction = GF = Proliferating cells (S or M phase) /resting cells (G0). Cell-cycle phase specific (phase specific) drugs Cell-cycle phase non-specific (cycle specific) drugs

Treatment Modalities: 1.Surgery (solid tumors). Antineoplastics Pharma-III Practical Treatment Modalities: 1.Surgery (solid tumors). 2. Radiation (solid tumors). 3. Drug therapy: -Disseminated cancers (leukemias, lymphomas & widespread metastases. -Some localized tumors e.g. testicular carcinoma. -Adjuvant to surgery & radiation.

- Cure e.g. Hodgkin̕ s disease - Prophylaxis of recurrence Antineoplastics Pharma-III Practical Goals of therapy: - Cure e.g. Hodgkin̕ s disease - Prophylaxis of recurrence - Prolong survival - Palliation of symptoms Outcome of therapy depends on: -General health of patient -Responsiveness of cancer type (size, location, grade, etc.). -Drug resistance.

Drug Selection Antineoplastics Pharma-III Practical Drug Selection Combination therapy is more effective than single drug therapy - Maximal cell kill - ↓ Injury to normal cells. - Slow/prevent development of drug resistant Criteria of drug selection for combination therapy - Different MOAs (act at diff. cell-cycle stages) - Different toxicities (↓overlapping toxicities) - Each drug effective by itself

Cell-Cycle Drug Effects Antineoplastics Pharma-III Practical Cell-Cycle Drug Effects Cell-cycle phase-specific drugs: Must be present for an extended time → given by infusions or in frequent small doses. G1-phase specific: Asparaginase (Enzyme). S-phase specific: Methotrexate, Fluorouracil, Mercaptopurine (Antimetabolites). G2-phase specific: Bleomycin (Antitumor antibiotic) M-phase specific: Vinca alkaloids (Vincristine, Vinblastine) (Mitotic inhibitors).

2. Cell-cycle phase non-specific drugs (cycle-specific): Antineoplastics Pharma-III Practical 2. Cell-cycle phase non-specific drugs (cycle-specific): Act during any phase including G0. More toxic to proliferating cells than G0 cells. cyclophosphamide. Carmustine: Alkylating agents. Cisplatin, Carboplatin: Platinium compds. Doxorubicin: Antitumor antibiotics.

Toxicity to malignant tissues & normal tissues with↑ growth fraction Antineoplastics Pharma-III Practical Toxicity to malignant tissues & normal tissues with↑ growth fraction (bone marrow – GIT epithelium – hair follicles – sperm-forming cells) Myelosuppression “most common” Neutropenia, Thrombocytopenia, Anemia. GIT Toxicities Nausea & Vomiting GI mucosal irritation (stomatitis, diarrhea) Dermatologic Disorders: Alopecia, Extravasation, Photosensitivity. Infertility Tumor Lysis Syndrome (TLS): Massive cell death & DNA degradation → hyperuricemia → renal injury

Unique toxicities Antineoplastics Cardiotoxicity: Doxorubicin Pharma-III Practical Unique toxicities Cardiotoxicity: Doxorubicin B. Nephrotoxicity: Cisplatin & Methotrexate. C. Pulmonary Toxicity: Bleomycin. D. Hepatotoxicity: Asparaginase E. Hemorrhagic cystitis: Cyclophosphamide → acrolein F. Neurotoxicity: Vincristine, Cisplatin.

Rescue Drugs Antineoplastics Pharma-III Practical Rescue Drugs Combat chemotherapy-induced toxicity Filgrastim: (granulocyte colony-stimulating factor) ↓ duration and depth of neutropenia after chemotherapy Allopurinol: (↓xanthine oxidase) Management of hyperuricemia Glucocorticoids & others… (dexamethasone + ondansetron - rantidine? - strong anti-emetic) Glucocorticoids & Antihistaminics ↓ hypersensitivity

Rescue Drugs Antineoplastics Pharma-III Practical Rescue Drugs Mesna: treatment of acrolein induced hemorrhagic cystitis Leucovorin or folinic acid : reduces toxicity of methotrexate to normal cells.

ERA & PRA Estrogen Receptor Assay Antineoplastics Pharma-III Practical ERA & PRA Estrogen Receptor Assay Progesterone Receptor Assay Lab test done to find out if cancer cells have estrogen (progesterone) receptors Cells with ERs need E to grow while cells with PRs need P to grow. ER+  growth of cancer cells is E-dependant ER¯  growth of cancer cells is E-independent

Tumor markers Antineoplastics Pharma-III Practical Tumor markers Tumor markers are substances found in blood, urine and tissues, produced by tumor cells or by other body cells in response to cancer or certain benign conditions. An elevated level of a tumor marker can indicate cancer; however, there can also be other causes of the elevation. Tumor marker levels are checked at the time of diagnosis; before, during, and after therapy; and then periodically to monitor for recurrence.

Tumor Marker Associated Tumor Antineoplastics Pharma-III Practical Tumor Marker Associated Tumor CEA Carcinoembryonic Antigen GIT, BREAST, LUNG CANCERS CA-125 Cancer Antigen-125 OVARIAN CANCER PSA Prostate Specific Antigen PROSTATE CANCER β-HCG Human Chorionic Gonadropin TESTICULAR CANCER AFP Alpha-fetoprotein LIVER CANCER Tg Thyroglobulin THYROID CANCER

Antineoplastics If a man has ↑ PSA level  Search for PC Pharma-III Practical If a man has ↑ PSA level  Search for PC If a person has ↑ β-HCG level  Search for testicular cancer If a person has ↑ AFP level  Search for liver cancer

 No distant metastasis Nx means…  Lymph nodes not assessed Antineoplastics Pharma-III Practical M0 means…  No distant metastasis Nx means…  Lymph nodes not assessed Mx means….  Distant metastasis not assessed