TY - JOUR
T1 - OSI-211, a novel liposomal topoisomerase I inhibitor, is active in SCID mouse models of human AML and ALL
AU - Tomkinson, Blake
AU - Bendele, Ray
AU - Giles, Francis J.
AU - Brown, Eric
AU - Gray, Atherton
AU - Hart, Karen
AU - LeRay, Jeremy D.
AU - Meyer, Denny
AU - Pelanne, Michelle
AU - Emerson, David L.
PY - 2003/11/1
Y1 - 2003/11/1
N2 - OSI-211 (liposomal lurtotecan), was evaluated using several different dose schedules (1mg/kg, d1-5, 1.75mg/kg d1, 3, 5 and 6mg/kg d1, 8) in severe combined immunodeficient (SCID) mouse models of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) with early treatment (ET, days 6-8) or late treatment (LT, days 15-19), examining early and advanced disease, respectively. Due to the aggressive nature of the Molt-4 model, the ET and LT were accelerated to day 3 or 4 and day 8 post-implant, respectively. For each model, 2×107 (KBM-3B) or 1×107 (Molt-4, HL-60 and CEM) leukemia cells were injected intravenously into the tail vein. Each control and test group consisted of eight animals. All three schedules (1mg/kg qd1-5, 1.75mg/kg d1, 3, 5 and 6mg/kg d1, 8) increased the life span of OSI-211 treated animals in each model, with a tendency toward improved efficacy with the 6mg/kg d1, 8 schedule. As a result, the activity of the 6mg/kg d1, 8 schedule is detailed for each model. ET significantly (P<0.005) increased survival in the KBM-3B model with 86% long-term survivors (LTS). Using PRC analysis, human β-globin gene sequences in one or several tissues were amplified in all but 3 LTS, suggesting minimal residual disease in 26 of the 29 LTS. LT also significantly (P<0.005) improved average life span in the KBM-3B model, with an average ILS=196±11% and one LTS. Treatment of HL-60 leukemia animals significantly (P<0.005) increased life span, with an ILS=213±9% and two LTS for ET, and with an ILS=219±4% and no LTS for LT. Treatment of Molt-4 animals, the most aggressive leukemia model tested, significantly (P<0.005) increased life span, with an average ILS=181±3% and no LTS for ET and an average ILS=172±1% with no LTS for LT. In the CEM model, ET resulted in a significantly (P<0.005) improved ILS=244±24% with one LTS. In comparison to OSI-211, treatment with DaunoXome, the liposomal formulation of daunorubicin, a drug with clinical efficacy in AML and ALL, had no effect on survival in the KBM-3B, nor Molt-4 A4 leukemia models when administered at its maximum or near maximum tolerated doses of 3mg/kg d1, 8. These data demonstrate that OSI-211 has potent antileukemia activity in preclinical SCID mouse AML and ALL leukemia models, supporting the clinical investigation of OSI-211 for hematological malignancies.
AB - OSI-211 (liposomal lurtotecan), was evaluated using several different dose schedules (1mg/kg, d1-5, 1.75mg/kg d1, 3, 5 and 6mg/kg d1, 8) in severe combined immunodeficient (SCID) mouse models of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) with early treatment (ET, days 6-8) or late treatment (LT, days 15-19), examining early and advanced disease, respectively. Due to the aggressive nature of the Molt-4 model, the ET and LT were accelerated to day 3 or 4 and day 8 post-implant, respectively. For each model, 2×107 (KBM-3B) or 1×107 (Molt-4, HL-60 and CEM) leukemia cells were injected intravenously into the tail vein. Each control and test group consisted of eight animals. All three schedules (1mg/kg qd1-5, 1.75mg/kg d1, 3, 5 and 6mg/kg d1, 8) increased the life span of OSI-211 treated animals in each model, with a tendency toward improved efficacy with the 6mg/kg d1, 8 schedule. As a result, the activity of the 6mg/kg d1, 8 schedule is detailed for each model. ET significantly (P<0.005) increased survival in the KBM-3B model with 86% long-term survivors (LTS). Using PRC analysis, human β-globin gene sequences in one or several tissues were amplified in all but 3 LTS, suggesting minimal residual disease in 26 of the 29 LTS. LT also significantly (P<0.005) improved average life span in the KBM-3B model, with an average ILS=196±11% and one LTS. Treatment of HL-60 leukemia animals significantly (P<0.005) increased life span, with an ILS=213±9% and two LTS for ET, and with an ILS=219±4% and no LTS for LT. Treatment of Molt-4 animals, the most aggressive leukemia model tested, significantly (P<0.005) increased life span, with an average ILS=181±3% and no LTS for ET and an average ILS=172±1% with no LTS for LT. In the CEM model, ET resulted in a significantly (P<0.005) improved ILS=244±24% with one LTS. In comparison to OSI-211, treatment with DaunoXome, the liposomal formulation of daunorubicin, a drug with clinical efficacy in AML and ALL, had no effect on survival in the KBM-3B, nor Molt-4 A4 leukemia models when administered at its maximum or near maximum tolerated doses of 3mg/kg d1, 8. These data demonstrate that OSI-211 has potent antileukemia activity in preclinical SCID mouse AML and ALL leukemia models, supporting the clinical investigation of OSI-211 for hematological malignancies.
KW - ALL
KW - AML
KW - Antileukemia
KW - OSI-211
KW - Topoisomerase I
UR - http://www.scopus.com/inward/record.url?scp=0037677433&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037677433&partnerID=8YFLogxK
U2 - 10.1016/S0145-2126(03)00092-4
DO - 10.1016/S0145-2126(03)00092-4
M3 - Article
C2 - 12859997
AN - SCOPUS:0037677433
SN - 0145-2126
VL - 27
SP - 1039
EP - 1050
JO - Leukemia Research
JF - Leukemia Research
IS - 11
ER -
