CANCER CHEMOTHERAPY

General Principles of Action of Anticancer Drugs A. Treatment strategies B. Treatment regimens and scheduling C. Problems associated with chemotherapy

A. Treatment strategies 1. Goal of treatment 2. Indications for treatment 3. Tumor susceptibility and growth cycle i. Cell-cycle specificity ii. Tumor growth rate

B. Treatment regimens and scheduling 1. Log kill 2. Pharmacologic sanctuaries 3. Treatment protocols a. Combination of drugs b. Advantages of drug combinations c. Treatment protocols

C. Problems associated with chemotherapy 1. Resistance 2. Multidrug resistance 3. Toxicity a. Common adverse effects b. Specific adverse effects c. Minimizing adverse effects d. Treatment-induced tumors

I. ANTIMETABOLITES Drug ClassMechanism of Action Adverse Effects Therapeutic Uses Methotrexate MTX inhibits dihydrofolate reductase and deplete FH4, leading to inhibition of thymidylate and purine synthesis. Nausea, vomiting, Diarrhea, stomatitis, Myelosupression, Renal damage Hepatotoxicity Pulmonary toxicity Acute lymphocytic leukemia Burkitt lymphoma Breast cancer Crohn disease Rheumatoid arthritis 6-Mercatopurine 6-Thioguanine Both drugs are activated by hypoxanthine –guanine Phosphoribosyl transferases to toxic nucleotide that inhibit several enzymes involved in purine metabolism Bone marrow depression Nausea, vomiting& Diarrhea Hepatotoxicity Acute leukemia Chronic myelocytic leukemia Allopurinol inhibits metabolism of 6-MP and increases its effect and toxicity Fludarabine Cladribine Both drugs inhibit DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase Nausea, vomiting, diarrhea Myelosuppression Fever, edema Neurologic toxicity Chronic lymphocytic Leukemia Non-Hodgkin Lymphoma Hairy cell leukemia

In the body, 6-MP is converted to the corresponding ribonucleotide. 6-MP ribonucleotide is a potent inhibitor of the conversion of a compound called inosinic acid to adenylic acid. Without adenylic acid, DNA cannot be synthesized. It also inhibits the conversion of inosinic acid to xanthylic acid that is necessary for the synthesis of guanylic acid.

Fludrabine 5’-phosphate of 2-fluoroarabinose Cladribine 2-chorodeoxy adenosine 5-Fluorouracil

Drug ClassMechanism of Action Adverse EffectsTherapeutic Uses Fluorouracil (5-FU) 5 – FU is biotransformed to 5-fluoro-2’- deoxyuridine-5’- monophosphate (5- FdUMP), which inhibits thymidylate synthase leading inhibiting DNA (but not RNA) synthesis. Nausea, vomiting, diarrhea, ulceration of oral & GIT mucosa, alopecia Bone marrow depression Anorexia Slowly growing solid tumors: Colorectal, breast, ovarian, pancreatic & gastric carcinomas. As an adjuvant With levamisole Capecitabine It is converted in-vivo by Thymidine Phosphorylase into 5-fluorouracil Similar to 5-fluorouracilMetastatic breast cancer Colorectal cancers Cytarabine (cytosine arabinoside) It is most specific for the S phase of cell cycle. It is a Pyrimidine antimetabolite. The drug is activated by kinases to Ara-CTP, an inhibitor of DNA polymerases. Severe myelosuppression Nausea, vomiting, diarrhea Hepatic dysfunction Acute myeloid leukemia in combination with 6-TG and daunorubicin Gemcitabine (Pyrimidine analog) It is phosphorylated by the enzyme deoxycytidine kinase to the di- and triphosphate nucleotide forms, which replaces cytidine & inhibit DNA synthesis Myelosuppression Nausea, vomiting, alopecia Flu-like syndrome Pancreatic cancer Lung cancer

II. Antibiotics Drug ClassMechanism of Action Adverse Effects Therapeutic Uses Dactinomycin (Actinomycin D) It intercalates DNA, forming a stable dactinomycin-DNA complex. The complex interferes with DNA- dependent RNA polymerase 1.Bone marrow depression 2.Nausea, vomiting, diarrhea, alopecia Melanoma & Pediatric tumors as Wilms’ tumor (neoplasm of the kidneys that occurs in children) Doxorubicin, Daunorubicin Idrarubicin Epirubicin These anthracyclines can intercalate between base pairs, inhibit topoisomerase II, and generate free radicals. They block the synthesis of RNA and DNA and cause DNA strand scission. They must be given intravenously They are metabolized in the liver & excreted in the bile & urine (red color) Bone marrow depression GI distress & Alopecia Doxurubicin causes cardiac toxicity Dexrazoxane (derivative of EDTA and chelates iron), may protect against cardiotoxicity. Doxorubicin is used in Hodgkin’s disease Breast cancer Lung cancer Ovarian cancer Daunorubicin is used in the treatment of acute leukemias Idrarubicin is used for certain types of acute leukemia Bleomycin It generates free radicals which bind to DNA, cause strand breaks, and inhibit DNA synthesis. Pulmonary fibrosis 2. Allergic reaction 3.Little myelosuppression Testicular tumors Hodgkin’s disease

III. Alkylating Agents Drug ClassMechanism of Action Adverse Effects Therapeutic Uses Mechloroethamine It is administered only IV Mechloroethamine spontaneously converts in the body to a reactive cytotoxic product 1.Nausea, vomiting 2.Myelosuppression 3.Immunosuppression 4.Alopecia 1. Hodgkin's disease (MVPP) 2. Solid tumors as breast, prostate and ovarian carcinoma Cyclophosphamide Ifosfamide They can be given orally Cyclophosphamide is a prodrug that undergoes metabolic activation to produce the active compounds: phosphoramide mustard, and acrolein Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. Toxic metabolites of cyclophosphamide & ifosfamide are excreted in the urine 1. Urinary tract hemorrhagic cystitis (due to a toxic metabolite; acrolein). So, patients should be hydrated and treated with sodium 2- mercaptoethane sulfonate (MESNA). This interacts with acrolein forming non toxic complex. Bone marrow depression Nausea, vomiting, alopecia testicular atrophy Neurotoxicity Burkitt lymphoma Non-Hodgkin’s lymphoma Breast & ovarian cancer

Alkylating Agents (Cont.) Drug ClassMechanism of Action Adverse Effects Therapeutic Uses Nitrosoureas: Carmustine Lomustine Semustine They are highly lipophilic and can cross BBB, making them useful in the treatment of brain tumors. Hematopoietic depression Aplastic anemia, Renal toxicity Pulmonary fibrosis Brain tumors Temozolomide (orally) Dacarbazine (IV) Both undergo biotransformation to an active metabolite, methylhydrazine. Temozolamide inhibits the repair enzyme, O 6 – guanine-DNA- alkyltransferase. Myelosuppression (neutropenia and thrombocytopenia) Nausea, vomiting Temozolamide approved for use against astrocytomas Both drugs used in melanoma

IV. Microtubule Inhibitors Drug ClassMechanism of Action Adverse Effects Therapeutic Uses Vinca Alkaloids: Vincristine Vinblastine They bind to the microtubular protein, tubulin and blocks the ability of tubulin to polymerize to form microtubules, preventing spindle formation in mitosing cells and causing cell arrest at metaphase. Both produce: vomiting, diarrhea, and alopecia For Vincristine: Peripheral neuropathy (Parasthesia, loss of reflexes) Paralytic ileus For Vinblastine: Myelosuppression GI distress Alopecia Vincristine: acute leukemias, lymphomas, Wilms’ tumor Vinblastine: Hodgkin’s disease and lymphomas and testicular carcinoma Paclitaxel Docetaxel They bind reversibly to the  - tubulin subunit, but unlike vinca alkaloid, they promote polymerization and assembly of non- functional mitotubules. This results in death of the cell. Neutropenia Peripheral neuropathy Fluid retention (Docetaxe) Hypersensitivity Advanced ovarian cancer Metastatic breast cancer

Dynamic instability of microtubules

V. Steroid Hormones & Their Antagonists A. Hormones 1. Glucocorticoids: Prednisone 2. Estrogens: Fosfestrol 3. Progestogens: Megestrol & Medroxyprogesterone. B. Hormone Antagonists 1. Anti-estrogens: Tamoxifen & Toremifene 2. Anti-androgens: Flutamide & Cyproterone C. Aromatase Inhibitors 1. Aminoglutethimide 2. Anastrozole & Letrozole (nonsteroidal) 3. Exemestane D. Gonadotropin–releasing hormone analogs 1. Leuprolide2. Goserelin3. Nafarelin

VI. Monoclonal Antibodies Trastuzumab Trastuzumab (Herceptin®) is a humanized monoclonal antibody that acts on the HER2/neu (erbB2) receptor. Its principal use is as an anticancer therapy in breast cancer patients whose tumors overexpress this receptor. It is administered either once a week or once every three weeks IV. Rituximab Rituximab is a genetically engineered chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders. The antibody binds to the cluster of differentiation 20 (CD20). CD20 is widely expressed on B-cells and plays a role in activating cell cycle initiation and differentiation. The CD20 antigen is expressed on nearly all B cell non-Hodgkin lymphomas but not in other bone marrow cells.

VII. Others 1. Cisplatin & Carbopaltin 2. L-Asparaginase 3. Etoposide & Teniposide 4. Procarbazine Cisplatin

5. Imatinib Imatinib is used mainly for the treatment of chronic myeloid leukemia and other types of tumors. It acts as a signal transduction inhibitor, used specifically that inhibits tumor tyrosine kinase (TK) activity. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene). In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinase, imatinib is used to decrease bcr-abl activity. Philadelphia chromosome

THANK YOU