AntiCancer-kemoterapi.ppt

PHARMACOLOGY CANCER CHEMOTHERAPY Heny Ekowati Pharmacy Departement Faculty of Medicine and Health Sciences Unsoed heny_apt@ yahoo.com  Cancer (Neoplastic Disease) Cancer is many diseases – common feature: abnormal cell growth; Shift in control mecha...

PHARMACOLOGY CANCER CHEMOTHERAPY Heny Ekowati Pharmacy Departement Faculty of Medicine and Health Sciences Unsoed heny_apt@ yahoo.com  Cancer (Neoplastic Disease) Cancer is many diseases – common feature: abnormal cell growth; Shift in control mechanisms for growth and differentiation; cancer cells infiltrate into organs; interfere with normal functioning; no single cure Second leading cause of death in the US (500,000/yr) –Males: lung; prostate; colon and rectum –Females: lung; breast; colon and rectum; uterus  Types of Cancers Hematologic Malignancies Leukemias Lymphomas Hodgkin’s Disease Non-Hodgkin’s Lymphoma Solid Tumors Carcinomas Sarcomas  Hematologic Malignancies Tumors of blood forming organs and cells  Leukemias: Proliferation of immature progenitors which circulate in blood  Acute lymphocytic leukemia (ALL, BM lymphblasts)  Chronic lymphocytic leukemia (CLL- immature B cells)  Acute myelocytic leukemia (AML, BM myeloid cells)  Chronic myelocytic leukemia (CML, myeloid cells; Philadelphia chromosome)  Lymphomas: Lymph System  Hodgkin’s Disease: lymph nodes  Non-Hodgkin’s lymphoma: lymphocytes (CLL)  Solid Tumors Can occur in any organ or tissue; malignant (metastatic and invasive)  Carcinomas: Arises from epithelial cells; malignant by definition eg., squamous cell carcinoma (basal cells of skin); glandular epithelial cells of breast  Sarcomas: Cancer of connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue eg., osteogenic sarcoma (osteoblasts, chondroblasts, fibroblasts) Cancer Chemotherapy I. Goal II. Selective Toxicity III. Immune System IV. Kinetics of killing  Goal  CCT: Kill as many tumors cells as possible without killing too many normal cells; tumor regression, increased patient survival time, alleviation of symptoms  Selective Toxicity  CCT: Only quantitative differences between normal and neoplastic cells; differences in growth rate treatment is nonselective  Immune System  CCT: Minimal immune response; tumors not recognized as different, can overwhelm immune system; effective CCT- need total cell kill since a single malignant cell can give rise to sufficient progeny to kill the host  Kinetics First order kinetics: each regimen of CT kills constant % (log kill) CCT: very effective treatment kills 99.9% cells (3 log kill) 1012 cells  109 cells  Tumor Cell Killing: First Order Kinetics 1012 Stationary phase Tumor burden 109 New steady state 106 Time  Total Tumor Burden (Size) - Clinical detectable tumor: 109 cells (1 cm); lethal tumors: 1012 cells - The larger the tumor the harder it is to kill -more difficult for drugs to penetrate (poor vascularization) -many cells not proliferating (less sensitive CCT) -increased incidence of metastasis -incr. time of CCT required  incr. toxicity tumor size susceptibility to CCT  Cell Cycle M (2%) G2 (20%) G1 (40%) S (40%) **CCT  Cell Cycle Phase Tumors: consist of heterogeneous populations of cells, some growing, some dormant; in different phases of cell cycle Phases of Cell Cycle  M (mitosis, 2%) – some CCT  G1 (gap 1, 40%) - determines length of cell cycle, varies: G0 - dormant cells, differentiation  S (DNA synthesis, 40%) – most susceptible phase for CCT  G2 (gap 2, 20%) – RNA and protein synthesis Ideal CCT: Kill all cancer cells Practical: Kill all growing cells  Cancer Chemotherapy Cell Cycle Specific Agents (self limiting) Antimetabolites Bleomycin peptide antibiotics Podophyllin alkaloids Vinca alkaloids Cell Cycle Nonspecific Agents Alkylating Agents Antibiotics (actinomycin) Cisplatin Nitrosoureas  Drug Resistance Mechanisms vary with drug Decreased drug uptake Increased drug inactivation Mutations in activating enzymes Increased drug extrusion Multidrug resistance (MDR) p-glycoprotein (p53)- transmembrane protein; grabs drug and effuses it (doxorubicin, actinomycin D, VCR, VBL, eptoposide, taxol, mithramycin); not routinely tested for  Host Determinants General health status of patients -ability to tolerate drugs and side effects -nutritional state -infections -renal and bm function Immune status -natural antitumor defense mechanisms (macrophages, T cells, NK cells) Site of Tumor and blood supply  General Considerations Cancer Chemotherapy Choice of Drug Depends on tumor type and location CCT Regimens: intermittent high dose therapy to permit normal cell recovery, tumor cells also recover Combination Chemotherapy Guidelines: select drugs with different mech. action and minimal overlapping toxicity Ex., adriamycin, cyclophosphamide, vincristine, prednisone (Lymp. Hodgkins) Ex., vincristine, methotrexate, 6-mercaptopurine, prednisone (acute childhood lymphoblastic leukemia)  Adjuvant Therapy Use drugs as adjuvants to surgery and radiation therapy Remove localized tumor, then use CCT to get rid of remaining tumor cells and any metastatic cells Immunotherapy – use drugs to nonspecifically stimulate immune system  Drug Toxicity Most CCT agents: therapeutic index = 1 (therapeutic dose = toxic dose) Cytotoxic agents- kill all rapidly growing cells, nonselective – Bone marrow – GI tract – Hair follicles – Tissues undergoing repair  Side Effects of Anticancer Drugs  Bone marrow Leukopenia, lymphopenia (infections); Imunosuppression, thrombocytopenia (hemmorhage), anemia  Digestive tract Oral and intestinal ulceration; vomiting and diarrhea  Hair follicles Alopecia  Tissues under- going repair Impaired wound healing  Tumor mass Hyperuricemia adenine + inosine = hypoxanthine HX X uric acid kidney damage XO mediated (allopurinol) Cancer Chemotherapeutic Agents Inhibitors of DNA synthesis -Alkylating agents -Antifolates (MTX) -Antibiotics Antimetabolites -Purine analogs (6-MP, 6-TG) -Pyrimidine analogs (5-FU, Ara-CTP) Microtuble inhibitors -Vinca alkaloids -Paclitaxal (Taxol) and Docetaxel Chromatin function inhibitors -Podophyllotoxins (etoposide, teniposide) -Camptothecin  Alkylating Agents History: first used in WW I (1917) as nerve gas (nitrogen mustards); extremely irritant, vesicant, produced leukopenia, bm aplasia, GI ulceration; 1942: used clinically to treat lymphosarcoma Mechanism of Action: mono- and bifunctional; all contain highly reactive alkyl groups; form covalent bonds with nucleophilic groups which become alkylated; targets: amino acids, carboxyl, sulfhydryl and imidazole groups in proteins and nucleic acids  Mechanism of Action CH2-CH2-Cl CH2-CH2-Cl R-N R-N--------CH2 CH2-CH2-Cl CH2 (Immonium ion) CH2-CH2-Cl N-7 Guanine R-N-CH2-CH2+ (Carbonium ion) Alkylated DNA Immonium ion Carbonium ion Reaction with N7 guanine Cross-linked DNA  Mechanism of Action Results of DNA alkylation: cross linking strands, mutations, disruption of base pairing; depurination of DNA, strand breaks Alkylation inhibits a variety of biochemical events in nucleic acid and protein synthesis Evidence in mammalian cells: cytotoxicity at therapeutic levels due to inhibition of DNA synthesis Bi-functional: more toxic can cross link DNA Resistance: excision/DNA repair enzymes; get rid of alkylated DNA  Mechanism of Action Cell cycle nonspecific Can interact with DNA of resting (G0) and proliferating cells; more toxic to growing cells; dormant cells (G0) can repair alkylation damage Proliferation dependent Amount of damage dependent on growth fraction of tumor Drug resistance Decreased drug uptake Increased repair of drug defect Cross resistance between drugs  Classes of Alkylating Agents Nitrogen Mustards  Side effects: immunosuppression; acute nausea, vomiting; alopecia, amenorrhea;  Cyclophosphamide: Most commonly used; **immunosuppresion,  Others: – Mechlorethamine- 1st anticancer drug used – Chlorambucil – Melphalan (L-PAM) Classes of Alkylating Agents Nitrosoureas  Very reactive chemically; Non cross-reactive (resistance)  Lipophilic: penetrate CNS  Examples: BCNU; CCNU; methyl-CCNU  Side effects: nausea, vomiting, BM depression (delayed leukopenia) Classes of Alkylating Agents Streptozotocin Naturally occurring nitrosourea Antibiotic isolated from Streptomyces Specifically retained in  cells of pancreas Low bone marrow toxicity Severe nausea and vomiting, insulin shock Used for metastatic islet cell carcinoma  Classes of Alkylating Agents Methane sulfonate esters (Alkyl sulfonates) Busulfan (Myleran): bifunctional; less active than nitrogen mustards; very selective depression of BM granulocytes; used clinically for CGL Triazenes Dicarbazine (DTIC) – Structural analog of intermediate in purine synthesis; cytotoxicity due to alkylation; acute severe nausea and vomiting, BM depression used for malignant melanoma, Hodgkin’s diseases  Classes of Alkylating Agents Ethyleneimines (Aziridines) Contain 3-membered ethyleneimmonium rings Triethylenemelamine (TEM) Triethylenethiophosphamide (thiotepa) More reactive at acid pH BM depression Bladder cancer (direct installation)  Classes of Alkylating Agents Platinum VIIIb transition metal; cell cycle nonspecific; direct interaction with DNA; forms GpG adducts; cross links DNA, induces apoptosis Analogs: Cisplatin, carboplatin, oxaliplatin Toxicity: nephrotoxicity (limits use); GI**, ototoxicity (hearing loss), alopecia  Folic Acid Analogs-Antifolates Folic acid (FH2) -essential vitamin required in diet (spinach) -required for the transfer of 1-carbon (CH3) units during nucleic acid and protein synthesis FH2 FH4 DHFR (1 carbon unit acceptor, acts as a coenzyme) MTX NADPH NADP Methotrexate, Aminopterin, Amethoperin- analogs of FH2  Methotrexate Mechanism of Action -Competitive inhibitors of dihydrofolic acid reductase (DHFR) -Bind tightly to DHFR “pseudo-irreversible” -Inhibit all one carbon transfer reactions; involved in the synthesis of thymidylate (dTMP), purines, glycine and methionine; results in inhibition of DNA, RNA and protein synthesis -S phase specific  Cytotoxic Effects of Inhibiting DHFR TS Inhibition of thymidylate synthetase (dUMP dTMP) Inhibition of de novo purine synthesis: blocks two steps in pathway that require one carbon transfer reactions Inhibiton of protein synthesis: MET; SER GLY Inhibition of protein and RNA synthesis slows entry of cells into S phase- self limiting Mechanisms of cell killing: “ Thymineless Death”- depletion of thymidine and purines  Leucovorin Rescue MTX binds equally well to normal and tumor cell DHFR Selectively based on differences in growth fraction, transport rates, DHFR levels, DHFR synthesis rates, and folate coenzyme pool sizes MTX most effective against rapidly proliferating cells; use intermittent high dose therapy of short duration to kill tumor cells; rescue normal cells with leucovorin (citrovorum factor, folinic acid); transported into normal cells, converted into FH4, bypasses MTX block MTX FH2 FH4 methylene-FH4 FH2 Follic acid Leucovorin CH3  Resistance to Methotrexate -Decreased transport into cells (active) -Production of altered DHFR with decreased affinity for drug -Increased amount of DHFR (gene amplification); cells make more enzyme  Use and Toxicity Used with leucovorin rescue Combination chemotherapy Adjuvant to surgery Toxicity: BM depression GI toxicity (depends on dose)  Antimetabolites Interfere with nucleic acid biosynthesis  Nucleic Acids RNA- ribose sugars, phosphate, bases (A-U, C-G) DNA –deoxyribose sugars, phosphate, bases ( A-T, C-G) double helical structure -s--P—s—P—s—P—s– B B B B B B -s--P—s—P—s—P—s--  Purine and Pyrimidine Bases Purines NH2 R = none: adenine N R = NH2: guanine HN Base pairing: AT or AU, GC R N NH R1 Pyrimidines HN R2 R1: (=O) uracil, thymine (-NH2) cytosine NH  Nucleic Acid Biosynthesis DE NOVO SALVAGE C, H, N, O S-Base sugar + base DNA + ribose sugar (nucleoside) 5’PRPP catabolism phosphorylase RNA S-Base-MP (nucleotide) nucleotide-TP nucleotide-DP ribonucleotide reductase deoxynucleotide-DP RNA deoxynucleotide-TP DNA  DNA Synthesis Salvage Pathways Reuse degraded DNA products (sugars, bases and phosphates) Type I (purines and pyrimidines) Base + 5’PRPP nucleotide MP HGPRT Type II (pyrimidines only) (specific kinases) Base + ribose-1-P nucleoside nucleotide phosphorylase kinase  Purine Analogs 6-mercaptopurine (6MP) 6-thioguanine (6TG), cladribine; fludarabine Used mainly to treat leukemia and lymphomas Must be converted to nucleotides to be active cytotoxic agents; lethal synthesis: converted to nucleotides by salvage pathways  Purine Analogs Mechanisms of Cytotoxicity Inhibition of first step in de novo purine synthesis; negative feedback mechanism “pseudo –feedback inhibitors” Inhibition later steps in purine synthesis; purine-RP (eg., 6MPRP) structural analog inosinic acid (IMP), covalent binding to enzyme Incorporation of active purine-RP into DNA  De Novo Purine Biosynthesis 5’PRPP 5’PR-amine 6MP-RP (pseudofeedback) Adenylocuccinic acid AMP ADP ATP IMP 6MP-RP DNA Xanthylic acid GMP GDP GTP  Resistance -Loss of salvage enzymes required to activate purine analogs (HGPRT) -Enhanced drug inactivation by increased levels of alkaline phosphatase -Decreased feedback inhibition– subtle alteration in drug binding site on enzyme  Pyrimidines and Nucleic Acid Biosynthesis Aspartate + carbamyl phosphate orotic acid(Pyrimidine biosynthesis) 5’PRPP UTP UDP UMP OMP RNA dUDP CTP dUMP FdUMP (TS) CDP dCDP dTMP dCTP dTDP Ara-CTP DNA dTTP  Pyrimidine Analogs 5-Flurouracil (FU) Fluorine substituted analog of uracil Rational drug design; 5-FU with goal of inhibiting TMP formation O O Van der Waals radius F F=1.35 A HN HN H=1.2 A CF: more stable O O N N URACIL 5-FLUOROURACIL  Lethal Synthesis 5-FU converted to active cytototoxic nucleotide by pyrimidine salvage enzymes PRT 5PRPP + FU FUMP FUDP FUTP UK phosphorylase FUR FUdR FdUDP RNA UK FdUMP dUMP dTMP Irreversible Ic Thymidylate synthetase  5-Fluorouracil Mechanism of Action Lethal Synthesis: must be converted to active nucleotide for cytotoxic action (FdUMP) FdUMP- binds covalently to active site of thymidylate synthetase (irreversible competitive inhibition can only be overcome by giving thymidine Cell cycle specific Inhibition of DNA synthesis due to thymineless death; inhibition of thymidylate synthesis Inhibition of RNA synthesis; more 5FU is incorporated into RNA than DNA  Resistance Decreased salvage enzyme activity- decreased conversion to active form FdUMP Increased synthesis of thymidylate synthesis (gene amplification)  Cytarabine (cytosine arabinoside, ARA-C) Analog of cytidine Undergoes lethal synthesis converted to ARA-CTP by kinases Competitive inhibitor of CTP Inhibits DNA polymerase S phase specific Rapidly inactivated by deaminase Resistance: decreased activation; increased inactivation  Microtuble Inhibitors Microtubules -Protein polymers responsible for various aspects of cellular shape and movement -Major component: tubulin- protein containing two nonidentical subunits (alpha and beta) -Microtuble inhibitors act by affecting the equilibrium between free tubulin dimers and assembled polymers -Plant alkaloids (Vinca, Taxane) Microtuble Inhibitors: Vinca Alkaloids Vincristine (VCR) and Vinblastine (VBR) Derived from periwinkle plant VCR: BM sparing, peripheral neuropathy; used in with prednisone; induces ALL remission VBL: **BM depression; used with bleomycin and cis-Pt (testicular cancer) Mitotic inhibitors: M phase specific; spindle poisons; bind to tubulin; block aggregation of tubulin dimers and formation of microtubules; shift equilibrium toward microtuble disassembly and shrinkage; cause metaphase arrest Resistance: overexpression p-glycoprotein; decreased drug accumulation (MDR); alterations tubulin structure, decreased binding Microtuble Inhibitors: Taxanes - from bark of Yew tree Microtubulin antagonist; bind tubulin dimers and microtuble filaments; prevents microtuble disassembly, stablizes microtubles and formation of abnormal bundles of microtubles; causes disruption of mitosis and cytotoxicity Paclitaxel (Taxol) Docetaxel- more potent semisynthetic analog very active myelosuppression MDR  Chromatin Function Inhibitors Podophyllotoxin- May apple plant Etoposide Teniposide (more lipophilic) -semisynthetic derivatives; cytostatic glucosides Mechanism of action: inhibit topoisomerase II; single strand breaks; block G1 and S phase of cell cycle DNA in eukaryotic cells twisted extensively to compress it; Topoisomerases: enzymes that untangle specific regions of DNA to allow transcription and replication; break and reseal DNA strands Bind microtubles- not therapeutically relevant MDR  Chromatin Function Inhibitors  Camptothecins – Isolated from bark of a Chinese tree – Inhibit Topoisomerase I – Camptothecin- poorly soluble; significant toxicity – Soluble and less toxic derivatives developed (irinotecan, CPT-11) – One of the most active compounds available for treatment of non small cell lung cancer – Toxicity: leukopenia and diarrhea, most severe toxicities, also nausea and vomiting  Antibiotics Isolated from Streptomyces; act by altering DNA function Cell cycle nonspecific Dactinomycin (Actinomycin D)- intercalates into DNA (guanine); inhibits DNA dependent RNA polymerase Adriamycin (doxorubicin) and Daunorubicin- Anthracycline antibiotic; intercalate into major groove DNA; no specificity; inhibits DNA and RNA synthesis Mithramycin- Mithramycin chomomycin antibiotic; irreversible binding to DNA; Mg++ complex; guanine Mitomycin C-C alkylates DNA Bleomycin- Bleomycin water soluble glycopeptide; DNA fragmentation, strand scission; metal chelator- binds Fe; forms e- donating complex and generates ROI; induces DNA damage  Steroid Hormones Estrogens and Androgens Used for hormone sensitive tumors Test by steroid receptor assay Estrogens (DES)- testicular and prostate cancer Anti-estrogens (tamoxifen); androgens; Letrozole (Femera) - aromatase inhibitor Progestins- endometrial cancer Glucocorticoids Prednisone and prednisolone lympholytic (ALL, CLL, Hodgkin’s disease) Immunotherapy: Monoclonal Antibodies  Cancer cell-specific antigens  mAb modified for delivery of a toxin, drug (antibody directed enzyme prodrug therapy- ADEPT), radioisotope, cytokine or other active conjugate  Bispecific antibodies: bind with their Fab regions both to target antigen and to a conjugate or effector cell  Need chimeric or “humanized” antibodies; mAb that are more human like  Monoclonal Antibodies Target cancer cell specific antigens and induce immunologic response  Targeted Therapy  Monoclonal antibodies and small molecule inhibitors  Mechanisms of action distinct from traditional CCT  Individually tailored cancer treatment; drugs may be effective in patients whose cancers have a specific molecular target; efficacy may be influenced by patient ethnicity and sex, as well as by tumor histology  Targeted therapies require new approaches to determine optimal dosing, to assess patient adherence to therapy, and to evaluate treatment effectiveness  Expensive  Traditional CCT Targeted CCT Drugs inhibit proliferation Interfere with specific molecules required for tumor development and growth  Targeted Therapy Examples: receptor and signal transduction inhibitors – Rituximab: anti-CD20; B cell receptor; B cell non-Hodgkin’s lymphoma, B cell leukemia – Alemtuzumab: anti-CD52; glycoprotein on B and T cells – Gemtuzumab Ozogamicin: anti-CD33 linked to cytotoxic agent; CD33 is expressed in most leukemic blast cells; once internalized releases cytotoxic agent; AML – Trastuzumab (Herceptin): anti-HER2/neu (tyrosine kinase related to EGF receptor; overexpressed in 25% breast cancer – Panitumumab, Cetuximab: anti-EGF receptor; colorectal cancer – Gefitinib: EGF receptor tyrosine kinase inhibitor; signal transduction inhibitor – Bevacizumab: anti-VEGF antibody Thank You