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| Study on cytotoxicity of Gemtuzumab Ozogamicin in acute myeloid leukemia and its relationship with expression level of CD33 #br# |
| WANG Zhenzhen1 LI Weijing2 |
1.Department of Hematopathology, the Second Hospital of Hebei Medical University, Hebei Province, Shijiazhuang 050000, China;
2.Department of Hematopathology, the Fourth Hospital of Hebei Medical University, Heibei Province, Shijiazhuang 050011, China |
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Abstract Objective To explore the relationship between the cytotoxicity of Gemtuzumab Ozogamicin (GO) on acute myeloid leukemia (AML) cells and the expression level of CD33 and the mechanism of action. Methods Human myeloid OCI-AML3 and KG-1a cells were transfected with lentivirus containing CD33 plasmid, then the cells were divided into CD33 high expression group and CD33 low expression group according to CD33 expression level. Both groups were treated with 15 μg/L GO, and then the survival rate of cells in the two groups was determined by MTT assay. OCI-AML3 cells were treated with different concentrations of GO (0, 5, 10, 15 μg/L), and then the expression levels of apoptosis-related proteins Bcl-2, cleaved caspase 3, and caspase 3 were detected by Western blot. Results After transfection, the expression levels of CD33 on OCI-AML3 and KG-1a cells were higher than that before transfection, and the differences were statistically significant (P ＜ 0.05). After the same concentration of GO treatment, the survival rates of OCI-AML3 and KG-1a cells in CD33 high expression group were lower than those in CD33 low expression group, the differences were statistically significant (P ＜ 0.05). When GO concentration was 5, 10, 15 μg/L, the Bcl-2 level of OCI-AML3 cells was lower than those when GO concentration was 0, and cleaved-caspase 3 and caspase 3 levels were higher than those when GO concentration was 0. When GO concentration was 10, 15 μg/L, the Bcl-2 level of OCI-AML3 cells was lower than that when GO concentration was 5 μg/L, and cleaved-caspase 3 and caspase 3 levels were higher than those when GO concentration was 5 μg/L. When GO concentration was 15 μg/L, the Bcl-2 level of OCI-AML3 cells was lower than those when GO concentration was 10 μg/L, and cleaved-caspase 3 and caspase 3 levels were higher than those when GO concentration was 10 μg/L, the differences were statistically significant (P ＜ 0.05). Conclusion GO has enhanced inhibitory effect on proliferation of human myeloid cells with high CD33 expression, and can promote apoptosis of AML cells by regulating the expression of apoptotic proteins.
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[1] Chauhan L，Shin M，Wang YC，et al. CD33-PGx6-Score Predicts Gemtuzumab Ozogamicin Response in Childhood Acute Myeloid Leukemia：A Report From the Children’s Oncology Group [J]. JCO Precis Oncol，2019，1（3）：1-15
[2] Medeiros BC，Tanaka TN，Balaian L，et al. A Phase Ⅰ/Ⅱ Trial of the Combination of Azacitidine and Gemtuzumab Ozogamicin for Treatment of Relapsed Acute Myeloid Leukemia [J]. Clin Lymphoma Myeloma Leuk，2018，18（5）：346-352.
[3] Fenwarth L，Fournier E，Cheok M，et al. Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment [J]. Int J Mol Sci，2020，21（16）：5626.
[4] Goldenson BH，Goodman AM，Ball ED. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia in adults [J]. Expert Opin Biol Ther，2021，21（7）：849-862.
[5] Genthon A，Brissot E，Malard F，et al. Gemtuzumab Ozogamicin Combined With Intensive Chemotherapy in Patients With Acute Myeloid Leukemia Relapsing After Allogenic Stem Cell Transplantation [J]. Clin Lymphoma Myeloma Leuk，2020，20（12）：791-796.
[6] Yamauchi T，Uzui K，Nishi R，et al. Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells [J]. Anticancer Res，2014，34（10）：5487-5494.
[7] Yu B，Liu D. Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia [J]. Biomark Res，2019，7（1）：24.
[8] Zhang CC，Yan Z，Pascual B，et al. Gemtuzumab Ozogamicin（GO）Inclusion to Induction Chemotherapy Eliminates Leukemic Initiating Cells and Significantly Improves Survival in Mouse Models of Acute Myeloid Leukemia [J]. Neoplasia，2018，20（1）：1-11.
[9] Egan PC，Reagan JL. The return of gemtuzumab ozogamicin：a humanized anti-CD33 monoclonal antibody-drug conjugate for the treatment of newly diagnosed acute myeloid leukemia [J]. Onco Targets Ther，2018，11，8265-8272.
[10] Baron J，Wang ES. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia [J]. Expert Rev Clin Pharmacol，2018，11（6）：549-559.
[11] Lamba JK，Chauhan L，Shin M，et al. CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia：Report From Randomized Phase Ⅲ Children’s Oncology Group Trial AAML0531 [J]. J Clin Oncol，2017，35（23）：2674-2682.
[12] Pollard JA，Loken M，Gerbing RB，et al. CD33 Expression and Its Association With Gemtuzumab Ozogamicin Response：Results From the Randomized Phase Ⅲ Children’s Oncology Group Trial AAML0531 [J]. J Clin Oncol，2016，34（7）：747-755.
[13] Godwin CD，Gale RP，Walter RB. Gemtuzumab ozogamicin in acute myeloid leukemia [J]. Leukemia，2017，31（9）：1855-1868.
[14] Guest EM，Aplenc R，Sung L，et al. Gemtuzumab ozogamicin in infants with AML：results from the Children’s Oncology Group trials AAML03P1 and AAML0531 [J]. Blood，2017，130（7）：943-945.
[15] Mamolo C，Welch V，Walter RB，et al. Budget Impact Analysis of Gemtuzumab Ozogamicin for the Treatment of CD33-Positive Acute Myeloid Leukemia [J]. Pharmacoeconomics，2021，39（1）：121-131.
[16] Zahler S，Bhatia M，Ricci A，et al. A Phase Ⅰ Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia [J]. Biol Blood Marrow Transplant，2016，22（4）：698-704.
[17] Jen EY，Ko CW，Lee JE，et al. FDA Approval：Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia [J]. Clin Cancer Res，2018，24（14）：3242-3246.
[18] Lambert J，Pautas C，Terré C，et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia：final efficacy and safety updates from the open-label，phase Ⅲ ALFA-0701 trial [J]. Haematologica，2019，104（1）：113-119.
[19] Hills RK，Castaigne S，Appelbaum FR，et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia：a meta-analysis of individual patient data from randomised controlled trials [J]. Lancet Oncol，2014，15（9）：986-996.
[20] Khan N，Hills RK，Virgo P，et al. Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukaemia [J]. Leukemia，2017，31（5）：1059-1068.
[21] Daver N，Kantarjian H，Ravandi F，et al. A phase Ⅱ study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome [J]. Leukemia，2016，30（2）：268-273.
[22] Sievers EL. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukaemia in first relapse [J]. Expert Opin Biol Ther，2001， 1（5）：893-901.
[23] Stasi R. Gemtuzumab ozogamicin：an anti-CD33 immunoconjugate for the treatment of acute myeloid leukaemia [J]. Expert Opin Biol Ther，2008，8（4）：527-540.
[24] Niktoreh N，Lerius B，Zimmermann M，et al. Gemtuzumab ozo children with relapsed or refractory acute myeloid leukemia：a report by Berlin-Frankfurt-Munster study group [J]. Haematologica，2019，104（1）：120-127.
[25] Linenberger ML. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia：progress in understanding cytotoxicity and potential mechanisms of drug resistance [J]. Leukemia，2005，19（2）：176-182. |
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