Biotechnology and drug discovery: from bench to bedside.
Abstract: New biotechnology and drug discovery technologies are facilitating the rapid expansion of the clinical drug chest, empowering clinicians with a better understanding of disease as well as novel modalities for treating patients. Important research tools and themes include genomics, proteomics, ligand-receptor interaction, signal transduction, rational drug design, biochips, and microarrays. Emerging drug classes include monoclonal antibodies, cancer vaccines Cancer vaccines
A treatment that uses the patient's immune system to attack cancer cells.
Mentioned in: Pancreatic Cancer, Exocrine , gene therapy, antisense strands, enzymes, and proteins. In this article, we review these topics and illustrate their potential impact by presenting an overview of promising drugs in the pipeline. Clinicians who use these novel treatments must become familiar with these trends.
Key Words: biotechnology, drug classes, drug development
Biotechnology is introducing new capabilities to drug discovery, which were considered until recently to be impractical and futuristic. There has been continuous evolution in the integrated approach to the development of therapies in medicine. This effort relies on clinicians, basic scientists, and feedback from novel translational applications.
Initially, biotechnology was synonymous with the emerging recombinant deoxyribonucleic acid Noun 1. recombinant deoxyribonucleic acid - genetically engineered DNA made by recombining fragments of DNA from different organisms
recombinant DNA (DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. ) technology and was used for the large-scale production of proteins, initially "replacement" proteins such as insulin and factor VIII factor VIII
A factor in the clotting of blood, a deficiency of which is associated with hemophilia A. Also called antihemophilic factor, antihemophilic globulin, antihemophilic globulin A, . Later, developments were based on an understanding of ligand-receptor interactions, their impact on disease processes, and the ability to manufacture such large macromolecular mac·ro·mol·e·cule
A very large molecule, such as a polymer or protein, consisting of many smaller structural units linked together. Also called supermolecule. proteins for therapeutic purposes. Today, signal transduction and cell signaling and their role in normal and disease states are taking center stage. Small-molecule drug (SMD (1) (Storage Module Device) A high-performance hard disk interface used with minis and mainframes that transfers data in the 1-4 MBytes/sec range (SMD-E provides highest rate). See hard disk. ) discovery, which uses and builds on organic molecules as starting materials, is also benefiting from the input of newer technologies such as combinatorial chemistry and high-throughput screening.
Although many physicians are not exposed to biotechnology, we think that it is valuable for clinicians to gain some fluency in the important trends in this field because the fruits of biotechnological research are reaching the clinic. The speed of events that are occurring in biotechnology is breathtaking and inspiring indeed. The younger generation of physicians has had the privilege of studying molecular biology molecular biology, scientific study of the molecular basis of life processes, including cellular respiration, excretion, and reproduction. The term molecular biology was coined in 1938 by Warren Weaver, then director of the natural sciences program at the Rockefeller as medical students. Even those physicians who did study molecular biology in medical school, however, must be excited but somewhat bewildered and uncomfortable about the advent of novel treatment modalities involving the use of antisense strands and monoclonal antibodies (MAb). This review is aimed at practitioners and specialists who are not closely involved in the process of drug discovery and intends to highlight the main developments in biotechnology and their impact on medicine.
Overview of Biotechnology
Drug discovery and development are costly and complicated processes. More than 99% of experimental compounds ultimately fail or are discarded as treatment regimens. Of the chemicals evaluated as part of drug discovery and preclinical testing, only a few proceed to human clinical trials and are approved for marketing. (1) To address this issue, new therapeutic approaches based on genomic and proteomic technology have been developed during the past several years. The -omic suffix is an example of the lexicon that has emerged to define the varied populations and subpopulations in the cell. These terms generally carry the -ome suffix, with an associated research topic denoted by the -omics appellation ap·pel·la·tion
1. A name, title, or designation.
2. A protected name under which a wine may be sold, indicating that the grapes used are of a specific kind from a specific district.
3. The act of naming. . The "genome"--that is, the full complement of an organism's genetic information that includes both coding and noncoding DNA sequences--provides a basis for defining the "proteome pro·te·ome
The complete set of proteins that are produced by the genes of an organism.
the entire complement of proteins produced by a cell. ," which is a list of only the encoding DNA regions that result in protein products. (2) Genomics and proteomics enable the discovery of new genes and proteins and the comparison of their levels in diseased cells, normal cells, and cells treated with compounds that vary in their efficacy and toxicity. Thus, they could prove valuable in identifying new drug targets.
[FIGURE 1 OMITTED]
In drug discovery, the drug target is key. A target for pharmaceutical intervention is almost invariably in·var·i·a·ble
Not changing or subject to change; constant.
in·vari·a·bil a protein whose function or dysfunction is implicated im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. in a disease process--for instance, growth factors and their receptors, which are frequently overexpressed in carcinomas. (3) A case in point is the epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation and differentiation. Human EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds. (EGF EGF
epidermal growth factor ) receptor family, which is the most studied growth factor receptor A growth factor receptor is a receptor which binds to growth factor. External links
• • system. These receptors are composed of an extracellular binding domain, a transmembranous lipophilic lipophilic,
adj/n the ability to dissolve or attach to lipids.
adj 1. showing a marked attraction to, or solubility in, lipids.
2. segment, and an intracellular protein tyrosine kinase tyrosine kinase An enzyme intimately linked to signal transduction–ST, either as a receptor-type TK, which participates in transmembrane signaling, or as an intracellular TK, participating in ST to the nucleus; ↑ or ↓ TK activity is associated with domain with a regulatory segment. The interaction of the extracellular growth factor with its receptor (ie, ligand-receptor interaction) results in the activation of cell signaling pathways that lead ultimately to cell division, the synthesis of new proteins, and tumor progression. This cascade of events is known as signal transduction. Figure 1 illustrates the different steps along the EGF signal transduction pathway that can serve as targets, some of which are being addressed already.
Manifold new drug targets are expected to sprout from the Human Genome Project, which has focused much attention on biotechnology. Indeed, the insight that the Human Genome Project provides with regard to the cell's genetic makeup as well as disease states can be used to understand the cell's protein makeup to generate new protein targets for intervention, such as the EGF family. However, the gene-protein-disease triangle is complex. Therefore, additional contributions from genomic and proteomic technologies is necessary to understand the genetic makeup and expression of diseased cells as well as how the resulting cellular proteins interact to cause disease. For example, biochips are one key technology that enables mutational analysis, gene sequencing, and protein expression testing. They consist of many small arrangements called microarrays that contain DNA, ribonucleic acid Ribonucleic acid (RNA)
One of the two major classes of nucleic acid, mainly involved in translating into proteins the genetic information that is carried in deoxyribonucleic acid (DNA). (RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic ), or protein affixed af·fix
tr.v. af·fixed, af·fix·ing, af·fix·es
1. To secure to something; attach: affix a label to a package.
2. to a small wafer such as that used in computers. Each microarray, or chip, contains thousands of different sequences of nucleotides or proteins. When a gene chip is reacted with a sample of unknown nature, only complementary sequences of DNA bind to the chip; unbound unbound
said of electrolytes, e.g. iron and calcium, and other substances which are circulating in the bloodstream and are not bound to plasma proteins so that they are available immediately for metabolic processes. See also calcium, iron. strands are washed away. One illustration of a gene chip's utility is that by using a gene chip with different tumor-associated genes, it is possible to determine whether a mutant gene mutant gene
A gene that has lost, gained, or exchanged some of the material it received from its parent, resulting in a permanent transmissible change in its function. , or oncogene oncogene
Gene that can cause cancer. It is a sequence of DNA that has been altered or mutated from its original form, the proto-oncogene (see mutation). Proto-oncogenes promote the specialization and division of normal cells. , is present in a suspected cancer cell. Biochips are thus useful for identifying potential new drug targets. (4), (5)
Once a target with a pivotal role in disease is identified, the next step requires designing a drug that will interact with it and deliver a therapeutic effect. Understanding ligand-receptor interaction is a key element in designing a drug to interact with a target. To bind with the target, most drug molecules insert themselves into a functionally critical site of the target protein, like a key in a lock. The molecule then either induces or, more commonly, inhibits the protein's function. Thus, a better understanding of the target's structure and functionality is key to designing better therapeutics, or ligands, that bind to the target. In recent years, better understanding of protein structure and function has yielded sophisticated approaches to the generation and optimization of drug candidates. These methods are commonly referred to as rational drug design. In essence, rational drug design tailors drug candidates to their target proteins by first elucidating the three-dimensional structure, the binding site, and the active site of the target. (6) Next, medicinal chemists apply combinatorial chemistry techniques and high-throughput screening tools to generate large libraries of compounds whose structure corresponds to the target's strategic site. With the use of biologic assays that reflect the activity of the target protein, researchers can modify the drug candidate to achieve the ideal in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. effect and test antitargets to determine the drug's specificity.
Biotechnology Drug Classes and Selected Drugs in the Pipeline
A snapshot of some drug candidates in development is beneficial to the understanding of how the technologies discussed in this article are used in drug development and in highlighting areas in medicine in which they may have a significant impact in the near future. We analyzed publicly available information, including the medical literature as well as U.S. Food and Drug Administration (FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. ) and drug company reports, to generate a representative but by no means exhaustive list of drug candidates currently in clinical trials. To facilitate this discussion, we found it valuable to assign drugs into classes according to their chemical composition.
Small-Molecule Drugs. SMDs normally have limited biologic interaction capability and less specificity than other drugs for desired targets. In general, an SMD acts as a "spoiler spoiler: see airplane.
1. spoiler - A remark which reveals important plot elements from books or movies, thus denying the reader (of the article) the proper suspense when reading the book or watching the movie.
2. ," because its therapeutic effect is limited to the inhibition of an effector effector /ef·fec·tor/ (e-fek´ter)
1. an agent that mediates a specific effect.
2. an organ that produces an effect in response to nerve stimulation. protein. For example, by interacting with a hormone receptor, the SMD can inhibit the binding activity of the respective hormone by occupying its docking site or by causing a change in the receptor's three-dimensional configuration. Both patients and the pharmaceutical industry favor the use of SMDs rather than other modalities because of their attractive pharmacokinetic properties, especially their suitability for oral administration and ease of development. (7) SMDs are well positioned to target intracellular proteins (ie, enzymes), because cell membrane Cell membrane
The membrane that surrounds the cytoplasm of a cell; it is also called the plasma membrane or, in a more general sense, a unit membrane. This is a very thin, semifluid, sheetlike structure made of four continuous monolayers of molecules. penetration is often feasible.
The tyrosine kinase inhibitor Noun 1. tyrosine kinase inhibitor - a drug used in cases of chronic myeloid leukemia
medicament, medication, medicinal drug, medicine - (medicine) something that treats or prevents or alleviates the symptoms of disease ST1571 (imatinib mesylate imatinib mesylate Warning - Hazardous drug!
Gleevec, Glivec (UK)
Pharmacologic class: Protein-tyrosine kinase inhibitor
Therapeutic class: Antineoplastic
, Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ) is an SMD that has had an exceptional impact on the management of Philadelphia-positive chronic myelogenous leukemia Chronic myelogenous leukemia (CML)
Also called chronic myelocytic leukemia, malignant disorder that involves abnormal accumulation of white cells in the marrow and bloodstream.
Mentioned in: Bone Marrow Transplantation (ie, Bcr-Abl-positive) and gastrointestinal stromal tumors with Kit mutations. (8), (9) ST1571 was first developed to target the platelet-derived growth factor receptor The platelet-derived growth factors PDGF-A and -B have for already more than 30 years been recognized as important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. but then was found to be an inhibitor of a specific target protein: the Bcr-Abl protein kinase protein kinase /pro·tein ki·nase/ (pro´ten ki´nas) an enzyme that catalyzes the phosphorylation of serine, threonine, or tyrosine groups in enzymes or other proteins, using ATP as a phosphate donor. . Bcr-Abl had previously been implicated in the pathogenesis of Philadelphia mutation-positive leukemia, and ST1571 was then developed through a rational process of screening and refining potential small molecules. It therefore serves as a fitting example of the way in which rational drug design is effecting drug development and disease management. (10) Selected SMDs that are currently in clinical trials for different applications are listed in Table 1. (11-30)
Protein Drugs. Protein drugs can be subdivided according to their mechanism of action. This categorization scheme helps to create order in the world of protein drugs, yet overlaps exist between different subtypes. Until the early 1970s, proteins were derived from animals or were manufactured synthetically. This process greatly limited their use as pharmaceuticals because of availability and cost issues. Recombinant DNA technology recombinant DNA technology
Recombining of DNA molecules from two different species that are inserted into a host organism to produce new genetic combinations that are of value to science, medicine, agriculture, or industry. significantly changed these circumstances. Scientists could now insert into a bacterial or yeast cell the human DNA comprising a gene and use the host to manufacture the human protein. With the use of that technology, the bottleneck in protein therapeutics shifted from protein manufacturing to the identification of drug targets and the generation of drug candidates.
Therapeutic Hormones and Enzymes. Hormones have been an important subject in pharmaceutical research, because the biology of various hormone deficiencies is relatively straightforward, and thus animal models can be created for research purposes. For instance, insulin was discovered in 1921, leading to the advent of replacement therapy with porcine porcine /por·cine/ (por´sin) pertaining to swine.
pertaining to pig. See also hog (1), swine.
porcine circovirus 1
a nonpathogenic virus. insulin and a better understanding of diabetes. Furthermore, because hormones are circulating entities, they are more accessible than other proteins--especially intracellular proteins--for research purposes. Hence, early protein therapeutics targeted hormone deficiency states, and when recombinant DNA technology emerged, it was used to manufacture replacement proteins, whose role in disease was relatively clear. Enzymes have enormous potential to serve as pharmaceuticals because of their vast number and ubiquitousness. That many enzymes operate intracellularly poses practical problems, however, because protein delivery into the cell is currently next to impossible. More intracellular enzymes are continually being discovered, and methods of enabling oral and intracellular protein delivery are among the most burning challenges in biotechnology. (31) Notable protein drugs that are in the advanced development to launch stages include a T cell-modulating fusion protein for patients with psoriasis and various other autoimmune diseases Autoimmune diseases
A group of diseases, like rheumatoid arthritis and systemic lupus erythematosus, in which immune cells turn on the body, attacking various tissues and organs.
Mentioned in: Complement Deficiencies, Premature Menopause , as well as recombinant natriuretic peptide for the treatment of patients with congestive heart failure congestive heart failure, inability of the heart to expel sufficient blood to keep pace with the metabolic demands of the body. In the healthy individual the heart can tolerate large increases of workload for a considerable length of time. (see Table 2) (33-47)
Monoclonal Antibodies. Antibodies (immunoglobulins) are proteins manufactured by B-lymphocytes. They consist of a highly diverse binding site known as the variable region (Fab), which sticks to a corresponding antigen, and a crystallizable crys·tal·lize also crys·tal·ize
v. crys·tal·lized also crys·tal·ized, crys·tal·liz·ing also crys·tal·iz·ing, crys·tal·liz·es also crys·tal·iz·es
1. fragment domain (Fc), which determines the antibody's functionality. MAb are products of a distinct clone of B cells and are usually derived by immunizing mice against the desired antigen. The reactive B cells are fused with myeloma myeloma /my·elo·ma/ (mi?e-lo´mah) a tumor composed of cells of the type normally found in the bone marrow.
giant cell myeloma see under tumor (1). cells to create hybridomas, which are essentially clones of immortalized B cells that share specificity for the same antigen. (48) The hybridomas' identical product antibody is called a monoclonal antibody monoclonal antibody, an antibody that is mass produced in the laboratory from a single clone and that recognizes only one antigen. Monoclonal antibodies are typically made by fusing a normally short-lived, antibody-producing B cell (see immunity) to a fast-growing , or MAb.
The ability to manufacture clones of identical MAb enables different strategies to create MAb therapeutics. By recruiting the immune system's lytic lytic /lyt·ic/ (lit´ik)
1. pertaining to lysis or to a lysin.
2. producing lysis.
1. Of, relating to, or causing lysis.
2. action, MAb lead to the destruction of antigens implicated in disease. MAb can be used to target toxic drugs such as chemotherapy directly at their site of action, thereby reducing side effects Side effects
Effects of a proposed project on other parts of the firm. and the required dosage. MAb can be used as diagnostic agents to locate, for instance, residual tumor cells after surgery. (49)
In recent years, MAb have made the leap from promising investigational therapies to the clinic, and currently there are 12 approved MAb in the United States. Eight of those 12 MAb are approved for therapeutic indications, including cancer, autoimmune disease autoimmune disease, any of a number of abnormal conditions caused when the body produces antibodies to its own substances. In rheumatoid arthritis, a group of antibody molecules called collectively RF, or rheumatoid factor, is complexed to the individual's own gamma , viral infection viral infection,
n an infection by a pathogenic virus. A virus acts on the cell nucleus, taking over the genetic material within the nucleus and replicating itself. , and myocardial infarction myocardial infarction: see under infarction. . In addition, four MAb have been approved for use as diagnostic agents. Most of these have had a significant impact on disease, as evidenced in the discussion of selected MAb in the next few paragraphs.
Rituximab (Rituxan; Genentech, Inc., South San Francisco South San Francisco, city (1990 pop. 54,312), San Mateo co., W Calif.; inc. 1908. South San Francisco has several industrial parks; its manufactures include medical supplies and equipment, foods, paint, paper products, consumer goods, and clothing. , CA), the first MAb approved for the treatment of cancer patients, is indicated for non-Hodgkin's B cell lymphoma. It is directed against the cytosine cytosine (sī`tōsēn'), organic base of the pyrimidine family. It was isolated from the nucleic acid of calf thymus tissue in 1894. deaminase deaminase /de·am·i·nase/ (de-am´i-nas) an enzyme causing deamination, or removal of the amino group from organic compounds, usually cyclic amidines.
n. 20 (CD20) protein, which is found on the surface of normal and malignant B cells. As a single agent, rituximab induces meaningful responses in approximately one-half of patients with relapsed indolent lymphomas and in approximately one-third of patients with relapsed aggressive lymphomas. Because it is a nonchemotherapeutic agent, it also presents a relatively benign side effect profile. Rituximab is currently being tested for other B cell disorders. (50), (51)
Infliximab (Remicade; Centocor, Inc., Malvern, PA) is a chimeric chi·mer·ic
1. Relating to a chimera.
2. Composed of parts of different origin. (human-mouse) MAb that neutralizes tumor necrosis tumor necrosis Death of tumor tissue, a common event in aggressive CAs in which the tumor rapidly outgrows its blood supply, resulting in tumor cell death. Cf Apoptosis. [alpha], a proinflammatory cytokine Cytokine
Any of a group of soluble proteins that are released by a cell to send messages which are delivered to the same cell (autocrine), an adjacent cell (paracrine), or a distant cell (endocrine). . It is approved for the treatment of patients with rheumatoid arthritis rheumatoid arthritis
Chronic, progressive autoimmune disease causing connective-tissue inflammation, mostly in synovial joints. It can occur at any age, is more common in women, and has an unpredictable course. and Crohn's disease Crohn's disease: see colitis. . In clinical trials for rheumatic rheu·mat·ic
Relating to or characterized by rheumatism.
One who is affected by rheumatism.
pertaining to or affected with rheumatism. arthritis, infliximab produced significant improvements in all measures of disease, and treatment with infliximab combined with methotrexate methotrexate, drug used in halting the growth of actively proliferating tissues. Introduced in the 1950s, it is used in the treatment of leukemia, psoriasis, and non-Hodgkin's lymphoma. was found to be superior to treatment with methotrexate alone. (52) In Crohn's disease, clinical trials showed infliximab to be effective in producing and maintaining a clinical response in patients with refractory moderate to severe disease. (53)
Trastuzumab (Herceptin; Genentech, Inc.) is a humanized MAb that targets the extracellular portion of the human epidermal growth factor receptor This article is about a cell suface receptor. For estimated measure of kidney function (eGFR), see Glomerular filtration rate.
The epidermal growth factor receptor 2 (HER2)/Neu receptor. The latter is a member of the EGF receptor family, the blockade of which inhibits the growth of tumors that express it. HER2/Neu is overexpressed in 25 to 30% of breast cancers, increasing tumor aggressiveness. In HER2/Neu-positive patients, the use of trastuzumab with chemotherapy was associated with improved time until disease progression and with overall survival. (54) Several promising MAb currently in late-stage clinical trials are targeting non-Hodgkin's lymphoma non-Hodg·kin's lymphoma
Any of various malignant lymphomas characterized by the absence of Reed-Sternberg cells.
Non-Hodgkin's lymphoma , asthma, psoriasis, and different solid organ tumors (Table 2). (33-47)
Chemicals made by the cells that act on other cells to stimulate or inhibit their function. Cytokines that stimulate growth are called "growth factors. . Cytokines are proteins that regulate cells that belong to the immune system immune system
Cells, cell products, organs, and structures of the body involved in the detection and destruction of foreign invaders, such as bacteria, viruses, and cancer cells. Immunity is based on the system's ability to launch a defense against such invaders. , such as lymphocytes Lymphocytes
Small white blood cells that bear the major responsibility for carrying out the activities of the immune system; they number about 1 trillion. and macrophages Macrophages
White blood cells whose job is to destroy invading microorganisms. Listeria monocytogenes avoids being killed and can multiply within the macrophage. . Cytokines have a pivotal role in normal and disease mechanisms in which immune processes play a role, including chronic infectious, autoimmune, cancer, and coronary heart diseases. Many cytokines and cytokine inhibitors are available or are being developed as therapeutics. (55-59)
Interleukins (ILs) and interferons are a large and varied family of compounds produced by lymphocytes, macrophages, and monocytes monocytes,
n.pl the largest of the white blood cells. They have one nucleus and a large amount of grayish-blue cytoplasm. Develop into macrophages and both consume foreign material and alert T cells to its presence. . The FDA has approved the use of recombinant IL-2 for the treatment of patients with renal cell carcinoma renal cell carcinoma
Malignant tumour of the cells that cover and line the kidney. It usually affects persons over age 50 who have vascular disorders of the kidneys. It seldom causes pain, unless it is advanced. , but IL-2 is highly toxic highly toxic Occupational medicine adjective Referring to a chemical that 1. Has a median lethal dose–LD50 of ≤ 50 mg/kg when administered orally to 200-300 g albino rats 2. because of its central role in the immune system, which thus far has limited its impact. (60) The FDA has approved the use of recombinant interferons for patients with human immunodeficiency virus-related Kaposi's sarcoma Kaposi's sarcoma (käp`əshē', kəpō`sē), a usually fatal cancer that was considered rare until its appearance in AIDS patients. , genital warts genital warts: see human papillomavirus. , hairy cell leukemia Hairy Cell Leukemia Definition
Hairy cell leukemia is a disease in which a type of white blood cell called the lymphocyte, present in the blood and bone marrow, becomes malignant and proliferates. , and hepatitis B Hepatitis B Definition
Hepatitis B is a potentially serious form of liver inflammation due to infection by the hepatitis B virus (HBV). It occurs in both rapidly developing (acute) and long-lasting (chronic) forms, and is one of the most common chronic and C. (59)
Colony-stimulating factors (CSFs) stimulate bone marrow stem cells stem cells, unspecialized human or animal cells that can produce mature specialized body cells and at the same time replicate themselves. Embryonic stem cells are derived from a blastocyst (the blastula typical of placental mammals; see embryo), which is very young to differentiate toward a particular cell type. Recombinant versions of CSF Cerebrospinal Fluid (CSF) Analysis Definition
Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord. , including granulocyte-macrophage CSF, granulocyte granulocyte /gran·u·lo·cyte/ (gran´u-lo-sit?) granular leukocyte.granulocyt´ic
band-form granulocyte band cell.
n. CSF, and erythropoietin erythropoietin /eryth·ro·poi·e·tin/ (-poi´e-tin) a glycoprotein hormone secreted by the kidney in the adult and by the liver in the fetus, which acts on stem cells of the bone marrow to stimulate red blood cell production have revolutionized the ability to treat myelosuppression. Most notably, these agents have had a significant impact in cancer treatment, in which myelosuppression is a common complication of chemotherapy. Proved and suggested effects of treatment include shortening the duration of febrile febrile /feb·rile/ (feb´ril) pertaining to or characterized by fever.
Of, relating to, or characterized by fever; feverish. neutropenia Neutropenia Definition
Neutropenia is an abnormally low level of neutrophils in the blood. Neutrophils are white blood cells (WBCs) produced in the bone marrow that ingest bacteria. after myelosuppressive treatment, mobilization of hematopoietic stem cells for ensuing transplantation, and reductions in chemotherapy-associated infections, antibiotic use, hospital stay, and mortality. (61), (62) Erythropoietin has had a profound effect on the treatment of patients with end stage renal failure-associated anemia. (63) Some investigational cytokines are listed in Table 2.
Gene Therapy. Gene therapy may be defined as the transfer of recombinant DNA recombinant DNA
Genetically engineered DNA prepared by transplanting or splicing one or more segments of DNA into the chromosomes of an organism from a different species. Such DNA becomes part of the host's genetic makeup and is replicated. into human cells to achieve the production of a desired protein. Depending on the strategy used, DNA may be introduced into cells removed from the body (ie, the ex vivo ex vivo /ex vi·vo/ (eks´ ve´vo) outside the living body; denoting removal of an organ (e.g., the kidney) for reparative surgery, after which it is returned to the original site. approach) or directly into cells in their normal location (ie, the in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. approach). (64) Gene therapy has various potential applications, such as treating patients with enzyme deficiencies or cancer. Efficient gene transfer requires the use of a vector. All vectors contain, at a minimum, the transgene transgene
a gene that has been incorporated into the genome of another organism. of interest linked to a promoter to drive its expression. (65) Increasingly wider ranges of viral and synthetic vectors are available, each of which has characteristic advantages and limitations. Generally, viral vectors achieve better transfection trans·fec·tion
Infection of a bacterium or cell with DNA or RNA isolated from a bacteriophage or from an animal or a plant virus, resulting in replication of the complete virus. than other vectors but have other problems such as immunogenicity immunogenicity /im·mu·no·ge·nic·i·ty/ (-je-nis´it-e) the property enabling a substance to provoke an immune response, or the degree to which a substance possesses this property. and complicated manufacturing. Liposomes Liposomes
Aqueous compartments enclosed by lipid bilayer membranes; liposomes are also known as lipid vesicles. Phospholipid molecules consist of an elongated nonpolar (hydrophobic) structure with a polar (hydrophilic) structure at one end. are nonviral vectors that mitigate the immunogenicity problem but provide less efficient transfection and protein expression. Naked DNA is a third method that uses plasmids, which usually are administered by direct injection into tumor or muscle as opposed to systemic delivery. (66)
There are several strategies whereby gene therapy may be used to treat cancer. In the corrective gene therapy approach, when malignant transformation malignant transformation Oncology The constellation of changes in the growth properties of cells in culture evoked by various agents–eg, radiation, toxins, and viruses that result in development of tumors is associated with inactivity of tumor suppressor genes such as p53 and p21, supplying tumors with the intact gene may reverse malignant transformation by promoting apoptosis. (67-69) Another strategy is cytoreductive gene therapy, in which immunotherapy or cytolytic/proapoptotic approaches are used. Immunotherapy uses gene transfer to facilitate a dormant host immune response immune response
An integrated bodily response to an antigen, especially one mediated by lymphocytes and involving recognition of antigens by specific antibodies or previously sensitized lymphocytes. directed against the tumor. Evasion of autologous autologous /au·tol·o·gous/ (aw-tol´ah-gus) related to self; belonging to the same organism.
1. host cellular immunity cellular immunity
See cell-mediated immunity. is a common feature of tumor cell neoantigens, because tumor cells are poor antigen-presenting cells. Cancer vaccine strategies are based on optimization of the context in which tumor antigens or tissue-specific antigens are presented to the host immune system. When appropriately primed, the activated host immune system can then act against tumor cells systemically.
The ex vivo approach starts with inactivated inactivated
rendered inactive; the activity is destroyed.
treated so that they are no longer able to produce evidence of growth or damaging effect on tissue. cancer cells obtained from the patient. Different techniques are then used to enhance the immunogenicity of tumor-specific antigens, including growth in a cytokine-rich environment, coinjection of tumor cells along with cytokines back into the patient, or transfection of these cells in vitro with genes that encode immunostimulatory cytokines. A second approach is to administer an injection of a purified tumor-associated protein or peptide into the patient, without injecting the entire tumor cell. The third approach uses in vitro manipulation of host antigen-presenting cells such as dendritic cells, which are involved in initiating the T cell-mediated response against antigens. Confronting dendritic cells with the desired antigen in vitro stimulates an immune response upon injection into the patient. (70), (71) Enzyme/prodrug gene therapy, also referred to as suicide gene therapy, relies on the conversion of an inactive prodrug prodrug /pro·drug/ (-drug) a compound that, on administration, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent; a precursor of a drug. into a toxic drug with the use of an enzyme vectored only to the target tumor cells. In this way, active drug is limited spatially to the transduced cells and adjacent surrounding cells, facilitating higher tumor drug concentrations without increased normal tissue toxicity. Prodrug-activating enzymes that have been used in this approach include cytosine deaminase, which catalyzes the conversion of the nontoxic 5-fluorocytosine to the cytotoxic cy·to·tox·ic
Of, relating to, or producing a toxic effect on cells.
cyto·tox·ic 5-fluorouracil, and herpes simplex virus Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.
Mentioned in: Conjunctivitis
herpes simplex virus thymidine kinase, which, together with cellular enzymes, facilitates the conversion of ganciclovir into the toxic ganciclovir triphosphate triphosphate /tri·phos·phate/ (tri-fos´fat) a salt containing three phosphate radicals.
A salt or ester containing three phosphate groups. .
Viral vectors may themselves be designed to target and kill tumor cells without the insertion of a foreign transgene (eg, oncolytic viruses). The adenovirus adenovirus
Any of a group of spheroidal viruses, made up of DNA wrapped in a protein coat, that cause sore throat and fever in humans, hepatitis in dogs, and several diseases in fowl, mice, cattle, pigs, and monkeys. life cycle includes a lytic phase, which can result in host cell death independent of entry into the cell cycle. Adenovirus has evolved a potent repertoire of gene products that may exert profound effects on the growth regulation of the host cell to facilitate viral replication. The ONYX-015 vector, a replication-competent adenovirus designed to preferentially replicate in p53 mutant cells, is currently in clinical trials (Table 3). (72) ONYX-015 is the first genetically engineered genetically engineered adjective Recombinant, see there replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. (73)
Antisense antisense, DNA or RNA manipulated in a laboratory so that its components (nucleotides) form a complementary copy of normal, or "sense," messenger RNA (mRNA; see nucleic acid). Drugs. Although traditional drugs are designed to interact with protein molecules, antisense drugs are designed to inhibit the production of disease-causing proteins. During the transcription of information from DNA to messenger RNA mes·sen·ger RNA
See mRNA. (mRNA), two complementary strands of DNA partly uncoil such that one strand is used as a template for the transcribing enzymes, which assemble mRNA in a process called transcription. mRNA then migrates into the cell, where its encoded information is read by the ribosomes Ribosomes
Small particles, present in large numbers in every living cell, whose function is to convert stored genetic information into protein molecules. and translated to the specific protein. (95)
Antisense drugs are complementary strands of small segments of mRNA. To create antisense drugs, nucleotides are linked in short chains (ie, oligonucleotides). Each antisense drug is designed to bind to to contract; as, to bind one's self to a wife s>.
See also: Bind a specific sequence of nucleotides in its mRNA target to inhibit the production of the protein encoded by the target mRNA. Fomivirsen (Vitravene; Isis Pharmaceuticals, Inc., Carlsbad, CA) is an antisense strand complementary to the mRNA of a crucial cytomegalovirus cytomegalovirus (sī'təmĕg'əlōvī`rəs), member of the herpesvirus family that can cause serious complications in persons with weakened immune systems. protein. It is an FDA-approved medication indicated for patients with acquired immunodeficiency syndrome-related cytomegalovirus retinitis cytomegalovirus retinitis Ophthalmology CMV infection of the eye, a common opportunistic infection in AIDS, a complication of disseminated CMV infection Clinical Retinal inflammation, blindness Management Antivirals–eg, foscarnet, cidofovir, gancyclovir, . Oblimersen sodium (Genasense; Genta, Inc., Berkeley Heights, NJ) is an antisense drug that binds to the Bc1-2 mRNA, which is expressed by different cancers (Table 3).
The development of a new drug requires the identification of a protein target, techniques for the generation of compounds that react with the target in a desired fashion, and innovative delivery mechanisms by which to lead the drug to its target. The tools of biotechnology are effecting advancements on all of these fronts. An abundance of new gene and protein targets that can be targeted by therapeutics are being investigated. Moreover, whereas in the past most drugs were randomly generated small-molecule compounds that were limited to the blockade of certain pathways, other drug classes have emerged, including recombinant protein recombinant protein Molecular biology A protein encoded by recombinant DNA or generated from a recombinant gene. See Recombinant pharmacology. drugs and MAb, DNA and cellular vaccines, gene therapy, and antisense therapy. SMDs, which remain a fundamental weapon against many diseases, can be engineered to provide a better therapeutic profile than before. Some of the newer drug classes, including protein drugs and MAb, already have exhibited proof of concept as approved drugs on the basis of several years of experience. The potential impact on disease of cancer vaccines, gene therapy, and antisense therapy remains to be determined, but there seems to be consensus regarding the eventual important role of these technologies.
As a result of these developments, physicians will be able to attack the same target with a mix of various drug classes, such as combinations of MAb or a cancer vaccine against a tumor-associated protein, a cytokine to increase the antitumor an·ti·tu·mor also an·ti·tu·mor·al
Counteracting or preventing the formation of malignant tumors; anticancer.
Adj. 1. immune response, and gene therapy encoding for a suicide protein. Such an approach is not yet feasible, but the drugs that will allow experimentation with such combinations are at our doorstep.
Several drug candidates are far along the route to becoming FDA-approved drugs. These include a cellular vaccine for hormone-resistant prostate cancer prostate cancer, cancer originating in the prostate gland. Prostate cancer is the leading malignancy in men in the United States and is second only to lung cancer as a cause of cancer death in men. , a cancer vaccine and a small-molecule antiangiogenic an·ti·an·gi·o·gen·ic
Inhibiting the growth of blood vessels.
antiangiogenic drug for renal cell carcinoma, a new immune modulator Modulator
Any device or circuit by means of which a desired signal is impressed upon a higher-frequency periodic wave known as a carrier. The process is called modulation. The modulator may vary the amplitude, frequency, or phase of the carrier. protein drug directed against psoriasis and other autoimmune diseases, an SMD directed against transitional cell carcinoma tran·si·tion·al cell carcinoma
A malignant neoplasm derived from transitional epithelium and occurring primarily in the urinary bladder, ureters, or renal pelvises.
transitional cell carcinoma Bladder cancer, see there , and several MAb that target cancer, autoimmune disease, and graft versus host disease Graft versus host disease
A life-threatening complication of bone marrow transplants in which the donated marrow causes an immune reaction against the recipient's body.
Mentioned in: Bone Marrow Transplantation . Judging from the wealth of advanced clinical candidates in the pipeline, the impact of biotechnology on the practice of medicine will soon increase markedly, empowering clinicians with new ways to fight disease.
Better to be kind at home
Than to burn incense in a distant place.
Table 1. Small-molecule drug candidates (a) Drug brand name Drug manufacturer/ (generic name) developer, location Tarceva (OSI-774) OSI Pharmaceuticals, Inc., Melville, NY Incel (biricodar dicitrate, Vertex Pharmaceuticals, VX-710) Inc., Cambridge, MA Eflornithine -- (difluoromethylornithine, or DFMO) No brand name -- (CCI779) No brand name Abbott Laboratories, (atrasentan, ABT-627) Abbott Park, IL Velcade (bortezomib, Millennium PS-341) Pharmaceuticals, Inc., Cambridge, MA Apomine (SR-45023A) Ilex Oncology, Inc., San Antonio, TX Flavopiridol (HMR1275) Aventis Pharmaceuticals, Inc., Bridgewater, NJ No brand name -- (CEP701) No brand name GlycoDesign, Inc., (GD0039) Toronto, ON, Canada No brand name (UCN- -- 01) Iressa (gefitinib, AstraZeneca ZD1839) Pharmaceuticals LP, Wilmington, DE Thalomid (thalidomide) Celgene Corp., Warren, NJ No brand name (NV-06, Marshall Edwards, Inc., phenoxodiol) North Ryde, NSW, Australia Drug brand name (generic name) Condition Tarceva (OSI-774) Pancreatic, breast, non-small cell lung, and head and neck cancers Incel (biricodar dicitrate, Ovarian, liver, CAP, and small cell VX-710) lung cancers; sarcomas Eflornithine Colon and nonmelanoma skin cancers; (difluoromethylornithine, TCC; Barrett's esophagus or DFMO) No brand name Glioma, glioblastoma multiforme, (CCI779) melanoma, small cell lung cancer No brand name CAP (atrasentan, ABT-627) Velcade (bortezomib, Ovarian, head and neck, and refractory PS-341) hematologic malignancies, including multiple myeloma and breast cancer Apomine (SR-45023A) CAP Flavopiridol (HMR1275) Solid tumors and lymphoma No brand name CAP (CEP701) No brand name Colorectal and breast cancers and RCC (GD0039) No brand name (UCN- Advanced solid tumors 01) Iressa (gefitinib, RCC ZD1839) Thalomid (thalidomide) Multiple myeloma, CAP No brand name (NV-06, RCC and other solid tumors phenoxodiol) Clinical Drug brand name trial (generic name) phase (b) Comments Tarceva (OSI-774) III Selective, orally active inhibitor of ErbB1 tyrosine kinase (an epidermal growth factor receptor), a key oncogene in a variety of cancers, including ovarian, pancreatic, non- small cell lung, breast, and head and neck cancers. (11) Incel (biricodar dicitrate, II Small molecule blocker of VX-710) multidrug-resistant pumps MDR1 gene and multidrug resistance- associated protein. Intended to sensitize tumors to chemotherapy. (12) Eflornithine III Irreversible inhibitor of (difluoromethylornithine, ornithine or DFMO) decarboxylase, an enzyme elevated in most tumors and premalignant lesions. (13) No brand name II Binds to the immunophilin (CCI779) FK506-binding protein 12, and the resultant complex inhibits the activity of mammalian target of rapamycin (mTOR). (14) No brand name III Endothelin A receptor inhibitor (atrasentan, ABT-627) that inhibits endothelin-1 receptor-mediated effects, including stimulation of prostate cancer proliferation and apoptosis inhibition, and promotes osteoblast activity. (15) (Note: Abbott Labs stopped Phase III trial in February 2003.) Velcade (bortezomib, II Inhibitor of PS-341) ubiquitin-proteasome pathway that has an important role in cell cycle regulation by degradation of intracellular proteins. This results in shifts in favor of increased cell survival, metastasis, and angiogenesis. (16) Recent report (17) showed that PS-341 has activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma. Apomine (SR-45023A) II Bisphosphonate ester that binds to the farnesoid X nuclear receptor. Induces apoptosis of cancer cells. (18) Flavopiridol (HMR1275) II A potent inhibitor of cyclin-dependent kinases and others. (19) No brand name II Inhibitor of the receptor for (CEP701) nerve growth factor, a tyrosine kinase receptor implicated in cancer pathways. (20) No brand name II Inhibitor of Golgi enzyme (GD0039) mannosidase II, which is responsible for the synthesis of key carbohydrate structures involved in disease. (21) No brand name (UCN- II Nonspecific inhibitor of many 01) kinases causing cell cycle arrest in G1 and G2 phases in different cell types. (22) Iressa (gefitinib, II Inhibitor of epidermal growth ZD1839) factor receptor. (23) Thalomid (thalidomide) III Small molecule antiangiogenesis agent. Also being evaluated in early clinical trials for recurrent or malignant glioma, myelofibrosis with myeloid metaplasia, colorectal cancer, ovarian epithelial cancer, metastatic RCC, and non-small cell lung cancer. (24) No brand name (NV-06, II Signal transduction inhibitor. phenoxodiol) Blocks enzymes involved in cell division, including topoisomerase-2 and protein tyrosine kinases. Restores apoptosis in cancer cells. (c) Reminyl (galantamine Janssen Pharmaceutica HBr) Products LP, Titusville, NJ Neovastat (AE-941) AEterna Laboratories, Inc., Quebec City, QB, Canada 17-N-allylamino-17- -- demethoxy geldanamycin (17-AAG) No brand name Pfizer, Inc., New York, (indiplon, NBI-34060) NY, and Neurocrine Biosciences, Inc., San Diego, CA Rotigotine CDS Aderis Pharmaceuticals, (SPM-962) Hopkinton, MA, and Schwarz Pharma AG, Monheim, Germany No brand name (2- -- methoxyestradiol) No brand name Ilex Oncology, Inc., San (ILX295501) Antonio, TX, and Eli Lilly & Co., Indianapolis, IN Reminyl (galantamine Alzheimer's disease HBr) Neovastat (AE-941) Lung and breast cancers and RCC 17-N-allylamino-17- Epithelial and hematologic demethoxy malignancies, and sarcomas geldanamycin (17-AAG) No brand name Insomnia (indiplon, NBI-34060) Rotigotine CDS Parkinson's disease (SPM-962) No brand name (2- Advanced solid tumors methoxyestradiol) No brand name Solid tumors (ILX295501) Reminyl (galantamine III Inhibitor of HBr) acetylcholinesterase that also acts agonistically on nicotinic receptors. In clinical trials, patients who took galantamine experienced benefits in cognitive function and activities of daily living. (25) Neovastat (AE-941) III Antiangiogenesis drug (shark cartilage extract) that activates apoptosis of endothelial cells and inhibits the vascular endothelial growth factor-R2 pathway. (26), (27) 17-N-allylamino-17- I Heat shock protein 90 inhibitor. demethoxy It maintains the conformation, geldanamycin stability and function of (17-AAG) key oncogenic proteins involved in signal transduction pathways leading to proliferation, cell cycle progression and apoptosis, as well as other features of the malignant phenotype such as invasion, angiogenesis, and metastasis. (28) No brand name III Nonbenzodiazepine agent that (indiplon, NBI-34060) acts on a specific site of the [gamma]-aminobutyric acid A receptor in an agonistic fashion. (c) Rotigotine CDS III Lipid-soluble D2 dopamine (SPM-962) agonist in a transdermal delivery formulation (ie, patch). Intended to decrease motor complications associated with chronic use of dopamine agonists, which usually exhibit intermittent levels of dopamine stimulation. (29) No brand name (2- I Estrogen-related compound with methoxyestradiol) antiproliferative and antiangiogenic activities. (30) No brand name II Sulfonylurea with antitumor (ILX295501) activity against a broad spectrum of solid tumors. Inhibits the enzymes topoisomerase 1 and 2, causing DNA breaks and cell death in cancer cells. (c) (a) CAP, carcinoma of prostate; TCC, transitional cell carcinoma; RCC, renal cell carcinoma; DNA, deoxyribonucleic acid. (b) Phase relates to clinical trial stage in the United States as of April 2003. Some drugs may be in a more advanced clinical trial phase in other countries. (c) Unpublished data. Table 2. Protein drug candidates (a) Drug brand name Drug manufacturer/ (generic name) developer, location Plenaxis (Abarelix-Depot, Praecis Pharmaceuticals, PPI-149) Inc., Waltham, MA Ampligen (AMP 719) Hemispherx Biopharma, Inc., Philadelphia, PA No brand name Abgenix, Inc., Fremont, (ABX-EGF) CA, and Immunex Corp., Seattle, WA Multikine CEL-SCI Corp., Vienna, VA Avicidin NeoRx Corp., Seattle, WA Natrecor (nesiritide) Scios, Inc., Sunnyvale, CA Amevive (alefacept) Biogen, Inc., Cambridge, MA No brand name Abgenix, Inc., Fremont, (ABX-CBL) CA, and SangStat Medical Corp., Fremont, CA Xolair (omalizumab) Genentech, Inc., South San Francisco, CA, Novartis AG, East Hanover, NJ No brand name Amgen, Inc., Thousand (epratuzumab, AMG Oaks, CA 412) Bexxar (tositumomab and Corixa Corp., Seattle, WA, [.sup.131]I-tositumomab) and GlaxoSmithKline, Research Triangle Park, NC Antegren (natalizumab) Biogen, Inc., Cambridge, MA, and Elan Corp., plc, Dublin, Ireland Keyhole Limpet -- Hemocyanin (KLH, DRG-0070) Drug brand name Clinical trial (generic name) Condition phase (b) Plenaxis (Abarelix-Depot, CAP NDA action date PPI-149) extended 90 days from August 27, 2003, by FDA Ampligen (AMP 719) RCC II/III No brand name RCC II (ABX-EGF) Multikine CAP II Avicidin Lymphoma, CAP, II ovarian, and colon cancers Natrecor (nesiritide) Decompensated CHF M (FDA approval received 2001) Amevive (alefacept) Psoriasis M (FDA approval received January 30, 2003) No brand name GVHD II/III (ABX-CBL) Xolair (omalizumab) Asthma and seasonal M (FDA approval allergies received June 2003) No brand name Non-Hodgkin's III (epratuzumab, AMG lymphoma 412) Bexxar (tositumomab and Non-Hodgkin's M (FDA approval [.sup.131]I-tositumomab) lymphoma received June 30, 2003) Antegren (natalizumab) MS, Crohn's III Keyhole Limpet Superficial bladder III Hemocyanin (KLH, TCC DRG-0070) Drug brand name (generic name) Comments Plenaxis (Abarelix-Depot, Peptide antagonist to gonadotropin-releasing PPI-149) hormone, blocking its action on the pituitary gland. (32) Ampligen (AMP 719) Second-generation interferon that acts as an immune system stimulator. (33) No brand name Humanized monoclonal antibody against the (ABX-EGF) epidermal growth factor receptor, which is overexpressed in 70 to 90% of RCCs. (34) Multikine Immunotherapeutic agent that is a mixture of interleukins, interferons, and colony- stimulating factors; intratumoral administration. (35) Avicidin Streptavidin/biotin monoclonal antibody treatment. A multistep delivery system that involves the use of an antibody to target streptavidin to a tumor-associated antigen receptor. Biotin is then used to target the [.sup.90]Y radioisotope to the tumor-localized streptavidin. (36) Natrecor (nesiritide) Recombinant form of B-type natriuretic peptide that produces hemodynamic and symptomatic improvement through balanced vasodilatory effects, neurohormonal suppression, and enhanced natriuresis and diuresis. (37), (38) Amevive (alefacept) Human fusion protein obtained by recombinant DNA technology designed to modulate the activity of T-cells that play a critical role in the pathogenesis of psoriasis and other autoimmune diseases. Alefacept modulates the function of and selectively induces apoptosis of [CD.sup.2+] human memory effector T cells in vivo. Psoriatic plaques are characterized by infiltration with CD45RO+ memory effector T lymphocytes. The recombinant protein alefacept binds to CD2 on memory effector T lymphocytes, inhibiting their activation. (39), (40) No brand name A murine immunoglobulin M monoclonal (ABX-CBL) antibody that recognizes CD147 on the cell surface. Human CD147, also known as neurothelin or extracellular matrix metalloproteinase inducer, is a member of the immunoglobulin superfamily. On activation, CD147 is upregulated on T and B lymphocytes, which are then depleted through a complement-dependent cytotoxic mechanism. (41) Xolair (omalizumab) A novel humanized monoclonal antibody directed against the high-affinity Fc[euro]RI portion of the immunoglobulin E. It decreases serum immunoglobulin E levels in a dose-dependent manner. It was shown to significantly reduce the rate of exacerbation and improve disease control in patients at high risk for serious asthma-related morbidity and mortality. (42) No brand name Humanized anti-CD22 monoclonal antibody. (epratuzumab, AMG CD22 is commonly expressed by B-cell 412) malignant cells. (43) Bexxar (tositumomab and Anti-CD20 murine monoclonal antibody [.sup.131]I-tositumomab) conjugated with radioactive iodine ([.sup.131]I); radioimmunotherapy. (44) Antegren (natalizumab) Humanized monoclonal antibody and the first in a new class of potential therapeutics known as [alpha]4 integrin inhibitors that are designed to block immune cell adhesion to blood vessel walls and subsequent migration of lymphocytes into tissue. (45), (46) Keyhole Limpet Immune modulator protein derived from the Hemocyanin (KLH, mollusk Megathura crenulata (great keyhole DRG-0070) limpet), which is found along the coast of California and Mexico. (47) (a) CAP, carcinoma of prostate; NDA, new drug application to U.S. Food and Drug Administration (FDA); RCC, renal cell carcinoma; CHF, congestive heart failure; DNA, deoxyribonucleic acid; GVHD, graft versus host disease; MS, multiple sclerosis; TCC, transitional cell carcinoma; M, approved medication. (b) Phase relates to clinical trial stage in the United States as of April 2003. Some drugs may be in a more advanced clinical trial phase in other countries. Table 3. Cancer vaccines and gene therapy drug candidates (a) Drug brand Drug name (generic manufacturer/ name) developer, location Disease Advexin (INGN 201, Introgen Therapeutics, Head and neck, Ad5CMVp53) Inc., Austin, TX breast, lung, and pancreatic cancers and TCC OncoVAX Intracel, LLC, Frederick, Colorectal cancer MD and RCC Leuvectin Vical, Inc., San Diego, RCC and CAP CA Oncophage (HSPPC- Antigenics, Inc., New Lung cancer and 96) York, NY RCC melanoma Genasense (oblimersen Genta, Inc., Berkeley CLL, AML, sodium, G-3139; Heights, NJ melanoma, MM, formerly and CAP augmerosen) Provenge Dendreon Corp., Seattle, CAP WA GVAX Cell Genesys, Inc., South CAP, lung, and San Francisco, CA pancreatic cancers and AML Avicine AVI BioPharma, Inc., CAP Portland, OR Prostvac Therion Biologics Corp., CAP Cambridge, MA CG7060 (formerly Cell Genesys, Inc., South CAP CV706) San Francisco, CA CG7870 (formerly Cell Genesys, Inc., South CAP CV787) San Francisco, CA TG4010 (MVA-MUC- Transgene, S.A., CAP IL2) Strasbourg, France INGN 201 AD-p53 Introgen Therapeutics, CAP, TCC Inc., Austin, TX Prostate-specific PSMA Development Co., CAP membrane antigen LLC (Progenics (PSMA) vaccine Pharmaceuticals, Inc., Tarrytown, NY, and Cytogen Corp., Princeton, NJ, in collaboration with AlphaVax Human Vaccines, Inc., Research Triangle Park, NC) Drug brand name (generic Clinical trial name) phase (b) Type Advexin (INGN 201, II/III (FDA Gene Ad5CMVp53) designated Fast therapy Track Drug Product status September 2003) OncoVAX II Cellular cancer vaccine Leuvectin II Gene therapy Oncophage (HSPPC- III Peptide 96) cancer vaccine Genasense (oblimersen II/III Antisense sodium, G-3139; formerly augmerosen) Provenge III Cellular cancer vaccine GVAX II/III Cellular cancer vaccine Avicine II Peptide cancer vaccine Prostvac II Gene therapy CG7060 (formerly I/II Gene CV706) therapy CG7870 (formerly I/II Gene CV787) therapy TG4010 (MVA-MUC- I Gene IL2) therapy INGN 201 AD-p53 II Gene therapy Prostate-specific II Cellular membrane antigen cancer (PSMA) vaccine vaccine Drug brand name (generic name) Comments Advexin (INGN 201, Gene therapy applying the p53 gene using Ad5CMVp53) an adenoviral vector. Most advanced clinical trials are for head and neck cancers, whereas the same approach is in earlier trials for other oncologic indications. (74), (75) OncoVAX Irradiated autologous cancer cells obtained in surgery are attached to Bacille bilie de Calmette-Guerin vaccine and returned to patient to stimulate immune response. (76) Leuvectin Gene therapy based on the IL-2 gene. Evaluated for metastatic RCC and local CAP. Administered as direct intratumoral injection. (77) Oncophage (HSPPC- Vaccine consisting of autologous heat 96) shock protein-peptide complexes derived from patient's own tumor tissue. (78) Genasense (oblimersen An antisense oligonucleotide specific for sodium, G-3139; Bcl-2 that is expressed by most types of formerly cancer. (79) augmerosen) Provenge Therapeutic cellular vaccine for hormone- resistant CAP. Based on sensitizing patient's dendritic cells to a ubiquitous CAP antigen. (80), (81) GVAX Non-patient-specific cancer vaccine composed of irradiated tumor cells modified to secrete GM-CSF Administered intradermally. (80), (82) Avicine Cancer vaccine designed to induce an immune response against the hormone human chorionic gonadotropin, which is present in most prostate carcinomas. Consists of a short peptide part of human chorionic gonadotropin attached to the diphtheria toxoid. (83) Prostvac DNA vaccine based on PSA gene with a gene for an adjuvant attached, using a vaccinia virus vector. (84) CG7060 (formerly Adenovirus engineered to grow in cancer CV706) cells expressing PSA. (85) CG7870 (formerly Adenovirus engineered to grow in cancer CV787) cells expressing PSA. (86) TG4010 (MVA-MUC- Gene therapy using the genes for tumor- IL2) specific antigen MUC-1 and for IL-2, delivered by a vaccinia (ie, pox) virus vector. (87) INGN 201 AD-p53 P53 gene therapy using an adenoviral vector. A similar product is in Phase III clinical trials for head and neck cancer. (88) Prostate-specific Cancer vaccine based on the PSMA epitope membrane antigen found in CAP cells using ex vivo (PSMA) vaccine dendritic cell processing. (89) Anti-CEA vaccine Dendreon Corp., Seattle, RCC, TCC, CAP, WA and other Vitravene (fomivirsen) Isis Pharmaceuticals, CMV retinitis in Inc., Carlsbad, CA patients with AIDS Angiozyme Ribozyme Colon and breast Pharmaceuticals, Inc., cancers Boulder, CO, and Chiron Corp., Emeryville, CA Onyx-015 Onyx Pharmaceuticals, Head and neck, Inc., Richmond, CA, pancreatic, and XOMA (US) colorectal, and LLC, Berkeley, CA lung cancers Generx (Ad5FGF4) Schering AG, Berlin, Stable coronary Germany artery disease Anti-CEA vaccine I Cellular cancer vaccine Vitravene (fomivirsen) M Antisense Angiozyme II Antisense Onyx-015 III Gene/viral therapy Generx (Ad5FGF4) II/III Gene therapy Anti-CEA vaccine Patient T cells modified in vitro with anti- CEA immunoglobulin to serve as T cell receptors and reinfused in patients with CEA plus tumors. (c) Vitravene (fomivirsen) Antisense CMV inhibitor complementary to mRNA of major immediate-early region proteins of CMV. It was found to be a potent and selective antiviral agent for CMV retinitis. (90), (91) Angiozyme Inhibits the VEGF receptor, a key component in angiogenesis. This ribozyme is a catalytic RNA molecule that downregulates VEGF receptor function by specifically cleaving the mRNAs for the primary VEGF receptors Flt-1 and KDR. (92) Onyx-015 Recombinant adenovirus engineered to replicate only in cells expressing a p53 mutation. The virus carries a loss-of- function mutation that disables inactivation of tumor suppressor protein p53. Thus, in normal cells, p53 accumulates and inhibits viral replication, whereas cancer cells with a p53 mutation allow viral replication and cell death. (72), (93) (Note: Drug development discontinued in January 2003 pending developers' ongoing partnership discussions.) Generx (Ad5FGF4) Adenovirus vector containing human fibroblast growth factor-4 planned to trigger the production of new blood vessel growth. (94) (a) TCC, transitional cell carcinoma; RCC, renal cell carcinoma; CAP, carcinoma of prostate; CEA, carcinoembryonic antigen; CLL, chronic lymphatic factor; AML, acute myelogenous leukemia; MM, multiple myeloma; GM-CSF, granulocyte monocyte colony stimulating factor; mRNA, messenger ribonucleic acid; M, approved drug; CMV, cytomegalovirus; VEGF, vascular endothelial growth factor. (b) Phase relates to clinical trial stage in the United States as of April 2003. Some drugs may be in a more advanced clinical trial phase in other countries. (c) Unpublished data.
NJM NJM New Jersey Manufacturers (Insurance Company)
NJM New Jewel Movement (Grenada, West Indies) is a recipient of a fellowship from The American Physicians Fellowship for Medicine in Israel.
Accepted January 21, 2003.
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RELATED ARTICLE: Key Points
* As a result of new biotechnological capabilities, the understanding of disease processes and the development of new treatments are expanding rapidly.
* Important tools and developments include genomics, proteomics, ligand-receptor interaction, signal transduction, rational drug design, biochips, and microarrays.
* There are several novel drug classes, each with its own structural architecture and mechanism of action, including monoclonal antibodies, cancer vaccines, gene therapy, antisense strands, enzymes, and proteins.
* A wealth of promising new drugs will enable better treatments for patients with cancer, autoimmune disease, neurologic disease, allergy, and transplant rejection transplant rejection Graft rejection, organ rejection, tissue rejection Immunology The constellation of host immune responses evoked when an allograft tissue is transplanted into a recipient; rejection phenomena may be minimized by optimal matching of MHC antigens , among other entities.
Yoav Avidor, MD, MBA MBA
Master of Business Administration
Noun 1. MBA - a master's degree in business
Master in Business, Master in Business Administration , Nicola J. Mabjeesh, MD, PHD, and Haim Matzkin, MD
From Johnson & Johnson/Ethicon Endo-Surgery, Cincinnati, OH; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; and the Department of Urology, Sackler Faculty of Medicine Sackler Faculty of Medicine is a medical school which is part of Tel Aviv University in Tel Aviv, Israel.
It was named after Arthur M. Sackler, a U.S. doctor who made substantial donations to the school. , Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Each of us contributed equally to this article. We have no commercial, proprietary, or financial interest in any drug, device, or equipment mentioned in this article.
Reprint requests to Nicola J. Mabjeesh, MD, PhD, Department of Urology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Email: firstname.lastname@example.org
Copyright [c] 2003 by The Southern Medical Association