Other Novel Approaches To Therapy Of Relapsed

Imatinib-resistant cell lines have been shown to overexpress the multidrug-resistance drug transport protein P-glycoprotein. Sensitivity to imatinib could be partially restored in vitro when the cells were exposed to verapamil or PSC833, both P-glycoprotein inhibitors.42

Leptomycin B is a novel therapeutic responsible for nuclear entrapment of BCR/ABL. BCR/ABL exerts an antiapoptotic effect in the cytoplasm of cells. Leptomycin B is an inhibitor of the nuclear export of BCR/ABL, preventing it from reaching the cytoplasm, thus abrogating its antiapoptotic effect on cells. It has also been shown that nuclear BCR/ABL induces apoptosis of cells in vitro.43 Nuclear entrapment is thus another potential therapeutic strategy for imatinib-resistant disease.

Homoharringtonine (HHT) is a plant alkaloid derived from the Cephalotaxus fortuneii tree, known to have antileukemia activity when first used by the Chinese in the treatment of both acute myeloid leukemia (AML) and CML in the late 1970s.4445 MDACC has performed several studies in the pre-imatinib era using HHT alone and in combination with IFN-a in chronic phase CML, and has demonstrated the ability of this drug to induce CR. Seventy-two percent of 58 patients in late chronic phase were able to achieve a CHR with HHT alone. However, only 31% of patients had a cytogenetic response. In vitro data suggests that there is a synergistic effect of HHT in combination with imatinib in vitro, providing a potential rationale for combination therapy in resistant patients.46

The ubiquitin-proteasome pathway is the primary intracellular pathway responsible for the degradation of proteins. Proteasome inhibitors are being investigated as potential therapies in a wide variety of hema-tologic malignancies. Inactivation of NF-kB appears to be crucial in the activity of proteosome inhibitors. NF-kB is inhibited in the cytoplasm through binding to IkB, a substrate for proteasomes.47 In CML, BCR/ABL activates NF-KB-dependent transcription, and NF-kB is necessary for BCR/ABL-mediated cell proliferation.48-50 PS-341 is a potent and selective inhibitor of the pro-teosome that has shown significant clinical activity in multiple myeloma. In vitro, PS-341 induced significant growth inhibition and apoptosis in several BCR/ABL-positive cell lines, including both imatinib-sensitive and -resistant cell lines.51 Clinical studies in imatinib-resistant patients are ongoing.

0 0

Post a comment