2. Antineoplastics  W hat is Cancer ? Cancer is a disorder of cell division (leading cause of death).  C C ancers most commonly occur in: breast (♀) - prostate (♂) - lung - colon - rectum  C ommon characteristics of neoplastic cells: - Persistent proliferation and Immortality -Dedifferentiation. - Invasive growth - Formation of metastases -Sustained angiogenesis.

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4. Antineoplastics  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).

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6. Antineoplastics  T 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.

7. Antineoplastics  G Goals of therapy: - C ure e.g. Hodgkin ̕ s disease - Prophylaxis of recurrence - Prolong survival - Palliation of symptoms OOutcome of therapy depends on: - General health of patient -Responsiveness of cancer type (size, location, grade, etc.). -Drug resistance.

8. Antineoplastics 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

9. Antineoplastics Tumor staging  Most commonly applied staging system for solid tumors is TNM (tumor-nodes-metastases) 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. T 4 (large size tumor). N: refers to the extent of lymph nodes involvement (0-4) e.g. N 0 (no lymph node disease). N x (Lymph nodes not assessed). M: refers to the presence or absence of distant metastasis (0-1) e.g. M 1 (distant metastasis). M 0 ( No distant metastasis). M x (distant metastasis not assessed). T 2 N 1 M 0 (moderate size tumor with limited nodal disease and no distant metastases).

10. Antineoplastics Growth Fraction = GF = Proliferating cells (S or M phase) /resting cells (G 0 ). Cell-cycle phase specific (phase specific) drugs Cell-cycle phase non-specific (cycle specific) drugs G 1 = 40% S = 39% G 2 = 19% M = 2% Checkpoints: P27: G 1 -S P53: G 2 -M

11. Antineoplastics Cell-Cycle Drug Effects 1. 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).

12. Antineoplastics 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.

13. Antineoplastics 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

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

15. Antineoplastics Estrogen Receptor Assay Progesterone Receptor Assay  Lab test done to find out if cancer cells have estrogen (progesterone) receptors Lab testcancercellsestrogen (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

16. Antineoplastics  Combat chemotherapy-induced toxicity

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18. Antineoplastics 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.

19. Antineoplastics Tumor MarkerAssociated TumorCEA Carcinoembryonic Antigen GIT, BREAST, LUNG CANCERS CA-125 Cancer Antigen-125 OVARIAN CANCER OVARIAN CANCER PSA Prostate Specific Antigen PROSTATE CANCER β-HCG Human Chorionic Gonadropin TESTICULAR CANCER AFPAlpha-fetoprotein LIVER CANCER TgThyroglobulin THYROID CANCER

20. Antineoplastics 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

21. Antineoplastics M 0 means…  No distant metastasis N x means…  Lymph nodes not assessed M x means….  Distant metastasis not assessed