AbstractThe chemokine receptor CXCR4 is critically involved in the migration of hematopoietic cells towards the stromal derived factor (SDF-1α)-producing bone marrow microenvironment. We and others have previously demonstrated that stroma/leukemia interactions mediate protection of leukemic cells from chemotherapy-induced apoptosis (Konopleva, Leukemia 2002). Using a peptide analog of SDF-1α designated CTCE-9908, we tested the hypothesis that CXCR4 inhibition interferes with stromal/leukemia cell interactions resulting in increased sensitivity to chemotherapy. Our results showed that CTCE-9908 significantly inhibits SDF-1α-induced migration of U937 (43% inhibition) and OCI-AML3 cells (40% inhibition) in a dose-dependent manner. In three of the four primary AML samples which expressed CXCR4 on cell surface and migrated in response to SDF-1α, 50 μg/ml CTCE-9908 reduced SDF-1α-induced migration of leukemic blasts (60%, 19% and 50% inhibition respectively). In in vitro co-culture systems, stromal cells significantly protected OCI-AML3 cells from chemotherapy induced apoptosis [no MS-5, 75.2±5.2% annexinV(+); with MS-5, 59±1.1% annexinV(+)]. Western blot analysis revealed that CTCE-9908 inhibits Akt and Erk phosphorylation in a dose-dependent manner in the OCI-AML3 cell line stimulated by SDF-1α. Blockade of CXCR4 expression with CTCE-9908 markedly abrogated the protective effects of stromal cells on OCI-AML3 [Ara-C, 59±1.1% annexinV(+); Ara-C + CTCE-9908, 76.9±1.35 annexinV(+)]. Most importantly, it decreased stroma-mediated protection from AraC-induced apoptosis in four out of five primary AML samples with surface expression of functional CXCR4 (mean increase, 25.1±9.3% compared to chemotherapy alone). In vivo, subcutaneous administration of 1.25mg CTCE-9908 induced mobilization of leukemic cells from primary AML patient transplanted into NOD/Scid-IL2Rγ-KO mice (from 15% to 27% circulating leukemic cells 1 hour post CTCE-9908 injection). Taken together, our data suggest that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to chemotherapy-induced apoptosis via retention of leukemic cells in the bone marrow microenvironment niches. Disruption of these interactions by the potent CXCR4 inhibitor CTCE-9908 represents a novel strategy for targeting leukemia cell/bone marrow microenvironment interaction. Based on these observations, in vivo experiments are ongoing to characterize the efficacy of chemotherapy combined with CTCE-9908.

2008-05-01·Clinical & Experimental Metastasis3区 · 医学

Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases

3区 · 医学

Article

作者: Brieanne V. Midura ; Walter Korz ; Ling Ren ; Arnulfo Mendoza ; Hassan Salari ; Su Young Kim ; Ahmed Merzouk ; Hong Zhang ; Samuel T Hwang ; Chih Hung Lee ; Donald Wong ; Sung Hyeok Hong ; Chand Khanna ; Choh Yeung ; Lee J. Helman

Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50% reduction in the number of gross metastatic lung nodules and a marked decrease in micro-metastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action.

2005-11-16·Blood

A Stromal Cell Derived Factor 1 (SDF-1) Agonist Stimulates Neutrophil Mobilization in Normal Humans after Subcutaneous Injection.

作者: Korz, Walter ; Salari, Hassan ; William, Bensinger I. ; Wong, Donald ; Merzouk, Ahmed

AbstractStromal cell-derived factor-1 (SDF-1) is a well known key signaling molecule in the proliferation, homing, engraftment and expansion of hematopoietic stem cells and leukocytes. CTCE-0214, a peptide produced by rational drug design, is an analog of SDF-1 and agonist of the SDF-1 receptor, CXCR4. In vitro and in vivo models have shown that CTCE-0214 mobilized blood and progenitor cells and enhanced the survival and expansion of cord blood cells (Letters in Drug Design and Discovery.1:126, 2004; Exp Hematol.32:470, 2004; Exp Hematol.32:300, 2004; Stem Cells. In press). In this first phase I clinical trial of CTCE-0214, the safety and tolerability of single doses of CTCE-0214 given subcutaneously to healthy subjects as well as the pharmacokinetic profile and the pharmacodynamic effects were studied. The randomized, double-blinded, placebo-controlled dose-escalation trial enrolled 24 subjects in six dose-escalation groups. Four healthy human subjects in each cohort received either CTCE-0214 or Placebo, randomized in a 3:1 ratio. The starting dose for CTCE-0214 was 0.2 mg/kg. Successive dose cohorts received 0.5 mg/kg, 0.8 mg/kg, 1.5 mg/kg, 2.0 mg/kg, and 3.0 mg/kg. CTCE-0214 was shown to be safe with no serious adverse events reported in any of the dose levels studied. The most common drug related adverse events were injection site pain and erythema which were transient and resolved without intervention. The severity of injection site pain appeared to have an association with the overall quantity of study drug administered. Moderate or severe pain was reported only in subjects who received at least 80 mg of CTCE-0214 per syringe. Dilution across more than one syringe appeared to be effective in reducing injection site pain. Pharmacokinetic analysis of CTCE-0214 plasma concentrations showed that Tmax was reached at 0.25 hours post-administration for all CTCE-0214 treated cohorts. The apparent terminal elimination half-life (t1/2) values were estimated to be 0.41 to 0.32 hours. CTCE-0214 administration was associated with significant dose-dependent increases in total white blood cell and neutrophil counts in treated subjects, peaking at around 6 hours post-injection. In the 3.0 mg/kg arm, the mean difference in neutrophil count from baseline was more than three times the corresponding figure in the Placebo arm. The same trend was apparent in the 2.0 and 1.5 mg/kg arms with a greater than two times and two times increases, respectively. These results suggest that SDF-1 agonists may potentially be used in patients with low neutrophil count receiving chemotherapy with or without the use of G-CSF. The potential for CTCE-0214 to mobilize neutrophils and other blood cells merits serious consideration.

项与 Chemokine Therapeutics Corp. 相关的新闻（医药）

2007-10-01

·BioSpace

Chemokine Therapeutics Corp. to Present at BioContact Québec Annual Global Healthcare Conference

VANCOUVER, BRITISH COLUMBIA--(Marketwire - October 01, 2007) - Chemokine Therapeutics Corp. (the "Company") (TSX: CTI)(OTCBB: CHKT), a biotechnology company developing chemokine-based therapies to treat cancer, blood disorders and vascular diseases, today announced that Dr. Bin Huang, Vice President of Corporate Development will be presenting at the BioContact Annual Conference in Quebec City, Canada on Thursday, October 4th, 2007. Dr. Huang will provide an overview of the Company and the Company's two lead drug candidates, CTCE-9908 for the treatment of cancer and CTCE-0214 for neutrophil mobilization both in human clinical trials.

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药物(靶点)	适应症	全球最高研发状态

PTX-9908 ( CXCR4 )	实体瘤更多	终止
CTCE-0324 ( CXCR4 )	外周血管疾病更多	终止
CTCE-0422 ( Chemokines )	病毒感染更多	终止
CTCE-0019	器官移植排斥更多	无进展
CTCE-0012 ( Chemokine receptors )	黄斑变性更多	无进展