Improving the Treatment Outcome of Patients with Chronic Lymphocytic Leukemia Through Targeted Antibody Therapy

Stephens, Deborah M.; Byrd, John C.

doi:10.1016/j.hoc.2012.12.003

Cited by 9 publications

(5 citation statements)

References 129 publications

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“…Frontline therapies for CLL consist in the administration of the purine analogue fludarabine, alone or in combination with other drugs such as anti-CD20 monoclonal antibodies or kinase inhibitors [3]–[5]. Because CLL is a heterogeneous disease, patients carrying specific molecular markers such as del17p13, unmutated IgV H and/or high expression of ZAP-70 or CD38, do not respond well to these treatments [4], making it crucial to continue searching for new compounds useful in these cases.…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase-9 Is Involved in Chronic Lymphocytic Leukemia Cell Response to Fludarabine and Arsenic Trioxide

et al. 2014

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BackgroundMatrix metalloproteinase-9 (MMP-9) contributes to chronic lymphocytic leukemia (CLL) pathology by regulating cell migration and preventing spontaneous apoptosis. It is not known if MMP-9 is involved in CLL cell response to chemotherapy and we address this in the present study, using arsenic trioxide (ATO) and fludarabine as examples of cytotoxic drugs.MethodsWe used primary cells from the peripheral blood of CLL patients and MEC-1 cells stably transfected with an empty vector or a vector containing MMP-9. The effect of ATO and fludarabine was determined by flow cytometry and by the MTT assay. Expression of mRNA was measured by RT-PCR and qPCR. Secreted and cell-bound MMP-9 was analyzed by gelatin zymography and flow cytometry, respectively. Protein expression was analyzed by Western blotting and immunoprecipitation. Statistical analyses were performed using the two-tailed Student's t-test.ResultsIn response to ATO or fludarabine, CLL cells transcriptionally upregulated MMP-9, preceding the onset of apoptosis. Upregulated MMP-9 primarily localized to the membrane of early apoptotic cells and blocking apoptosis with Z-VAD prevented MMP-9 upregulation, thus linking MMP-9 to the apoptotic process. Culturing CLL cells on MMP-9 or stromal cells induced drug resistance, which was overcome by anti-MMP-9 antibodies. Accordingly, MMP-9-MEC-1 transfectants showed higher viability upon drug treatment than Mock-MEC-1 cells, and this effect was blocked by silencing MMP-9 with specific siRNAs. Following drug exposure, expression of anti-apoptotic proteins (Mcl-1, Bcl-xL, Bcl-2) and the Mcl-1/Bim, Mcl-1/Noxa, Bcl-2/Bax ratios were higher in MMP-9-cells than in Mock-cells. Similar results were obtained upon culturing primary CLL cells on MMP-9.ConclusionsOur study describes for the first time that MMP-9 induces drug resistance by modulating proteins of the Bcl-2 family and upregulating the corresponding anti-apoptotic/pro-apoptotic ratios. This is a novel role for MMP-9 contributing to CLL progression. Targeting MMP-9 in combined therapies may thus improve CLL response to treatment.

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Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase-9 Is Involved in Chronic Lymphocytic Leukemia Cell Response to Fludarabine and Arsenic Trioxide

et al. 2014

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“…Given the central role and functional significance of the BCR, strategies to target BCR signaling have appeared as emerging therapeutic options. In fact, inhibitors of BCR signaling, especially those targeting the BCR‐associated kinases (LYN, SYK, BTK, and PI3Kδ) have shown promising clinical benefits (Chart 1) …”

Section: B‐cell Receptor (Bcr) Signaling and The Key Bcr‐associatedmentioning

confidence: 99%

Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

et al. 2015

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Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off-target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B-CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3-kinase delta (PI3Kδ). Idelalisib, a first-in-class PI3Kδ-selective small molecule has received the FDA's fast-track approval in July of 2014 as a new treatment of CLL, indolent B-cell non-Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ-specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ-targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy.

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“…The latter biological phenomenon can potentially facilitate one of the therapeutic advantages of a covalent dexamethasone immunopharmaceutical because it modulates continual selective deposition and intracellular steroid moiety accumulation that can result in achieving cytosol concentrations 8.5-fold 32 to >100-fold 33 , 34 higher than those safely attainable by simple passive diffusion of a “free” noncovalently bound steroid analog from the extravascular fluid compartment postintravenous injection at clinically relevant dosages. In corticosteroid-sensitive leukemia and lymphoma cell populations, membrane-associated antigens and receptor complexes that are uniquely or highly overexpressed and are also known to be internalized by the active transport mechanism of receptor-mediated endocytosis include CCR7, 35 CXCR5, 36 TNFR1 (CD120a), 37 CD19, 38 , 39 CD20, 13 , 19 and CD52. 40 …”

Section: Introductionmentioning

confidence: 99%

Dexamethasone-(C<sub>21</sub>-phosphoramide)-[anti-EGFR]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency against pulmonary adenocarcinoma (A549)

Coyne¹,

Narayanan²

2016

DDDT

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PurposeCorticosteroids are effective in the management of a variety of disease states, such as several forms of neoplasia (leukemia and lymphoma), autoimmune conditions, and severe inflammatory responses. Molecular strategies that selectively “target” delivery of corticosteroids minimize or prevents large amounts of the pharmaceutical moiety from passively diffusing into normal healthy cell populations residing within tissues and organ systems.Materials and methodsThe covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide)-[anti-EGFR] was synthesized by reacting dexamethasone-21-monophosphate with a carbodiimide reagent to form a dexamethasone phosphate carbodiimide ester that was subsequently reacted with imidazole to create an amine-reactive dexamethasone-(C21-phosphorylimidazolide) intermediate. Monoclonal anti-EGFR immunoglobulin was combined with the amine-reactive dexamethasone-(C21-phosphorylimidazolide) intermediate, resulting in the synthesis of the covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide)-[anti-EGFR]. Following spectrophotometric analysis and validation of retained epidermal growth factor receptor type 1 (EGFR)-binding avidity by cell-ELISA, the selective anti-neoplasic cytotoxic potency of dexamethasone-(C21-phosphoramide)-[anti-EGFR] was established by MTT-based vitality stain methodology using adherent monolayer populations of human pulmonary adenocarcinoma (A549) known to overexpress the tropic membrane receptors EGFR and insulin-like growth factor receptor type 1.ResultsThe dexamethasone:IgG molar-incorporation-index for dexamethasone-(C21-phosphoramide)-[anti-EGFR] was 6.95:1 following exhaustive serial microfiltration. Cytotoxicity analysis: covalent bonding of dexamethasone to monoclonal anti-EGFR immunoglobulin did not significantly modify the ex vivo antineoplastic cytotoxicity of dexamethasone against pulmonary adenocarcinoma at and between the standardized dexamethasone equivalent concentrations of 10−9 M and 10−5 M. Rapid increases in antineoplastic cytotoxicity were observed at and between the dexamethasone equivalent concentrations of 10−9 M and 10−7 M where cancer cell death increased from 7.7% to a maximum of 64.9% (92.3%–35.1% residual survival), respectively, which closely paralleled values for “free” noncovalently bound dexamethasone.DiscussionOrganic chemistry reaction regimens were optimized to develop a multiphase synthesis regimen for dexamethasone-(C21-phosphoramide)-[anti-EGFR]. Attributes of dexamethasone-(C21-phosphoramide)-[anti-EGFR] include a high dexamethasone molar incorporation-index, lack of extraneous chemical group introduction, retained EGFR-binding avidity (“targeted” delivery properties), and potential to enhance long-term pharmaceutical moiety effectiveness.

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Improving the Treatment Outcome of Patients with Chronic Lymphocytic Leukemia Through Targeted Antibody Therapy

Cited by 9 publications

References 129 publications

Matrix Metalloproteinase-9 Is Involved in Chronic Lymphocytic Leukemia Cell Response to Fludarabine and Arsenic Trioxide

Matrix Metalloproteinase-9 Is Involved in Chronic Lymphocytic Leukemia Cell Response to Fludarabine and Arsenic Trioxide

Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond

Dexamethasone-(C<sub>21</sub>-phosphoramide)-[anti-EGFR]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency against pulmonary adenocarcinoma (A549)

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