The inhibitory effect of anti-CD33 monoclonal antibodies on AML cell growth correlates with Syk and/or ZAP-70 expression

Balaian, Larisa; Zhong, Rui-kun; Ball, Edward D.

doi:10.1016/s0301-472x(03)00044-4

Cited by 51 publications

(34 citation statements)

References 60 publications

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“…Anti-CD33 mAb-mediated growth arrest occurs in a dose-dependent manner, at concentrations greater than 0.1 mg/ml. 28,29 At optimal concentrations (0.1 mg/ml), anti-CD33 mAb inhibited colony formation of HL-60 cells by 450% and DNA synthesis in primary AML cells up to 40%. We previously found that CD33 ligation induced tyrosine phosphorylation of the tyrosine kinase Syk, but not of src-family tyrosine kinases (Fyn, Lyn).…”

Section: Resultsmentioning

confidence: 99%

“…We previously found that CD33 ligation induced tyrosine phosphorylation of the tyrosine kinase Syk, but not of src-family tyrosine kinases (Fyn, Lyn). 28,29 As these results suggested an important role of Syk in CD33 signaling, we tested a panel of 40 primary AML samples from different French-American-British (FAB) types for Syk expression (Table 1). All samples had high blast counts (data not shown), and the majority (36 of 40) contained high percentages (460%) of surface CD33.…”

Section: Resultsmentioning

confidence: 99%

“…[24][25][26][27] We extended these findings by demonstrating that Syk (or ZAP-70) play an important role in CD33 signaling. 28,29 Upon CD33 ligation, Syk becomes phosphorylated and creates complexes with phosphorylated forms of the CD33 molecule itself and protein phosphatase Src homology phosphatase-1 (SHP-1). Moreover, we showed that the anti-proliferative response of AML cells to CD33 ligation correlates with the level of Syk expression.…”

Section: Introductionmentioning

confidence: 99%

“…Significantly greater numbers of Syk/Zap-70-positive samples respond to anti-CD33 mAb treatment. 29 Recent discoveries established Syk as a tumor suppressor and linked deficient Syk expression to a variety of human hematopoietic [30][31][32][33] and solid tumors. [33][34][35] In breast cancer, Syk kinase is a potent modulator of malignant growth and a potential tumor suppressor, presumably by controlling cell division.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

Balaian

Ball

2006

Leukemia

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Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that, upon ligation with a monoclonal antibody (mAb), is a downregulator of cell growth in a Syk-dependent manner. An anti-CD33 mAb coupled to a toxin, gemtuzumab ozogamicin (GO), is used for the treatment of AML (Mylotarg). Therefore, we investigated whether the response of AML cells to GO treatment also depends on Syk expression. Forty primary AML samples (25 Syk-positive and 15 Syk-negative) were tested for their response to the anti-proliferative effects of GO and unmodified anti-CD33 mAb. A correlation between Syk expression and the response of leukemia cells to GO and anti-CD33 mAb was found. 'Blocking' of Syk by small interfering RNA resulted in unresponsiveness of AML cells to both GO and anti-CD33 mAb-mediated cytotoxicity. Syk upregulation by the demethylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, resulting in enhanced GO and anti-CD33-mediated inhibition of leukemia cell growth. Thus, the cytotoxicity of both GO and anti-CD33 in primary AML samples was associated with Syk expression. 5-Aza restored Syk and increased the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. These data have clinical significance for predicting response to GO and designing clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

Balaian

Ball

2006

Leukemia

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“…Also, cross-linking of CD33 with monoclonal antibodies on normal CD34 þ cells cultured with stem cell factor (SCF) and granulocyte macrophage colony-stimulating factor (GM-CSF) has been associated with inhibition of cell growth, suggesting a role for CD33 in the negative regulation of cell proliferation (Mingari et al, 2001). It has been shown that expression of the protein kinase Syk in AML cells correlates with responsiveness to CD33 ligation (Balailan et al, 2003). In the responding AML cases, CD33 ligation induces phosphorylation of Syk as well as the CD33 molecule, and the formation of a Syk/CD33 complex.…”

Section: Biological Characteristics and Therapeutical Opportunitiesmentioning

confidence: 99%

The role of Gemtuzumab Ozogamicin in the treatment of acute myeloid leukemia patients

et al. 2007

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Gemtuzumab Ozogamicin (GO) is an antibody-targeted chemotherapy agent consisting of the humanized murine CD33 antibody (clone P67.6) to which the calicheamicing1 derivative is attached via a hydrolysable bifunctional linker. GO is able to induce apoptosis in vitro in CD33-expressing cells and it has been approved in USA and in Europe as monotherapy for the treatment of elderly patients (older than 60 years) with relapsed acute myeloid leukemia (AML). GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adults AML patients (including also with incomplete platelet recovery). Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimens in adults and children. As for adverse events, veno-occlusive syndrome characterizes its tolerability profile, but GO is comparatively well tolerated by most patients.

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Therapeutic Antibodies in Clinical Use and Leading Clinical Candidates

Zhang

Williams

Lü

et al. 2009

Therapeutic Monoclonal Antibodies

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The inhibitory effect of anti-CD33 monoclonal antibodies on AML cell growth correlates with Syk and/or ZAP-70 expression

Cited by 51 publications

References 60 publications

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

The role of Gemtuzumab Ozogamicin in the treatment of acute myeloid leukemia patients

Therapeutic Antibodies in Clinical Use and Leading Clinical Candidates

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