DEPARTMENT OF PHARMACEUTICS 1

Cancer In most cases, causes of cancer is multifactorial (environmental, genetic) 25% of population of U.S will be diagnosed with cancer during their lifetime Cancer is ranked as a second cause of mortality after cardiovascular diseases Overall five-year survival rate for cancer patients is about 40% 2

Characteristics of cancer cells  Growth that is not subject to normal restrictions  Local invasiveness  Spread to other part of body (metastasis)  Less differentiated cell morphology 3

Therapeutic methods to treat Cancer  Surgery  Radiotherapy  Chemotherapy  Endocrine therapy  Immunotherapy  Biological therapy 4

Principles of cancer chemotherapy (CC) Cytotoxic chemotherapy exert their effects by inhibiting cell proliferation They interfere with cell division at various points of cell cycle Anticancer drugs affect all proliferating cells both normal & abnormal cells 5

Principles of cancer chemotherapy They attack metabolic sites essential to cell replication e.g. purines & pyrimidines synthesis that are building blocks for DNA & RNA synthesis 6

Goal of treatment -A cure (disease-free survival) that requires eradication of neoplastic cells -Palliation (Alleviation of symptoms & avoidance of life-threatening toxicity) 7

Indications for treatment  When neoplasms are disseminated & not amenable to surgery  Adjuvant therapy following surgery & radiation therapy 8

Tumor susceptibility & growth cycle  Both normal & tumor cells go through growth cycles  They differ number of cells in each stage  Rapidly dividing cells are more sensitive to anticancer drugs  Nonproliferating cells (those in G0) survive toxic effect of drugs 9

1. Cell cycle specific drugs  Effective only against replicating cells (high- growth-fraction malignancies e.g. hematologic cancers)  Antimetabolites, antibiotics, vinca alkaloids, Etoposide 10

2. Cell-cycle non-specific drugs -Effective for both low-fraction malignancies e.g. solid tumors as well as high growth fraction malignancies -Alkylating agents, Cisplatin, nitrosoureas 11

Effects of chemotherapeutic agents on growth cycle 12

Combinations of Drugs Combination-drug chemotherapy is more successful than single-drug treatment Cytotoxic agents with different toxicities, molecular sites & mechanisms of action are usually combined This results in higher response rate & non- overlaping host toxicities 13

Advantages of drug combinations  Provide maximal cell killing within range of tolerated toxicity  Are effective against broader range of cell lines  May delay or prevent development of resistant cell lines 14

Treatment protocols Many cancer treatment protocols have been developed A common regimen called POMP used for treatment of acute lymphocytic leukemia (ALL) consists of Prednisone, Oncovin (vincristine), Methotrexate & Purinethol (mercaptopurine) Therapy is scheduled intermittently to allow recovery of normal tissue 15

Problems associated with chemotherapy 1.Resistance 2.Multidrug resistance 3.Toxicity 16

1. Resistance  Some neoplastic cells inherent resistance to anticancer drugs e.g. melanoma  Others acquired resistance after prolonged administration of low drug doses  Drug resistance is minimized by short-term, intensive, intermittent therapy with combinations of drugs 17

2. Multidrug resistance MDR gene that codes for a transmembrane protein (P-glycoprotein) is responsible for multidrug resistance Resistance is due to ATP-dependent pumping of drugs out of cell 18

2. Multidrug resistance The six membrane- spanning loops of P- glycoprotein form a central channel for ATP- dependent pumping of drugs from cell 19

3. Toxicity  Therapy aimed at killing rapidly dividing abnormal cells  It also affects normal cells undergoing rapid proliferation e.g. cells of buccal mucosa, bone marrow, GI mucosa & hair folicle, contributing to toxic manifestation of chemotherapy 20

Common adverse effects  Severe vomiting  Stomatitis  Alopecia  Myelosuppression  Opportunistic infections (gram –ve)  Cardiotoxicity with doxorubicin  Pulmonary fibrosis with bleomycin 21

Minimizing adverse effects Perfusion tumor locally (sarcoma of arm) Removing patient’s marrow prior to intensive treatment & then reimplanting it Promoting intensive diuresis to prevent bladder toxicity 22

Minimizing adverse effects Administration of folinic acid (methotrexate- induced megaloblastic anemia) Filgrastim (neupogen) (human granulocyte colony-stimulating factor G-CSF) to counteract neutropenia 23

Anticancer drugs 1. Antimetabolites 2. Antibiotics 3. Alkylating agents 4. Microtubule inhibitors 5. Steroid hormones & their antagonists 6. Monoclonal antibodies 7. Others 24

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