PM 716 C54 Anticancer Slides PDF

PM 716 Pharmacology I Cancer Chemotherapy Chapter 54 RMRocco, PhD 1  Case Study 55 year old man with colorectal cancer (CRC), surgery removes cancer and 5 positive lymph nodes. 5-fluorouracil, leucovorin, oxaliplatin results in sev...

PM 716 Pharmacology I Cancer Chemotherapy Chapter 54 RMRocco, PhD 1  Case Study 55 year old man with colorectal cancer (CRC), surgery removes cancer and 5 positive lymph nodes. 5-fluorouracil, leucovorin, oxaliplatin results in severe toxicity (myelosuppression, diarrhea, altered mental state). Fluoropyrimidines require dihydrpyrimidine dehydrogenase (DPD) for biotransformation. Genetic polymorphisms in DPD can alter biotransformation and this might explain the toxicity. 2 Percival Pott (1714-1788) London physician. Described diagnosis and treatment for compound fracture of lower end of the fibula and medial malleolus of the tibia with dislocation of the foot outward and backward, called “Pott’s Fracture.” 3 Chimney Sweepers By 1700 in most European cities coal was the single most important source of home heating. Narrow chimney flues required yearly cleaning to prevent fires from coal tar residues. Young boys hired to climb down flues and perform the cleaning. 4  Percival Pott 1775 Finds cancer of the scrotum in boys 10 - 14 years old but not in age matched controls who lived outside London. Determines that cancer caused by constant contact with coal tar soot (benzo pyrene). So common among chimney sweeps that they call it “soot wart.” 5 Percival Pott 1775 “Ramazini has written a book… and everybody is acquainted with the disorders to which painters, plummers, glaziers, and the workers in white lead, are liable; but there is a disease as peculiar to a certain set of people which has not, at least to my knowledge, been publically noticed; I mean the chimney sweepers cancer.” 6 Charles Dickens, 1838 Novel Mr Gamfield asks the board that determines the fate of orphans to allow him to take Oliver to become a chimney sweep, “It’s humane too, cause even if they are stuck in the chimney, roasting their feet makes them struggle to extricate themselves.” 7  Percival Pott, 1775 Pott’s monograph is the first description of a carcinogen in the history of science. Opens up the field of oncology and the study of the causes of cancer. Pott proves that the workplace can cause cancer. British law enacted in 1788 that required that no one under the age of 8 be hired as a chimney sweep. In 1834 law changed to 10 years old. In 1840 law changed to 16 years old and new chimney flues must be 14 inches wide to prevent boys from getting stuck and suffocated. 8  Terms Cancer: G. karkinos, crab. Uncontrolled growth of cells, often with invasion into healthy tissues. Malignant: ME, maligne, malign, to bring harm. Disease tending toward death. Neoplasia: plassein, to form. Neoplasm: L. plasma, form, mold. A new or abnormal formation of tissue. 9  Terms Tumor: L. tumor, a swelling. Onco-: Gr. onkos, bulk or mass. When combined with a word adds swelling or mass to the word meaning. Oncogene: a gene in a virus that has the ability to induce a cell to become malignant. 10  Cancer Causes: Theories (1)Environmental exposure (ionizing radiation) (2)Chemical carcinogen (azo dyes, aflatoxins, asbestos, tobacco) (3)Viruses (human papillomavirus) 11  Treatment Modalities (1)Chemotherapy alone cures only about 10- 15% of all cancers. (2)Increased cure rates require surgery, radiation, chemotherapy etc. 12  Treatment Modalities (1) Primary Induction Chemotherapy for wide spread systemic disease, Hodgkins lymphoma (2) Neoadjunvant Chemotherpy for localized cancers, breats cancer, bladder cancer etc (3) Adjuvant Chemotherapy used along with surgery and radiation, most common treatment modality. 13  Anticancer Drugs Anticancer drugs can act on cells undergoing cell cycling or in resting phase. Drugs follow first-order kinetics in that they kill a constant proportion of cells in the population and not a constant number of cells. Doses are based on log kill function. A 3 log dose will reduce cell population from 1012 to 109 cells. 14  Anticancer Drugs cyclophosphamide bleomycin cisplatin imatinib methotrexate cetuximab leucocorin tamoxifen mercaptopurine fluorouracil vinblastine procarbazine paclitaxel 15  Cell Cycles G0 resting phase (many of the anticancer drugs) G1 synthesis phase, components needed for DNA synthesis prepared here. S phase, DNA synthesis G2 phase, synthesis of components needed for mitosis. 16  Cell Cycle Specific Drugs G0 G1 S antimetabolites; podophyllotoxins G2 podophyllotoxins, bleomycin M vinca alkaloids Non cell cycle specific drugs act in resting (G0 ) and all other phases. 17 Chapter 54 Cancer Chemotherapy 18 © The McGraw-Hill Companies, Inc, Cell Cycle 19  Drug Combinations (a) Provide maximum cell kill (b)Provide better coverage for heterogenous tumor types (c) Slow or prevent drug resistance (same concept as use of combinations in antibiotic chemotherapy). 20  Resistance Mechanisms of resistance include: (1) Increased DNA repair (cisplatin and most alkylating agents). (2) Formation of trapping agents (glutathione synthesis increased) which binds to anticancer drug (bleomycin, cisplatin, anthracyclines) (3) Change in target enzymes (enzyme target becomes less sensitive to drug’s inhibition, dihydrofolate reductase or cell synthesizes more enzyme) methotrexate. 21  Resistance (4) Decreased activation of prodrug (decreased activity of ezymes needed to convert prodrug to active drugs) purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouracil) 22  Resistance (5) Inactivation of drug (increased activity of drug inactivating enzymes) most of the purine and pyrimidine antimetabolites. (6) Decreased Drug accumulation (increased expression of multi-drug transporter (MDR) in the cell wall that pumps out the drug from the cell. 23  Alkylating Agents Drugs target DNA, intercalate with DNA and lead to cell death. Think ethidium bromide in its use on DNA electrophoresis. 24  Cyclophosphamide One of the very first anticancer drugs, discovered WWII at Yale Medical School Derived from the mustard gas used in war A typical alkylating anticancer agent Drug stops DNA replication 25  Cyclophosphamide Resistance: increase expression of DNA repair enzymes decrease transport drug into the cell increase glutathione levels which binds to and neutralizes the drug Drug given po or iv 26  Alkylating Agents Nitrogen mustards Misc chlorambucil cisplatin cyclophosphamide dacarbazine mechlorethamine procarbazine Nitrosoureas carmustine lomustine Alkylsufonates busulfan 27 Chapter 54 Cancer Chemotherapy 28 © The McGraw-Hill Companies, Inc, Chapter 54 Cancer Chemotherapy 29 © The McGraw-Hill Companies, Inc,  Alkylating Agents All are cell-cycle non-specific (CCNS) (resting and cells in cell cycle) Act through alkylation of DNA bases especially N-7 position of guanine. Bases become cross linked, abnormal base pairs result, DNA strand breaks. Modes of resistance include (1) (2) and (6) above. 30 Alkylating Agents Guanine Cyclophosphamide 31 Alkylating Agents Cisplatin Binding to DNA. 32  Alkylating Agents Phase I CYP450 required for activation of drug to metabolite which interacts with DNA (guanine) (cyclophosphamide) Direct acting with no biotransformation required (cisplatin). 33  Alkylating Agents Wide range of clinical uses including breast, ovarian, neuroblastomas, bladder etc. Among the major ADRs are: GI distress, myelosuppression, peripheral neuritis, acoustic nerve damage etc. 34  Cisplatin An inorganic platinum analog, another example of an alkylating agent Cisplatin binding to DNA blocks replication ADRs: nausea, vomiting, peripheral neuropathy, nephrotoxicity, ototoxicity etc. 35  Free Radical Generation Procarbazine is a reactive agent that forms hydrogen peroxide which generates free radicals that causes DNA strand scission. 36  Procarbazine Orally active with wide distribution into the tissues An alkylating agent with a different MOA. Used mostly for Hodgkin’s Disease (Thomas Hodgkin 1798-1866) malignant lymphoma characterized by giant multinucleated B lymphocytes. Found in single to multiple nodes. 37  Procarbazine When used for Hodgkin’s Lymphoma procarbazine is included in the ABVD-MOPP 8 drug dosing regimen mechlorethamine bleomycin vincristine lomustine procarbazine prednisone etoposide doxorubicin 38  Procarbazine: Major ADRs Myelosuppressant, GI irritant, CNS dysfunction, peripheral neuropathy, skin reactions. MOA is different in that the drug forms hydrogen peroxide which is toxic to cncer cells. 39  Antimetabolites All antimetabolite drugs are cell cycle specific inhibitors. Drugs resemble specific endogenous compounds and are antagonists to the systems which use these endogenous compounds. 40 Chapter 54 Cancer Chemotherapy 41 © The McGraw-Hill Companies, Inc,  Antimetabolites All are antagonists of folic acid (methotrexate) or purines (mercaptopurines, thioguanine) or pyrimidines (fluorouracil, cytarabine). 42 Methotrexate Folic Acid Leucovorin 43  Methotrexate Drug inhibits dihydrofolate reductase the enzyme which activates folate. 44  Methotrexate An antimetabolite that acts the sulfa drugs, it blocks folate synthesis in the cancer cells (and all other cells also, unfortunately) MOA: inhibits human dihydrofolate reductase which blocks synthesis of DNA 45  Methotrexate Resistance: decrease transport of drug into the cell decrease of cytotoxic drug metabolites increase expression of target enzyme (reductase enzyme) decrease affinity for target enzyme (reductase enzyme) 46  Methotrexate Dosing is po, iv and itrathecal Renal dysfunciton requires reduced dosing per CC levels Leucovorin is the rescue drug ADR: myelosuppression (neutropenia and thrombocytopenia) 47  Pteridine + Sulfa Competes Dihydropteroic Acid Trimethoprim Dihydrofolic Acid 48 Tetrahydrofolic Acid  Mercaptopurine (6-MP) Purine antimetabolite activated by hypoxanthine-guanine phosphoribosyltransferase to toxic nucleotide that inhibits enzymes involved in purine metabolism. 49  Mercaptopurine So unique in its MOA that the inventor won a Nobel prize, Gertrude B. Elion in 1988. A thiopurine analog (prodrug) that is activated to the monophosphate. The active drug inhibits numerous steps in DNA synthesis. 50  Fluorouracil (5-FU) Converted in cells to 5-fluoro-2’-deoxyuridine-5’- monophosphate which inhibits thymidylate synthase and causes cell death. 51  Plant Alkaloids Cell cycle selective drugs Vinca alkaloids (vinblastine) Taxanes (paclitaxel) 52  Vinblastine Block mitotic spindle formation by preventing tubulin dimers in microtubules. Act in M phase of cell cycle. Same actions with vincristine. Drug derived from Vinca rosea ADRs include myelosuppression and alopecia (hair loss) 53  Paclitaxel Drugs derived from the Pacific yew tree (Taxus brevifolia) Block mitotic spindle through inhibition of microtuble disassembly into tubulin monomers. 54  Antitumor Antibiotics Antibiotics with different structures and mechanisms of action. bleomycin 55  Bleomycin Cell cycle selective (G2 phase). Drug generates free radicals which bind to DNA and causes strand breaks. 56  Hormonal Agents Certain types of cancers require steroid hormones for continued growth. Most cancer cells produce cell surface receptors for steroids (in addition to regular intracellular receptors). Measurement of estrogen and progesterone receptor numbers on tumor tissues is standard practice. ER and PR receptor negative tumors fail to respond to hormonal therapy. 57  Tamoxifen Drug is antagonist at estrogen receptors on tumors. 58  Enzyme Inhibitors and Antibodies Includes a wide range of drugs that target either enzymes or metabolic pathways that shut down cancer cell growth. 59  Imatinib Inhibitor of tyrosine kinase domain of oncogene Bcr-Abl which prevents phosphorylation and activation. Used for treatment of chronic myelogenous leukemia (CML). A first of its kind drug that treats cancer by inhibiting an enzyme. 60  Growth Factor Receptor Inhibitors A number of different solid tumors overexpress epidermal growth factor (EGFR receptors. Block of these EGFR prevents a number of critical steps in tumor growth include the blockage of angiogenesis. 61  Cetuximab Cetuximab is a monoclonal antibody (“mab”) Drug binds to EGFR and blocks downstream EGFR signaling like angiogenesis Administered parenteral, once per week or every two weeks. 62  Cancer Chemotherapy: Drug Selection (1) Drug should be active against the cancer cells only. (2) Drugs used in combination should have different mechanisms of action. (3) Cross-resistance between drugs should be minimal (select drugs for mechanism of resistance) (4) Drugs should have different toxic effects (avoid cumulative effects) 63  Cancer Chemotherapy: Drug Usage (1) Pulse therapy. High (toxic) doses for short periods (once every three weeks). All system (bone marrow) to recover between dosing sessions. (2) Recruitment. Use cell cycle selective drug to achieve significant log kill and cause recruitment of resting G0 phase cells into cell division cycle. Use a drug active against dividing cells. 64  Cancer Chemotherapy: Drug Usage (3) Synchrony. Use drug like vinca alkaloids to stop cells in M phase, use S phase selective cytarabine which may increase the log kill of the drugs. (4) Rescue Therapy. Drugs are used to reverse toxic effects of anticancer drugs. Methotrexate given in high doses for 36-48 h followed by leucovorin rescue. Leucovorin does not require dihydrofolate reductase enzyme for activation (target of methotrexate). 65 The First Tumor Marker 1846 Bence Jones (1846) describes proteins in the urine that precipitate in acidified boiled urine but which re-dissolve on cooling. Now known as light chains (lambda and kappa) found when immunoglobulins are overproduced by bone marrow plasma cells in multiple myeloma. 66  Tumor Markers A tumor marker is a substance present in or produced by a tumor itself or produced by the host in response to a tumor, Tumor markers used to determine the presence of a tumor based on measurement in the blood or secretions. Tumors resemble fetal tissue more than adult tissue morphologically. 67  Tumors Tumors are graded based on degree of differentiation: (1) Well differentiated (2) Poorly differentiated (3) Anaplastic (without body) Tumor markers are re-expressions of substances produced normally by embryogenically closely related tissues. 68  Tumor Markers Major functions of laboratory testing of tumor markers: (1) Detection (screening) (2) Confirmation (3) Classification (staging) (4) Monitoring 69  Tumor Markers Classification Enzymes: catalytic activity vs mass measurment (immunoassay) Hormones: immunoassay. Oncofetal antigens:AFP, CEA, PSA proteins. Tumor antigen cell surface markers: CA 125, CA 15-3, CA 19-9. Genetic Markers: oncogene and tumor suppressor gene mutations (like BRCA 1 and 2). 70  Tumor Markers Applications include: Screening general population Differential diagnosis in symptomatic population. Clinical staging in cancer. Estimating tumor volume. Evaluation success of treatment. Detect recurrence. Monitor therapy response. Help determine direction of immunotherapy. 71  PSA Prostate specific antigen (PSA) an enzyme found in prostate tissue. Has protease acitivity. Prostate specific enzyme discovered in 1971. MW 28 430, a single chain glycoprotein. PSA in serum exists in two forms: bound and free. 72  hCG (Hormone Tumor Marker) Human Chorionic Gonadotropin (hCG) glycoprotein synthesized by placenta (used to pregnancy detection). Molecule made of two dissimilar units (alpha and beta units) Alpha units found on other protein hormnes (FSH, LH etc) Beta unit is specific to hCG. 73  hCG Beta subunit of hCG mw 45 000. Made of 28 - 30 amino acids. RI in males and non-pregnant females is < 5.0 IU/L serum. Elevated levels found in pregnancy and germ cell tumors (testis) (up to 1 000 000 IU/L). 74  Oncofetal Proteins Proteins produced in normal fetal tissues. Alpha feto protein (AFP) Carcinoembryonic antigen (CEA) Levels are high at birth and decline rapidly after birth. Return of high levels latter in life (60 years latter) suggests that a certain genes may be reactivated as an initial step in cancer formation. 75  AFP Marker for liver and germ cell carcinoma. AFP is a glycoprotein with mw 70 kd made of a single polypeptide chain. At 18 months levels decline to adult values (< 15 ng/mL) Fetal serum 4 000 000 ng/mL at birth. Serum levels in adults correlate with liver tumor size. Increased levels following surgery may indicate incomplete removal of the liver tumor. 76  CEA CEA is a marker for colorectal, GI, lung and breast cancer. Single glycoprotein polypeptide chain with mass of ~ 300 kd and 641 amino acids. RI normal up to 3 ng/mL. CEA elevated in too many non-cancer conditions, should not be used from screening. Main use is to follow therapy and to monitor for recurrence. 77  Carbohydrate Markers Carbohydrate tumor markers are either antigens on the tumor cell surface or are secreted by the tumor cell. Carbohydrate surface markers tend to be more specific compared to hormone and enzyme markers. Examples include CA 15-3, CA 549, CA 27.29 78  Carbohydrate Markers CA 125 ovarian, endometrial CA 15-3, CA 549 breast, ovarian CA 19-9 pancreas CA 19-5 GI, pancreas CA 72-4 Ovarian, breast, GI, colon. CA 50 Pancreas, GI, colon. 79