Rational approaches to design of therapeutics targeting molecular markers.
This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.
Klasa
R J
RJ
Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
List
A F
AF
Cheson
B D
BD
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects; D003546:Cysteine Endopeptidases; D015195:Drug Design; D016228:Endothelial Growth Factors; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D008222:Lymphokines / Q000187:drug effects; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009097:Multienzyme Complexes; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019938:Cyclin D1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex