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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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AntineoplasticsAntineoplastics 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 cancerChemicals,

viruses, radiation,etc.

Acquired mutations

Inherited 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 damage2- promotion : multiplication3- progression : growth and invasion

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AntineoplasticsAntineoplasticsTumor stagingTumor 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: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)

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Growth Fraction = GF = Proliferating cells (S or M phase) /resting cells (G0).

Cell-cycle phase specific (phase specific) drugsCell-cycle phase non-specific (cycle specific) drugs

G1 = 40%S = 39%G2 = 19%M = 2%

Checkpoints:P27: G1-SP53: G2-M

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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.

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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.

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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

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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).

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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.

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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

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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.

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Combat chemotherapy-induced toxicity

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ERA & PRAERA & 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

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Tumor markersTumor 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.

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Tumor Marker Associated Tumor

CEACEA Carcinoembryonic Carcinoembryonic AntigenAntigen

GIT, BREAST, LUNG GIT, BREAST, LUNG CANCERSCANCERS

CA-125CA-125 Cancer Antigen-125 Cancer Antigen-125 OVARIAN CANCEROVARIAN CANCER

PSA PSA Prostate Specific Prostate Specific AntigenAntigen

PROSTATE CANCERPROSTATE CANCER

β-HCGβ-HCG Human Chorionic Human Chorionic GonadropinGonadropin

TESTICULAR CANCERTESTICULAR CANCER

AFPAFP Alpha-fetoproteinAlpha-fetoprotein LIVER CANCERLIVER CANCER

Tg Tg ThyroglobulinThyroglobulin THYROID CANCERTHYROID CANCER

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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

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M0 means… No distant metastasis

Nx means…

Lymph nodes not assessed

Mx means…. Distant metastasis not assessed