) This is a Request for Application (RFA) Investigator Grant for Clinical Cancer Therapy Research. The objective of this work is to explore the potential clinical benefit of a differentiation-inducing agent, hexamethylene bisacetamide (HMBA) in patients with advanced refractory or relapsed multiple myeloma (MM). We have found that HMBA is a potent inducer of programmed cell death (apoptosis) in various human myeloma cell lines including cells overexpressing the multidrug resistant gene (MDR1) and its product p-glycoprotein. HMBA also induced apoptosis in freshly isolated human myeloma cells cultured in vitro. We have also shown that HMBA-mediated apoptosis is associated with marked down-regulation of bcl-2 protein expression. HMBA causes a profound G1 arrest in human myeloma cells and down-regulates the expression of cyclin dependent kinase proteins CDK2and CDK4. We therefore propose to use HMBA in a phase II clinical trial and concomitantly to extend our studies on the in vitro modulation of bcl-2 expression by HMBA and its effect on other pathways involved in the induction of apoptosis in this disease. We also intend to further explore the effect of HMBA on proteins regulating cell cycle progression in myeloma cells.
