XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34⁺38⁻ cells in a phase 1/2 study of patients with relapsed/refractory AML
XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AM...
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Published in | Apoptosis (London) Vol. 16; no. 1; pp. 67 - 74 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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Boston : Springer US
2011
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Abstract | XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12-350 mg/m² AEG35156) and eight in phase 2 (350 mg/m² AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28-35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42-100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34 ⁺ 38 ⁻ AML stem cells and all phase 2 patients showing apoptosis induction in CD34 ⁺ 38 ⁻ cells achieved response. We conclude that at 350 mg/m², AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34 ⁺ 38 ⁻ AML stem cells. |
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AbstractList | XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12-350 mg/m² AEG35156) and eight in phase 2 (350 mg/m² AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28-35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42-100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34+38- AML stem cells and all phase 2 patients showing apoptosis induction in CD34+38- cells achieved response. We conclude that at 350 mg/m², AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34+38- AML stem cells. XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12–350 mg/m 2 AEG35156) and eight in phase 2 (350 mg/m 2 AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28–35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42–100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34 + 38 − AML stem cells and all phase 2 patients showing apoptosis induction in CD34 + 38 − cells achieved response. We conclude that at 350 mg/m 2 , AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34 + 38 − AML stem cells. XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12–350 mg/m 2 AEG35156) and eight in phase 2 (350 mg/m 2 AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28–35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42–100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34 + 38 − AML stem cells and all phase 2 patients showing apoptosis induction in CD34 + 38 − cells achieved response. We conclude that at 350 mg/m 2 , AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34 + 38 − AML stem cells. XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12-350 mg/m² AEG35156) and eight in phase 2 (350 mg/m² AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28-35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42-100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34 ⁺ 38 ⁻ AML stem cells and all phase 2 patients showing apoptosis induction in CD34 ⁺ 38 ⁻ cells achieved response. We conclude that at 350 mg/m², AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34 ⁺ 38 ⁻ AML stem cells. |
Author | Kantarjian, Hagop Morris, Stephen J Borthakur, Gautam Andreeff, Michael Byrd, Anna L Konopleva, Marina Carter, Bing Z Mak, Duncan H Estey, Elihu |
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Snippet | XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial... |
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SubjectTerms | Aged AML Antigens, CD - analysis Antigens, CD - drug effects Antimetabolites, Antineoplastic - administration & dosage Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antisense oligonucleotide AEG35156 apoptosis Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Biomedicine Cancer Research Caspases - metabolism Cell Biology Clinical trial Cytarabine - administration & dosage Drug Administration Schedule Drug Dosage Calculations Female Gene Expression - drug effects Humans Idarubicin - administration & dosage Leukemia, Myeloid, Acute - drug therapy Male Middle Aged Myeloid Progenitor Cells - cytology Myeloid Progenitor Cells - metabolism Oligonucleotides - administration & dosage Oncology Original Paper Recurrence RNA, Messenger - biosynthesis Virology X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors X-Linked Inhibitor of Apoptosis Protein - genetics XIAP |
Title | XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34⁺38⁻ cells in a phase 1/2 study of patients with relapsed/refractory AML |
URI | https://link.springer.com/article/10.1007/s10495-010-0545-1 https://www.ncbi.nlm.nih.gov/pubmed/20938744 https://pubmed.ncbi.nlm.nih.gov/PMC3376026 |
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