Practices and Pitfalls of Mouse Cancer Models in Drug Discovery

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115 I. Why Are Animal Models Needed II. Model Types Tumor Locations A. Subcutaneous Xenograft Models D. Genetically Defined Tumor Models A. Efficacy Endpoints Is Tumor Growth Effected B. Functional and Molecular Endpoints Is the Target Modulated V. Animal Modeling in the Post-genomics Age VI. Conclusions Mouse models of cancer are critical tools for elucidating...

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...

Activation of Apoptosis Induced by External Stimuli

Situ Cell Death Fluorescein

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...