ABSTRACT
Traditionally, the design of cytotoxic agents used for the treatment of malignant disease has attempted to take advantage of unique biochemical characteristics of the tumor cell. For example, many of the most potent cytotoxic agents act at specific stages of the cell cycle and are most effective in tumors with a large growth fraction. Although the systemic toxicity of these agents is often quite high, this approach has produced treatment regimens with curative results in many tumor types. In contrast, multiple myeloma remains an incurable disease with a median survival of 30-40 months. The major obstacle to successful treatment of myeloma is the emergence of drug-resistant disease. Although 50-60% of patients initially respond to standard chemotherapeutic regimens, essentially all patients ultimately relapse with tumor that is refractory to further treatment. Recent advances in molecular genetics have provided the means to identify tumor-specific pathways that regulate myeloma cell growth and survival. Furthermore, in a revival of the ‘seed and soil’ hypothesis,1
the contribution of the tumor microenvironment to the growth and survival of malignant cells has identified tumorcell interactions with the microenvironment as a potential point of therapeutic intervention. Identification of the molecular mechanisms contributing to tumor cell survival and the pathways involved are providing fertile ground for the development of molecular inhibitors with high tumor specificity and low systemic toxicity.
