Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study analyzed the characteristics of 257 HLA-identical sibling transplants of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells depleted of T cells by CD34(+) positive selection (allo-PBT/CD34(+)) for their effect on the incidence of graft failure. Twenty-four patients developed graft failure (actuarial probability, 11%; 95% confidence interval, 7.1-14. 9). Prognostic factors considered were sex and age of donor and recipient, donor-recipient blood group compatibility, diagnosis, disease status at transplant, conditioning regimen, cytomegalovirus serology, number of CD34(+) and CD3(+) cells infused, and cryopreservation. The major factor associated with graft failure was the number of CD3(+) cells in the inoculum. Twenty-three of 155 patients receiving a T-cell dose in the graft less than or equal to 0.2 x 10(6)/kg experienced graft failure, compared with only one of 102 patients receiving more than 0.2 x 10(6)/kg (actuarial probability 18% vs 1%, respectively; P =.0001). The actuarial probability of graft failure progressively increased as the number of CD3(+) cells in the graft decreased, which was determined by grouping the number of CD3(+) cells in quartiles (log-rank P =.03; log-rank for trend P =.003). In the multivariate analysis by the proportional hazard method, 2 covariates entered into regression at a significant level: CD3(+) cells less than or equal to 0.2 x 10(6)/kg (risk ratio = 17; P <.0001), and patients with chronic myelogenous leukemia (CML) conditioned with busulphan-based regimens (risk ratio = 4.8; P =.001). From these results it appears that the number of CD3(+) cells in the inoculum-with a threshold of 0.2 x 10(6)/kg or less-is the most critical factor in maintaining a sustained engraftment in allo-PBT/CD34(+) from HLA-identical siblings. In addition, for patients with CML receiving 0.2 x 10(6)/kg or less CD3(+) cells, total body irradiation might be better than busulphan-based regimens.
 ...
PMID:The number of donor CD3(+) cells is the most important factor for graft failure after allogeneic transplantation of CD34(+) selected cells from peripheral blood from HLA-identical siblings. 1115 12

An allogeneic transplantation of CD34(+)-selected cells from peripheral blood (allo-PBT/CD34(+)) from HLA-identical sibling donors was performed in 50 adult patients with acute myeloid leukemia in first complete remission (AML CR1) (n = 29), myelodysplastic syndrome (MDS) (n = 4), or chronic myeloid leukemia in first chronic phase (CML CP1) (n = 17). Clinical results were compared to a concurrent group of 50 patients transplanted with unmodified peripheral blood progenitor cells (allo-PBT), matched for age, diagnosis, and disease stage. The median follow-up period was 29 months (range 1-69). The actuarial probability of developing acute GVHD clinical grade II to IV was 16% (95%CI: 6-26) for the allo-PBT/CD34(+) group and 41% (95%CI: 29-57) for the allo-PBT group (P = 0.002). The actuarial probability of developing extensive chronic GVHD was 22% (95%CI: 8-36) for the allo-PBT/CD34(+) group and 47% (95%CI: 31-63) for the allo-PBT group (P = 0.02). Recipients of allo-PBT/CD34(+) had less toxicity associated with the transplant and better Karnofsky index at the last follow-up. For AML/MDS patients, the actuarial probability of disease-free survival (DFS) for recipients of allo-PBT/CD34(+) and allo-PBT was 65% (95%CI: 45-85) vs43% (95%CI: 28-58) (P = 0.05), respectively. These data provide a rationale for a randomised trial of allo-PBT/CD34(+) vs allo-PBT in AML/MDS patients in early stage of the disease.
 ...
PMID:Allogeneic transplantation of CD34+-selected cells from peripheral blood in patients with myeloid malignancies in early phase: a case control comparison with unmodified peripheral blood transplantation. 1157 6

PBT-3 is one of a family of stable chemical analogs of the hepoxilins, products derived from arachidonic acid. We previously showed that PBT-3 caused apoptosis in the chronic myelogenous leukemia (CML) cell line K-562 in vitro (Anti-cancer Res 23: 3617-3622, 2003). It was as effective as Gleevec, a novel agent that blocks tyrosine kinase activity during treatment of CML. We describe, herein, the growth inhibiting effects of PBT-3 in nude mice into which K-562 cells were transplanted subcutaneously. Groups of mice were treated with vehicle as control, or PBT-3, or Gleevec. PBT-3 was effective during the 8-day treatment protocol in inhibiting the growth of the tumours in vivo as was Gleevec. Analysis of the tumours demonstrated the presence of apoptosis (DNA laddering and TUNEL assay) in both the PBT-3- and Gleevec-treated groups. These results demonstrate that PBT-3 is effective in vivo in controlling tumour growth and provides a novel platform for the therapeutic control of cancer.
 ...
PMID:The hepoxilin analog, PBT-3, inhibits growth of K-562 CML solid tumours in vivo in nude mice. 1579 72

Hepoxilins are biologically relevant epoxy-hydroxy eicosanoids synthesized through the 12S-lipoxygenase (12S-LOX) pathway of the arachidonic acid (AA) metabolism. The pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins. The present review gives an update on the biochemistry, biology and clinical aspects of hepoxilin-based drug development. The isolation, cloning and characterization of a rat leukocyte-type 12S-LOX from rat insulinoma RINm5F cells revealed a 12S-LOX possessing an intrinsic 8S/R-hydroxy-11,12-epoxyeicosa-5Z,9E,14Z-trienoic acid (HXA(3)) synthase activity. Site-directed mutagenesis studies on rat 12S-LOX showed that the HXA(3) synthase activity was impaired when the positional specificity of AA was altered. Interestingly, amino acid Leu353, and not conventional sequence determinants Met419 and Ile418, was found to be a crucial sequence determinant for AA oxygenation. The regulation of HXA(3) formation is dependent on the cellular overall peroxide tone. Cellular glutathione peroxidases (cGPxs) compete with HXA(3) synthase for 12S-HpETE as substrate either to reduce to 12S-HETE or to convert to HXA(3), respectively. Therefore, RINm5F cells, which are devoid of GPxs, are capable of converting AA or 12S-HpETE to HXA(3) under basal conditions, whereas cells overexpressing cGPx are unable to do so. HXA(3) exhibits a myriad of biological effects, most of which are associated with the stimulation of intracellular calcium or the transport of calcium across the membrane. The activation of HXA(3)-G-protein-coupled receptors explains many of the extracellular effects of HXA(3), including AA- and diacylglycerol (DAG) release in human neutrophils, insulin secretion in rat pancreatic beta-cells or islets, and synaptic actions in the brain. The availability of stable analogs of HXA(3), termed 10-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid derivatives (PBTs), recently made several animal studies possible and explored the role of HXA(3) as a therapeutic in treatment of diseases. Thus, PBT-3 induced apoptosis in K562 tumour cells and inhibited growth of K562 CML solid tumours in nude mice. HXA(3) inhibited bleomycin-evoked lung fibrosis and inflammation in mice and the raised insulin level in the circulation of rats. At low glucose concentrations (0-3 mm), HXA(3) also stimulated insulin secretion in RINm5F cells through the activation of IRE1alpha, an endoplasmic reticulum-resident kinase. The latter regulates the protein folding for insulin biosynthesis. In conclusion, HXA(3)-mediated signaling may be involved in normal physiological functions, and hepoxilin-based drugs may serve as therapeutics in diseases such as type II diabetes and idiopathic lung fibrosis.
 ...
PMID:Structure, biochemistry and biology of hepoxilins: an update. 1760 19