ABSTRACT

The success of imatinib mesylate demonstrates the value of rational drug design based on detailed knowledge of a molecular target. Heat-shock protein 90 has recently emerged as an attractive molecular target for the therapy of Chronic Myeloid Leukemia (CML). Geldanamycin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) were also found to inhibit the growth of murine cell lines transformed with breakpoint cluster region-Abelson, containing the Abl-kinase domain mutations T315I and E255K. Combination therapy with imatinib and 17-allylamino-17-demethoxygeldana-mycin may benefit patients, however, as the same group found that combining drugs led to synergistic inhibition of growth and induction of apoptosis in the cross resistant cell lines. The inhibitory effect of rapamycin on the in vitro growth of primary CML cells is due to induction of G1 cell cycle arrest and the induction of apoptosis. Combination treatment of CML cell lines with suberanoylanilide hydroxamic acid and imatinib resulted in a greater level of apoptosis than was achieved with either agent alone.