Functional cDNA Screening and Oncology

Genetic dissection of signaling pathways in human disease is the current challenge in drug target identification. The ability to generate libraries of cDNAs from human tissue sources and clone into mammalian expression vectors is enabling this field. Harnessing viruses to introduce libraries blan-ketly into cells, paired with advances in human tissue culture systems and phenotypic readouts have ushered in the age of human cell genetics. In the late 1980s, Brian Seed established the expression...

Pharmacodynamic Biomarkers for Molecular Cancer Therapeutics

Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, United Kingdom I. Introduction II. Types of Biomarkers III. The Pharmacological Audit Trail V. Rationale for Use of PD Markers to Facilitate Drug Development A. PD Markers in Preclinical Drug Development VI. The Need for Multidisciplinary and Broad-Based Collaborative Research and Development VII. Biomarker...

Small Molecule Screens In Oncology

While it is appreciated that oncogenesis arises as a result of the accumulation of selectively advantageous somatic mutations, many of which can be mapped and sequenced, therapies that effectively reverse the unchecked tumor growth phenotype are sorely needed. Although cDNA screens can identify proto-oncogenes, siRNA libraries can identify potential targets for therapeutic intervention, small molecule screens in cellular cancer models to selectively impair tumor cell growth may identify both...

HeLaHeLaHF Cervical Cancer Cell System and Anchorage Independent Growth

Cancers of cervical origin are the second most common gynecological cancers and HeLa is the most well-characterized experimental cell line of cervical cancer (adenocarcinoma) origin (Masters, 2002). HeLa cells show a strong transformed phenotype including anchorage-independent growth in vitro and tumorigenesis in vivo. HeLaHF is a revertant variant isolated from HeLa cells following exposure to the mutagen ethylmethane sulpho-nate (EMS) (Boylan et al., 1996). HeLaHF demonstrates a...

Ca125 Cea Ca199

Choriocarcinoma and testicular cancer Hepatic and testicular cancer Ovarian cancer Colorectal and pancreatic cancer Pancreatic cancer Prostate cancer aThese are some of the markers currently available in widespread clinical use. Due to the heterogenicity of tumors, some tumors do not secrete these proteins and that targeting them will not be effective. Moreover, in mixed clonality, tumor targeting may leave negative clones to survive be selected for. possibilities. The examples mentioned here...

Activation of Apoptosis Induced by External Stimuli

Another hallmark of cancer development is resistance to apoptosis. Apoptosis is normally triggered either intrinsically by stress conditions (DNA damage, protein misfolding, and so on) through the activation of caspase 9 or extrinsically by extracellular death ligands (FasL, TRAIL, TNF-a) through activation of caspase 8. These two pathways converge downstream leading to the activation of caspases 3 and 7 to irreversibly commit cells to apoptosis. These pathways are regulated at many steps by a...

Ribozyme Technology for Cancer Gene Target Identification and Validation

Qi-Xiang Li, Philip Tan, Ning Ke, and Flossie Wong-Staal Immusol, Inc., San Diego, California 92121 I. Brief Biology of Ribozymes II. Ribozymes as Tools for Gene Inactivation A. Design of Ribozymes for Targeting a Specific mRNA of Interest B. Delivery of Ribozymes into Cells C. Factors That Influence the Effectiveness of Ribozyme-Mediated Gene Inactivation III. Ribozymes as Tools in Gene Target Discovery and Validation A. Principles of Ribozyme-Based Gene Target Validation B. Drug Target...