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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, 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 (DNA) technology and was used for the large-scale production of proteins, initially "replacement" proteins such as insulin and factor VIII. Later, developments were based on an understanding of ligand-receptor interactions, their impact on disease processes, and the ability to manufacture such large macromolecular 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) 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 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. 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," 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.


In drug discovery, the drug target is key. A target for pharmaceutical intervention is almost invariably a protein whose function or dysfunction is implicated 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 (EGF) receptor family, which is the most studied growth factor receptor system. These receptors are composed of an extracellular binding domain, a transmembranous lipophilic segment, and an intracellular protein tyrosine kinase 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 (RNA), or protein affixed 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 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, or oncogene, 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 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) 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," because its therapeutic effect is limited to the inhibition of an effector 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 penetration is often feasible.

The tyrosine kinase inhibitor ST1571 (imatinib mesylate, 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 (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 but then was found to be an inhibitor of a specific target protein: the Bcr-Abl protein kinase. 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 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 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, as well as recombinant natriuretic peptide for the treatment of patients with congestive heart failure (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 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 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, or MAb.

The ability to manufacture clones of identical MAb enables different strategies to create MAb therapeutics. By recruiting the immune system's lytic 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 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, viral infection, and myocardial 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, 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 deaminase 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 (human-mouse) MAb that neutralizes tumor necrosis [alpha], a proinflammatory cytokine. It is approved for the treatment of patients with rheumatoid arthritis and Crohn's disease. In clinical trials for rheumatic arthritis, infliximab produced significant improvements in all measures of disease, and treatment with infliximab combined with methotrexate 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 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, asthma, psoriasis, and different solid organ tumors (Table 2). (33-47)

Cytokines. Cytokines are proteins that regulate cells that belong to the immune system, such as lymphocytes and macrophages. 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. The FDA has approved the use of recombinant IL-2 for the treatment of patients with renal cell carcinoma, but IL-2 is highly toxic 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, genital warts, hairy cell leukemia, and hepatitis B and C. (59)

Colony-stimulating factors (CSFs) stimulate bone marrow stem cells to differentiate toward a particular cell type. Recombinant versions of CSF, including granulocyte-macrophage CSF, granulocyte CSF, and erythropoietin 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 neutropenia 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 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 approach) or directly into cells in their normal location (ie, the in vivo 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 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 than other vectors but have other problems such as immunogenicity and complicated manufacturing. Liposomes 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 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 directed against the tumor. Evasion of autologous host cellular 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 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 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 5-fluorouracil, and herpes simplex virus thymidine kinase, which, together with cellular enzymes, facilitates the conversion of ganciclovir into the toxic ganciclovir triphosphate.

Viral vectors may themselves be designed to target and kill tumor cells without the insertion of a foreign transgene (eg, oncolytic viruses). The adenovirus 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 replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. (73)

Antisense 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 (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 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 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 protein. It is an FDA-approved medication indicated for patients with acquired immunodeficiency syndrome-related cytomegalovirus retinitis. 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 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 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, a cancer vaccine and a small-molecule antiangiogenic drug for renal cell carcinoma, a new immune modulator protein drug directed against psoriasis and other autoimmune diseases, an SMD directed against transitional cell carcinoma, and several MAb that target cancer, autoimmune disease, and graft versus host disease. 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.

--Chinese proverb
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 --
 or DFMO)

No brand name --

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 --

No brand name GlycoDesign, Inc.,
 (GD0039) Toronto, ON, Canada

No brand name (UCN- --

Iressa (gefitinib, AstraZeneca
 ZD1839) Pharmaceuticals LP,
 Wilmington, DE

Thalomid (thalidomide) Celgene Corp., Warren,

No brand name (NV-06, Marshall Edwards, Inc.,
 phenoxodiol) North Ryde, NSW,

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

No brand name Colorectal and breast cancers and RCC

No brand name (UCN- Advanced solid tumors

Iressa (gefitinib, RCC

Thalomid (thalidomide) Multiple myeloma, CAP

No brand name (NV-06, RCC and other solid tumors

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
 associated protein. Intended to
 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
 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
 including stimulation of
 prostate cancer
 proliferation and apoptosis
 inhibition, and
 promotes osteoblast activity.
 (15) (Note: Abbott
 Labs stopped Phase III trial
 in February

Velcade (bortezomib, II Inhibitor of
 PS-341) ubiquitin-proteasome pathway
 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

Apomine (SR-45023A) II Bisphosphonate ester that binds
 to the
 farnesoid X nuclear receptor.
 apoptosis of cancer cells.

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,
 with myeloid metaplasia,
 colorectal cancer,
 ovarian epithelial cancer,
 metastatic RCC,
 and non-small cell lung cancer.

No brand name (NV-06, II Signal transduction inhibitor.
 phenoxodiol) Blocks enzymes
 involved in cell division,
 topoisomerase-2 and protein
 kinases. Restores apoptosis in
 cancer cells. (c)

Reminyl (galantamine Janssen Pharmaceutica
 HBr) Products LP, Titusville,

Neovastat (AE-941) AEterna Laboratories, Inc.,
 Quebec City, QB,

17-N-allylamino-17- --

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- --

No brand name Ilex Oncology, Inc., San
 (ILX295501) Antonio, TX, and Eli
 Lilly & Co.,
 Indianapolis, IN

Reminyl (galantamine Alzheimer's disease

Neovastat (AE-941) Lung and breast cancers and RCC

17-N-allylamino-17- Epithelial and hematologic
 demethoxy malignancies, and sarcomas

No brand name Insomnia
 (indiplon, NBI-34060)

Rotigotine CDS Parkinson's disease

No brand name (2- Advanced solid tumors

No brand name Solid tumors

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
 angiogenesis, and metastasis.

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
 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,
 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,

Avicidin NeoRx Corp., Seattle, WA

Natrecor (nesiritide) Scios, Inc., Sunnyvale, CA

Amevive (alefacept) Biogen, Inc., Cambridge,

No brand name Abgenix, Inc., Fremont,
 (ABX-CBL) CA, and SangStat
 Medical Corp., Fremont,

Xolair (omalizumab) Genentech, Inc., South San
 Francisco, CA, Novartis
 AG, East Hanover, NJ

No brand name Amgen, Inc., Thousand
 (epratuzumab, AMG Oaks, CA

Bexxar (tositumomab and Corixa Corp., Seattle, WA,
[.sup.131]I-tositumomab) and GlaxoSmithKline,
 Research Triangle Park,

Antegren (natalizumab) Biogen, Inc., Cambridge,
 MA, and Elan Corp.,
 plc, Dublin, Ireland

Keyhole Limpet --
 Hemocyanin (KLH,

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

Multikine CAP II

Avicidin Lymphoma, CAP, II
 ovarian, and colon

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

Xolair (omalizumab) Asthma and seasonal M (FDA approval
 allergies received June

No brand name Non-Hodgkin's III
 (epratuzumab, AMG lymphoma

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

Drug brand name
(generic name) Comments

Plenaxis (Abarelix-Depot, Peptide antagonist to gonadotropin-releasing
 PPI-149) hormone, blocking its action on the
 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
 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
 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
 cancers and TCC

OncoVAX Intracel, LLC, Frederick, Colorectal cancer
 MD and RCC

Leuvectin Vical, Inc., San Diego, RCC and CAP

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

Provenge Dendreon Corp., Seattle, CAP

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

OncoVAX II Cellular

Leuvectin II Gene

Oncophage (HSPPC- III Peptide
 96) cancer

Genasense (oblimersen II/III Antisense
 sodium, G-3139;

Provenge III Cellular

GVAX II/III Cellular

Avicine II Peptide

Prostvac II Gene

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

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)

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

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

Vitravene (fomivirsen) M Antisense

Angiozyme II Antisense

Onyx-015 III Gene/viral

Generx (Ad5FGF4) II/III Gene

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

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 is a recipient of a fellowship from The American Physicians Fellowship for Medicine in Israel.

Accepted January 21, 2003.


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* 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, among other entities.

Yoav Avidor, MD, MBA, 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, 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:

Copyright [c] 2003 by The Southern Medical Association

COPYRIGHT 2003 Southern Medical Association
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2003, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Title Annotation:Original Article
Author:Matzkin, Haim
Publication:Southern Medical Journal
Date:Dec 1, 2003
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