2024SP Anti-cancer 1-3.pdf

The Anti-cancer Drugs (1-3) ! Cancer is the 2nd leading cause of death behind cardiovascular disease in US. Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths by Sex, United States, 2023 (Cancer Statistics, 2023) PCOL 826B Medicinal Chemistry Course Handouts-Spring 2024 Daekyu Su...

The Anti-cancer Drugs (1-3) ! Cancer is the 2nd leading cause of death behind cardiovascular disease in US. Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths by Sex, United States, 2023 (Cancer Statistics, 2023) PCOL 826B Medicinal Chemistry Course Handouts-Spring 2024 Daekyu Sun, PhD. Office: Drachman Hall, Room B211-M4 Tel:626-0323, [email protected] Learning Objectives ! To recognize the molecular basis for the antitumor activity and structure–activity relationship (SAR)of clinically useful chemotherapeutic agents used to treat cancer ! To recognize the molecular basis for the antitumor activity of antibody therapeutics " DNA-Reactive Drugs " Natural Product Antitumor antibiotics Nitrogen mustards: Mustine, Chlorambucil, and Bendamustin DNA topoisomerase II inhibitors: Anthracyclines (DNA intercalators) and Etoposide (non intercalator) Phosphoramide mustards: Cyclophosphamide DNA topoisomerase I inhibitors: Camptothecin; Topotecan; Irinotecan N-Alkyl-N-Nitrosoureas: Carmustine; Lomustine Other alkylating agents: Procarbazine; Dacarbazine; Temozolomide Transcription inhibitor: Actinomycin D Platinum compounds: Cisplatin; Carboplatin; Oxaliplatin Mitotic inhibitors: Vinca alkaloids. Paclitaxel and Docetaxel " Antimetabolites Thymidylate synthase inhibitors: 5FU; Capecitabine Dihydrofolate reductase (DHFR) inhibitor: Methotrexate DNA replication inhibitor: Gemcitabine; Fludarabine DNA degradation: Bleomycin " Antibody therapy HER2: Trastuzumab; Trastuzumab emtansine; Pertuzumab EGFR: Cetuximab; Panitumumab VEGF: Bevacizumab CD20: Rituximab; Ofatumumab PD-1: Nivolumab; Pembrolizumab CTLA-4: Ipilimumab Brief Primer on Cancer ! Cancer is a disease caused by uncontrolled growth of cells. ! Cancer is caused mainly by mutations in somatic cells, whereas other genetic diseases are caused solely by mutations in the germline. ! Occasionally, the inherited germ-line mutations increase cancer risk (e.g., BRCA1, BRCA2, and MLH1 genes). ! An individual cancer does not result from a single mutation, but rather from the accumulation of multiple (≥3) mutations in genes that normally regulate cell multiplication. ! Cancer is mainly a disease of the aged, because it takes years for many mutations to accumulate. Characteristics of Cancer Cells Normal Cancer Large number of dividing cells Large, variable shaped nuclei # Self-sufficiency in growth signals # Insensitivity to antigrowth signals # Evasion of programmed cell death (apoptosis) # Unlimited replicative potential Small cytoplasmic volume relative to nuclei Variation in cell size and shape Loss of normal specialized cell features # Sustained ability to form new blood vessels (angiogenesis) # Invasion and metastasis to distant organs or distant lymph nodes A C Angiogenic factors Disorganized arrangement of cells Poorly defined tumor boundary B Nutrients from blood Small tumor Sprouting capillary Metastatic spread Growing tumor Differences between Cytotoxic Agents and Molecular-Targeted Agents for Cancer Treatment ! Cytotoxic Agents (lectures 1-2) # Target Cell division or DNA and DNA associated targets # Mainly affect tumors with high growth fractions - broad spectrum of activity # Side effects mainly affecting the fast-dividing normal cells (e.g., stem cells, blood cells) of the body # DNA alkylating agents, antimetabolites, natural products, topoisomerase inhibitors etc. ! Molecular-Targeted Agents (lectures 3-4) # Target a molecular abnormality in certain types of cancer # Have better toxicity profiles than conventional cytotoxic agents # Monoclonal antibodies (Herceptin, Avastin) and tyrosine kinase inhibitors (Gleevec) # Therapeutic index is higher compared to cytotoxic agents DNA as a Molecular Target for Anticancer Drugs ! DNA is a major critical target of alkylating anticancer drugs. ! Alkylation can occur at any nucleophilic positions shown in this diagram (the darker orange circles denote the most reactive positions). # N7 of guanine is so vulnerable to addition via alkylating agents, especially compared to N7 of adenine and the other nitrogen atoms of guanine. # Some anticancer drugs can methylate the O6 and N7 positions of guanine. Strategies for Inhibiting DNA Replication ! DNA replication is catalyzed by a DNA polymerase. dATP, dGTP, dTTP, dCTP DNA replication # During this process, the polymerase incorporates 2'-deoxynucleoside triphosphates opposite a DNA template which guides each incorporation event. ! Chemotherapeutic strategies used to inhibit DNA replication include: 1) DNA damaging agents; 2) inhibition of DNA modifying enzymes; 3) inhibition of enzymes involved in nucleotide metabolism; and 4) nucleoside analogs that directly inhibit DNA polymerase activity. 1. DNA damaging agents 2. Topoisomerase inhibitors 3. Antimetabolites 4. Nucleoside analogs Nitrogen Mustards: Formation of Aziridinium Ion from Nitrogen Mustard and Its DNA Alkylating Activity X Mustards Chloroethyl substituted compounds X=N, Nitrogen mustard; X=S, Sulfur mustard SN2 ! In nitrogen mustard, the nitrogen atom displaces the chloride to result in a strained, three-membered intermediate cation, called aziridinium. ! Aziridium ion reacts easily with ! The second chemical transformation of nitrogen mustard provides another nucleophiles such as the N-7 aziridinium ion, which, upon reaction position of guanine in DNA that with another DNA nucleophile, forms is strongly nucleophilic and can a DNA crosslink. be readily alkylated by the aziridium cation. Chlorambucil and Bendamustin: Aryl-substituted Nitrogen Mustard # Chlorambucil (oral tablet or solution) as an aryl-substituted nitrogen mustard is less likely to form an aziridinium ion than other alkyl-substituted nitrogen mustards (Mustine; IV), because the aromatic ring decreases the nucleophilicity of the nitrogen atom. # Bendamustine (Ribomustin®, Treandra®, Levact®) is a related nitrogen mustard in which the benzene ring has been replaced by a benzimidazole. Mustine (HN2) Chlorambucil Bendamustine # Chlorambucil acts more slowly and is less toxic than Mustine. # Chlorambucil is indicated especially in treatment of chronic lymphocytic leukemia (CLL). Other indications are lymphosarcoma and Hodgkins disease. # Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Phosphoramide Mustards: Cyclophosphamide ! An alkylating agent of the nitrogen mustard type that is metabolically activated to phosphoramide mustard (Prodrug) Prodrug Monoalkylation Cyclophosphamide 4-Hydroxyclophosphamide Aldophosphamide Interstrand DNA crosslink Intrastrand DNA crosslink ion t a yl alk Ifosfamide (IV) Acrolein Aziridinium A DN PO3- + NH3 Phosphoramide Mustard Active drug # Active orally and parenterally; can be given in fractionated doses over long periods of time and used frequently in combination therapy. # The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors. N-Alkyl-N-Nitrosourea: Carmustine and Lomustine ! First decomposes to isocyanic acid and alkyl diazohydroxide, subsequently producing alkyl diazonium ion. ! Alkyl carbonium ion (CH3+) from alkyl diazonium ion is the ultimate alkylating species. ! Lipophilic and thus can cross the blood–brain barrier, making them useful in the treatment of brain tumors, non-Hodgkin's lymphoma and Hodgkin's lymphoma as a second-line option. Drugs Producing Methyldiazonium Ion that Alkylates DNA # Methylation of the O6 and N7 positions of guanine: The major DNA lesion and methyl adduct, (O6-meG), results in a continuous cycle of DNA base MMR with eventual strand breaks and ultimately cellular apoptosis. # Cytotoxic O6-methylguaine lesions formed by TMZ are repaired by O6-methyl-guanine DNA methyltransferase (MGMT). + DNA O6-methylguanine DNA N7-methylguanine DNA Temozolomide, Dacarbazine, and Procarbazine Temozolomide Dacarbazine Procarbazine ! Potential clinical advantage of temozolomide (TMZ) is based, in part, on the nonenzymatic, pH-dependent generation of the cytotoxic intermediate MTIC at physiological pH. ! Low interpatient variability in TMZ clearance because generation of MTIC is consistent between patients. ! High systemic availability after oral administration of TMZ ! A significant therapeutic advantage of TMZ over i.v. dacarbazine and i.v. procarbazine, which require metabolic activation via cytochrome P450 enzymes. ! Dacarbazine and temozolomide are clinically useful for the treatment of some brain tumors and glioblastoma multiforme. ! Procarbazine remains a major anticancer drug in the management of Hodgkin's lymphoma and gliomas. " Continuous response to temozolomide (A) MRI before TMZ, (B) after 12 cycles of TMZ, (C) after 24 cycles of TMZ. Kalosh et al, Neurology 2007;68(21):1831 Nitrogen Mustards Mustine N-Alkyl-NNitrosourea Chlorambucil Carmustine Bendamustine Imidazole Carboxamides Temozolomide Lomustine Dacarbazine R Cyclophosphamide R Alkyl diazonium ion Alkylating species Procarbazine Aziridinium ion Aziridinium ion R Alkylating species Alkylating species Methyldiazonium ion Platinum Compounds ! Platinum compounds (cisplatin, carboplatin, oxaliplatin) are metal coordinate complex. NH3 Cisplatin Ligands +H2O Sphere Active -Cl Pt Cl NH3 H2 O Pt H2 O Cl -H2O Slow exchange +X NH3 Cisplatin +X (nucleophile) Transplatin NH3 NH3 Cl NH3 Pt X Cl Inactive # Platinum compounds react with DNA in vivo, causing monoalkylation or crosslinking of DNA, which ultimately triggers apoptosis (programmed cell death). Platinum Compounds (cont.) Leaving group Leaving group Cyclobutane dicarboxylic acid Cisplatin Carboplatin Leaving group Oxalic acid Diaminocyclohexane Oxaliplatin ! Cisplatin is used to treat various types of cancers, including sarcomas, small cell lung cancer, ovarian cancer, lymphomas, bladder cancer, cervical cancer, and germ cell tumors. ! Cisplatin is particularly effective against testicular cancer (cure rate; about 85%). ! Carboplatin has also been used to treat testicular cancer patients. ! Oxaliplatin is more water-soluble than cisplatin and more active compared with cisplatin and currently approved in advanced colorectal cancer. Summary of DNA-Reactive Drugs ! Nitrogen mustards: Mustine, Chlorambucil, and Bendamustin ! Phosphoramide mustards: Cyclophosphamide and Ifosfamide ! N-Alkyl-N-Nitrosoureas: Carmustine and Lomustine ! Drugs producing methyldiazonium ion: Procarbazine, Dacarbazine and Temozolomide ! Platinum compounds: Cisplatin, Carboplatin, and Oxaliplatin Sample Exam Questions Q1. All of the following statements regarding chlorambucil are correct EXCEPT A. B. C. D. Aromatic ring increases the nucleophilicity of the nitrogen atom. It is the least toxic of any nitrogen mustard derivative in use. It is indicated especially in treatment of chronic lymphocytic leukemia (CLL). It is less likely to form an aziridinium ion than are the alkyl-substituted nitrogen mustards. Q2. Platinum compounds are widely used to treat various types of cancers. Please choose the incorrect statement regarding platinum compounds. A. They cause crosslinking of DNA as monoadduct, interstrand crosslinks, or intrastrand crosslinks. B. Mostly they act on the adjacent N-7 position of guanine. C. Each substituent is covalently attached to platinum. D. They are coordination complexes of platinum. Antimetabolites: 8-Azaguanine, 6-Mercaptopurine, Azathioprine, 5-FU, Capecitabine, Gemcitabine, Fludarabine, and Methotrexate ! 8-Azaguanine, 6-Mercaptopurine, Azathioprine # Closely resemble purines and appears to be competitive with them in the biosynthesis or utilization of purine metabolites. # Triphosphate form of these compounds can interfere with DNA or RNA synthesis by incorporating into growing DNA or RNA instead of GTP or dGTP. # Used as immuno-suppressants and anti-cancer agents (Leukemia) 5-Fluorouracil (5FU) ! One of the first examples of rationally designed antimetabolite of uracil. ! The 5-position was chosen for a substituent in order to block the conversion of uridylate to thymidylate. ! Fluorine was chosen as the substituent because of the increased energy required to cleave the C–F bond relative to C–H. ! 5-Fluorouracil is activated by anabolism to 5-fluorodeoxyuridyl monophosphate (FdUMP), which acts as a thymidylate synthase (TS) inhibitor. Mechanism of Thymidylate Synthase (TS) Inhibition by FdUMP ! 5-FU is widely used for the treatment of cancer, particularly for colorectal cancer. ! Co-treatment with leucovorin can increase the anticancer activity of 5-FU by increasing the amount of TS complexed with FdUMP. Capecitabine (Xeloda) Increased levels are found in many tumors Carboxyl esterases Capecitabine 5’-Deoxy-5fluorocytidine Cytidine deaminase 5’-Deoxy-5fluorouridine Thymidine phosphorylase 5-Fluorouracil ! Capecitabine is an orally administered systemic prodrug, which is metabolized to 5-FU (a thymidylate synthase inhibitor). ! Cytidine deaminase is at higher concentrations in many tumors than in most normal tissues. ! Activation to 5-FU by thymidine phosphorylase occurs preferentially at tumor sites. ! Treatment of colorectal cancer and breast cancer as monotherapy or combo therapy. Gemcitabine (Gemzar) ! Mechanism of action of Gemcitabine Deoxycytidine Gemcitabine # Two H atoms at 2'C of deoxycytidine are replaced by fluorine atoms. Ribonucleotide reductase # Diphosphate form of gemcitabine (dFdCDP) is a strong inhibitor of Ribonucleotide Reductase, resulting in inhibiting the synthesis of dNDP from NDP. # Triphosphate form of gemcitabine replaces dCTP during DNA replication, arresting DNA synthesis followed by tumor growth arrest and apoptosis. # Gemcitabine is used in various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. Fludarabine ! Fludarabine is a purine analogue and antineoplastic agent. ! It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate (Fludara). ! Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. # Used in the treatment of leukemia and lymphoma, including chronic lymphocytic leukemia, non-Hodgkin's lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. # It is given both orally and intravenously. Folates and One-Carbon Metabolism NADPH 7,8-Dihydrofolate (H2folate) NADP+ Dihydrofolate Reductase 5,6,7,8-Tetrahydrofolate (H4folate) RNA synthesis ADP GDP DNA synthesis Protein synthesis Methotrexate as a DHFR Inhibitor Folic Acid 5’-Substituted 2,4-diaminopyrimidine pharmacophore Methotrexate: R = CH3 ! Methotrexate and related compounds inhibit the enzyme dihydrofolate reductase (DHFR). ! They bind so tightly to DHFR that their inhibition has been termed “pseudo-irreversible.” ! Methotrexate kills cells by inhibiting DNA synthesis in the S-phase of the cell cycle by depleting the pool of tetrahydrofolic acid. ! Used for the treatment of a number of cancers including breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, and bladder cancers. Natural Products ! DNA-Interactive drugs # Actinomycin # Bleomycin ! DNA–Topoisomerase Poisons # Camptothecin, Topotecan, and Irinotecan # Anthracyclines and Etoposide ! Tubulin-Interactive Compounds # Vinca Alkaloids: Vincristine; Vinblastine, and Vinorelbine # Paclitaxel and Docetaxel DNA-interactive Drug: Actinomycins ! A substituted 3-phenoxazone-1,9-dicarboxylic acid known as actinocin. ! They intercalate into double helical DNA, permitting the flat phenoxazone chromophore to fit in between successive base pairs; Additional stability is conferred by the interaction between the pentapeptide lactone chains and DNA. Actinomycin D (Dactinomycin) Actinomycin D–DNA Complex ! Actinomycin D inhibits transcription by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase. ! Most commonly used in treatment of Gestational trophoblastic neoplasia, Wilms' tumor, Rhabdomyosarcoma, and Ewing's sarcoma DNA-cleaving Drug: Bleomycins ! Inside the cell, bleomycin forms a chelate with Fe(II) that has square pyramidal geometry. ! Bleomycin chelated with Fe(II) binds to DNA and gives rise to hydroxyl radicals and superoxide radicals, causing cleavage of the phosphodiester bonds. # Bleomycin is used against testicular cancer, ovarian cancer, and Hodgkin's disease. # The most side effect of bleomycin is pulmonary fibrosis and impaired lung function presumably by inducing sensitivity to oxygen toxicity. Mechanism of Action of Topoisomerase I and II Poisons ! Topoisomerase I produces single stranded breaks in one of the DNA backbones, allowing one of the phosphodiester bonds to rotate freely around the other relieving torsional stress. ! Topoisomerase II changes DNA topology by breaking and rejoining double-stranded DNA. Chemistry & Biology, 17, 421-433, 2010 Topoisomerase I Inhibitors: Topotecan and Irinotecan ! Topoisomerase I inhibitors exert their cytotoxic effects by stabilizing the covalent DNA–topoisomerase I cleavable complex, thus prevent DNA religation. ! When a DNA replication fork encounters a topotecan-stabilized cleavable complex, these lesions convert into lethal double-stranded DNA damage. ! Unlike topotecan, Irinotecan is a prodrug, which is converted to a biologically active metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38) by a carboxylesterase-converting enzyme (CCE). Topoisomerase II Inhibitors: Anthracyclines ! Intercalate into double helical DNA to inhibit DNA and RNA synthesis, thus preventing the replication of rapidly growing cancer cells. ! Stabilize the topoisomerase II complex after it has broken the DNA chain, leading to topoisomerase II mediated DNA-cleavage, thus blocking DNA transcription and replication. # Epirubicin has a different spatial orientation of the hydroxyl group at the 4' carbon of the sugar, which may account for its faster elimination and reduced cardiotoxicity toxicity. # Doxorubicin (Adriamycin) is one of the most effective antitumor agents, producing regressions in acute leukemias, Hodgkin’s disease and other lymphomas, breast carcinoma, ovarian carcinoma, and etc. Molecular Basics of the Mechanism of DoxorubicinInduced Cardiotoxicity NAD(P)H NAD(P)H oxidase or nitric oxide synthases NAD(P)+ # Administration of doxorubicin can lead to both short- and long-term cardiotoxic effects, ranging from subclinical alterations of myocardial structure and function to severe cardiomyopathy and heart failure, which may result in heart transplantation or death. Non-intercalating Topoisomerase II inhibitor: Etoposide ! This compound is a semisynthetic derivative of podophyllotoxin : a glycoside of podophyllotoxin with a D-glucose derivative. ! Although etoposide does not bind directly to the DNA, it stabilizes a covalent intermediate form of the DNA–topoisomerase II complex. ! Etoposide in combination with other chemotherapeutic agents is the first choice treatment for small cell lung cancer. Topo II poison Microtubule destabilizer Podophyllotoxin Etoposide Tubulin-interactive Natural Products as Mitotic Inhibitors ! Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow and eventually spread through the body (metastasize) through continuous mitotic division. ! Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Microtubule structure S phase Vinca Alkaloids as Mitotic Inhibitors ! Complex structures composed of an indole-containing moiety (catharanthine) and an indoline-containing moiety (vindoline) Isolated from the periwinkle Catharanthus rosea at the Eli Lilly Company. ! Mitotic spindle poisons that blocks the polymerization of tubulins into microtubules. ! These compounds are used against different types of tumors, despite the similarity of their structures. b a Vinorelbine # VINBLASTINE (Velban): Hodgkin's disease, testicular cancer # VINCRISTINE (Oncovin): Leukemia, lymphomas # VINORELBINE (Navelbine): Solid tumors, lymphomas, lung cancer Microtubule Stabilizing Agents: Paclitaxel (Taxol) and Docetaxel (Taxotere:a semisynthetic analogue of paclitaxel ) ! Paclitaxel was discovered in 1962 as a result of the NCI-funded screening program; being isolated from the bark of the Pacific Yew, Taxus brevifolia. Taxol b a # Paclitaxel and docetaxel consist of a tetracyclic 17-carbon (heptadecane) skeleton. # Both are mitotic spindle poisons that block the depolymerization of microtubules into tubulins. # Refractory ovarian cancer, metastatic breast cancer, metastatic melanoma, and non-small cell lung cancer in combinations containing doxorubicin and cisplatin. # Paclitaxel albumin-stabilized nanoparticle formulation (Abraxane) is a form of paclitaxel contained in nanoparticles. Abraxane works better than other forms of paclitaxel and have fewer side effects. Common Combination Chemotherapy Regimens Review Questions Q1. The thymidylate synthase (TS) is a known target for 5-fluorouracil (5-FU). Which of the following statements regarding the mechanism of thymidylate synthase (TS) inhibition by 5-fluorouracil is NOT correct? A. The active metabolite of 5-FU is a powerful noncompetitive inhibitor of (TS). B. FdUMP can form a stable ternary complex with TS and CH2THF, C. Its metabolite blocks the access of dUMP to the nucleotide-binding site. D. Folic acid is required for the inhibition of TS by its metabolite. Q2. Which of the following statements about these compounds is NOT correct? A. Compound 1 belongs to anthracyclines. B. Compound 2 is doxorubicin. C. Compound 3 is a prodrug. D. Compound 1 targets topoisomerase II. Molecular-Targeted Agents for Cancer Treatment " Strategies to Interfere with RTK Signal Transduction ! Receptor tyrosine kinases (RTKs) are key regulators of normal cellular processes, but the deregulation of the RTK signaling networks is crucial for the development and progression of cancer. GFs RTK # Neutralizing antibodies, which block the bioactivity of RTK ligands, RTKtargeted antibodies, which either target overexpressed receptors or receptor heterodimerization. # Small-molecule inhibitors of RTK kinase activity have been developed to interfere with RTK signal transduction. Humanized Antibodies: Antibodies from Non-Human Species ! Protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans using a recombinant DNA technology. # Murine mAbs have limited activity due to human anti-mouse antibody (HAMA) immune responses (anti-globulin response). # Human-mouse chimeric mAbs created (_ximab). e.g. Rituximab & Cetuximab # Fully “humanized” mAbs also created (_zumab). e.g. Trastuzumab & Bevacizumab # Human mAbs (_umab). e.g. Ipilimumab # Therefore, rationale is to minimize immunogenicity. Trastuzumab (Herceptin®) & Pertuzumab (Perjeta®): Humanized Anti-HER2 Mabs ! Herceptin binds HER2 subdomain IV, inhibiting the activation of HER2, while Perjeta binds HER2 subdomain II, inhibiting the activation of HER2 by interaction with HER1/3/4 molecules. ! Both also induce Antibody Dependent Cellular Cytotoxicity (ADCC) system to destroy cancer cells onto which it is attached. # An effective treatment both before and after surgery for patients with HER2-positive metastatic breast cancer and patients with HER2 positive metastatic stomach or gastroesophageal junction (GEJ) cancer. Trastuzumab Emtansine (Kadcyla) ! An antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent maytansine (DM1). Discovery Medicine, 10, 329 (2010) # Delivers a highly potent toxic drug (Maytansine) to the cancer cells. # The maytansine binds beta tubulin in eukaryotic cells and prevents the formation of the mitotic spindle, resulting in the inhibition of cell division. # Approved specifically for treatment of HER2-(+) metastatic breast cancer patients who have been treated previously with trastuzumab and a taxane (paclitaxel or docetaxel); advanced HER2(+) breast cancer patients resistant to trastuzumab alone. Epidermal Growth Factor Receptor (EGFR)-targeted Therapy ! Cetuximab (Erbitux) and Panitumumab (Vectibix) inhibit EGFR-mediated intracellular signaling pathways by inhibiting EGF binding to EGFR and dimerization. # Panitumumab: EGFR-expressing metastatic colorectal cancer; Cetuximab: metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. Bevacizumab (Avastin): Tumor Angiogenesis Inhibitor ! Tumors can produce angiogenic factors (e.g., VEGF, bFGF, etc.) to stimulate the growth of new blood vessels to feed growing tumors with oxygen and nutrients. ! Bevacizumab (Avastin) is a humanized monoclonal antibody against VEGF thereby decreasing the blood supply to the tumor and slowing tumor growth. # Avastin is used to treat kidney, colon, rectal cancer, lung cancer (non-small cell type), ovarian, and certain types of brain tumors (NOT Approved for Breast Cancer). # Common side effects include nose bleeds, headache, high blood pressure, and rash with other severe side effects (gastrointestinal perforation, internal bleeding). Rituximab (Rituxan; MabThera; Zytux) and Ofatumumab (Arzerra): B Cell Targeting Monoclonal Antibodies ! A chimeric or human monoclonal antibodies against the protein CD20 found on the surface of immune system B cells. N c B cell # The Fc portion of rituximab and ofatumumab mediates antibody-dependent cellular cytotoxicity (ADCC) by macrophage, complement-dependent cytotoxicity (CDC), and direct lysis by NK cells. # Used to treat diseases with excessive numbers of B cells, overactive B cells, or dysfunctional B cells such as leukemias and lymphomas, including non-Hodgkin's lymphoma. # Other use: transplant rejection and autoimmune disorders Checkpoint Blockade by Therapeutic Antibodies for Cancer Immunotherapy ! Nivolumab (Opdivo) & Pembrolizumab (Keytruda) PD-L1/PD-1 complex PD-L1 Opdivo/PD-1 complex Opdivo Ketruda/PD-1 complex Ketruda PD-1 PD-1 Molecules 2019;24(6):1190 PD-1 #T-cell activation is suppressed by the interaction between programmed death 1 (PD-1) on T cells and PD-L1 on tumor cells. # The two PD1- inhibitors Keytruda® (pembrolizumab) and Opdivo® (nivolumab) blocks PD-L1 from binding to PD-1, resulting in reactivation of T-cell-mediated tumor cell killing. # Approved for the treatment of melanoma, metastatic non-small cell lung cancer, and advanced renal cell carcinoma. Checkpoint Blockade by Therapeutic Antibodies for Cancer Immunotherapy (cont.) ! Ipilimumab (Yervoy) # T cells are activated by the interaction between B7 ligands of antigenpresenting cell (APC) and CD28 on T cells. # Cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) suppresses Tcell activation by competitive binding to B7 as a negative regulator of T-cell activation). CTLA-4 Yervoy/CTLA-4 complex Yervoy # Therapeutic antibodies (e.g., Ipilimumab) against CTLA-4 block the CTLA-4/B7 interaction. # Approved for the treatment of metastatic melanoma by activating the immune system. Radiopharmaceuticals ! Ibritumomab tiuxetan (Zevalin) is a radioimmunotherapeutic agent. # Binds to the CD20 antigen found on the surface of normal and malignant B cells (but not B cell precursors) # Radiation from the attached isotope (b-emission from yttrium-90 or indium111) to kill it and some nearby cells. # Antibody itself may trigger cell death via ADCC, CDC, and apoptosis. # Active against all B cell lymphomas, non-Hodgkin’s lymphoma and leukemias. ! Bone-targeting radiopharmaceuticals # Samarium Sm-153 lexidronam is commonly used in lung cancer, prostate cancer, breast cancer, and osteosarcoma. # Radium-223 and Strontium-89 are radiopharmaceuticals that chemically similar to calcium and used to treat metastatic cancers in bone. Proteasome Inhibitor Bortezomib (Velcade) ! Proteasome is a multienzyme complex (700 kd threonine protease) with a broad substrate specificity that degrades unneeded or damaged protein, controlling levels of proteins that are important for cell cycle progression and apoptosis. # Bortezomib is an N-protected dipeptide (Pyz-Phe-boroLeu), which consists of pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid.. # Boronic acid of bortezomib interacts with hydroxyl group of the threonine active site of the 26S proteasome to form a very tight complex as a competitive but reversible inhibitor. # Bortezomib is the first therapeutic proteasome inhibitor approved for treating relapsed multiple myeloma and mantle cell lymphoma (MCL). Myeloma (Cancer of Plasma cells) Hormone Therapy for Treating Breast Cancer Aromatase Testosterone Estradiol Aromatase Androstenedione Estrone ! Aromatase Inhibitors: Anastrozole (Arimidex), Letrozole (Femara), and Exemestane (Aromasin) 4-hydroxytamoxifen (red) overlaid with 17β-estradiol (black) ! Selective estrogen receptor degraders (SERDs): Fulvestrant (Faslodex) Fulvestrant Anastrozole Letrozole ! Selective Estrogen Receptor Modulators (SERMs): Tamoxifen, Raloxifene (Evista), and Toremifene (Fareston) Exemestane Tamoxifen Raloxifene Toremifene Hormone Therapy for Treating Prostate Cancer ! Agonists or antagonist of Gonadotropin-releasing hormone (GnRH or LHRH: pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2); GnRH analogues were synthesized by specifically modifying the natural GnRH decapeptide, typically in position 6 (amino acid substitution), 9 (alkylation) and 10 (deletion). # GnRH agonists: Leuprolide (Lupron®, Eligard®), Goserelin (Zoladex®), Triptorelin (Trelstar®), and Histrelin (Vantas®) downregulate GnRH Receptors by internalization of receptors and suppress serum testosterone levels. # GnRH antagonist: Degarelix (Firmagon®) reduces testosterone levels more quickly. ! Abiraterone (Zytiga®) works by suppressing the production of androgens specifically by inhibiting CYP17A1 (17α-hydroxylase and 17,20-lyase), thereby decreasing the production of testosterone. ! Nonsteroid antiandrogens: Flutamide (Eulexin®), Bicalutamide (Casodex®), Nilutamide (Nilandron®), and Enzalutamide (Xtandi®) act as antagonist of the androgen receptor. Abiraterone Flutamide Bicalutamide Nilutamide Enzalutamide Review Questions Q1. Herceptin (Trastuzumab) is a humanized monoclonal antibody. Which of following statements is INCORRECT? A. Herceptin binds HER2 blocking receptor to binding other ErbBs. B. Herceptin destroys target cancer cells by inducing antibody dependent cellular cytotoxicity. C. Herceptin delivers highly potent toxic drugs to the cancer cells. D. Herceptin is an effective treatment both before and after surgery for people with HER2-positive metastatic breast cancer. Q2. Bortezomib (Velcade) is a __________approved by the U.S. FDA for treating relapsed multiple myeloma. A. metalloproteinase inhibitor B. proteasome inhibitor C. topoisomerase II inhibitor D. beta-tubulin inhibitor Summary of Anticancer Drugs ! DNA-Reactive Drugs # Nitrogen mustards (Mustine, Chlorambucil, and Bendamustine) # Phosphoramide Mustard (Cyclophosphamide) # N-Alkyl-N-Nitrosoureas (Carmustine and Lomustine) # Procarbazine; Dacarbazine; Temozolomide # Platinum compounds (Cisplatin, Carboplatin, and Oxaliplatin) ! Antimetabolites # 5FU; Capecitabine; Gemcitabine; Fludarabine; Methotrexate ! Antitumor antibiotics derived from Natural Products # Actinomycin D; Bleomycin # Anthracyclines (Doxorubicin & Epirubicin); Etoposide # Camptothecin; Topotecan; Irinotecan # Vinca alkaloids (Vinblastine, Vincristine, and Vinorelbine) # Paclitaxel, Docetaxel, and Abraxane ! Antibody therapy # Trastuzumab; Trastuzumab emtansine; Pertuzumab; Cetuximab; Panitumumab; Bevacizumab; Rituximab; Ofatumumab; Nivolumab; Pembrolizumab; Ipilimumab ! Proteasome Inhibitor # Bortezomib