ENMD-1198: a microtubule destabilizing agent active against drug resistant leukemia cell lines and human leukemia xenografts Free

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Resistance to chemotherapy in acute lymphoblastic leukemia (ALL) patients poses a major clinical problem and novel chemotherapies could prove highly valuable to treat drug resistant disease. One such agent, ENMD-1198 (2-methoxyestra-1, 3, 5, (10) 16-tetraene-3-carboxamide), an analogue of 2 methoxyestradiol (2ME2), has both anti-angiogenic and anti-proliferative effects in various tumour types. Moreover, ENMD-1198 inhibits microtubule polymerization by binding to β-tubulin at the colchicine-binding site. ENMD-1198 is currently in Phase 1 clinical trials. To investigate the anti-proliferative activity of ENMD-1198 against drug resistant leukemia, we examined CCRF-CEM leukemia cells selected for resistance to vincristine, vinblastine, desoxyepothilone B or 2ME2. Despite these cells harbouring a range of resistance mechanisms associated with drug transport or microtubule alterations, no significant cross-resistance was observed with ENMD-1198. The exceptions were low level cross resistance in the vinblastine-selected cells (1.6-fold; P < 0.05) and 2ME2-selected cells that exhibit 47-fold resistance to the parent compound but only 1.7-fold resistance to ENMD-1198 (P < 0.001). To assess the preclinical efficacy of ENMD-1198, a clinically relevant model of primary human ALL cells xenografted into immuno-deficient (NOD/SCID) mice were used (1). Three human ALL xenografts (ALL3, ALL7 and ALL19) that exhibit intrinsic differences in response to vincristine (1) were treated with 100mg/kg ENMD-1198 by gavage (every day for 28 days), when engraftment rates reached 1% human CD45+ in mouse peripheral blood. Treatment with ENMD-1198 significantly prolonged the mouse survival rates compared to vehicle control in all three xenografts (P < 0.005). Growth delay factors induced by ENMD-1198 for ALL3, ALL7 and ALL19, ranged between 17 and 21 days. In summary, ENMD-1198 is a promising agent that is active against anti-microtubule-resistant leukemia cell lines and human ALL xenografts. ENMD-1198 may prove to be a valuable agent to treat drug resistant leukemia and warrants further investigation in this malignancy.

1.Liem, N. L., Papa, R. A., Milross, C. G., Schmid, M. A., Tajbakhsh, M., Choi, S., Ramirez, C. D., Rice, A. M., Haber, M., Norris, M. D., MacKenzie, K. L., and Lock, R. B. Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies. Blood, 103: 3905-3914, 2004.