title: Bortezomib interactions with chemotherapy agents in acute leukemia in vitro.
abstract: Although there is effective chemotherapy for many patients with leukemia, 20% of children and up to 65% of adults relapse. Novel therapies are needed to treat these patients. Leukemia cells are very sensitive to the proteasome inhibitor bortezomib (VELCADE(R), PS-341), which enhances the in vitro cytotoxic effects of dexamethasone and doxorubicin in multiple myeloma. To determine if bortezomib enhances the cytotoxicity of agents used in leukemia, we employed an in vitro tetrazolium-based colorimetric assay (MTT) to evaluate the cytotoxic effects of bortezomib alone and in combination with dexamethasone, vincristine, doxorubicin, cytarabine, asparaginase, geldanamycin, trichostatin A, and the bcl-2 inhibitor HA14.1. We demonstrated that primary leukemia lymphoblasts and leukemia cell lines are sensitive to bortezomib, with an average IC(50) of 12 nM. Qualitative and quantitative bortezomib-drug interactions were evaluated using the universal response surface approach (URSA). Bortezomib was synergistic with dexamethasone in dexamethasone-sensitive leukemia cells, and additive with vincristine, asparaginase, cytarabine, and doxorubicin. The anti-leukemic activity of bortezomib was also additive with geldanamycin and HA14.1, and additive or synergistic with trichostatin A. These results were compared to analysis using the median-dose effect method, which generated complex drug interactions due to differences in dose-response curve sigmoidicities. These data suggest bortezomib could potentiate the cytotoxic effects of combination chemotherapy in patients with leukemia.
authors.affiliation: Texas Children's Cancer Center/Baylor College of Medicine, 6621 Fannin, MC 3-3320, Houston, 77030, USA. tmhorton@txccc.org
authors.forename: Terzah M
authors.initials: TM
authors.lastname: Horton
authors.forename: Anurhadha
authors.initials: A
authors.lastname: Gannavarapu
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib