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Biomedical subjects

E Worthington

Publications and source records attributed to E Worthington.

6 recordsLinked to original sources
PubMed2001

Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Brc-Abl-positive acute leukemia cells.

By inhibiting the tyrosine kinase (TK) activity of Bcr-Abl, STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 (containing endogenous expression of p210 Bcr-Abl) but not of the control HL-60 cells. Treatment with arsenic trioxide (As2O3) lowers Bcr-Abl protein levels and induces apoptosis of the Bcr-Abl-positive leukemic blasts (Blood 2000; 95: 1014). Here, we demonstrate that compared to treatment with STI-571 (0.25 to 1.0 microM) or As2O3 (0.5 to 2.0 microM) alone, combined treatment with As2O3 and STI-571 induced significantly more apoptosis of HL-60/Bcr-Abl and K562 but not HL-60/neo cells (P < 0.05). Combined treatment with As2O3 and STI-571 also resulted in greater reductions in the levels of Bcl-x(L), XIAP and Akt, and inhibition of Akt kinase activity. Co-treatment with As2O3 inhibited STI-571-induced hemoglobin, which was associated with the cleavage and downregulation of GATA-1 transcription factor involved in erythroid differentiation. These data demonstrate that a treatment strategy which combines an agent that lowers Bcr-Abl levels, eg As2O3, with an agent that inhibits Bcr-Abl TK activity, eg STI-571, can potently induce apoptosis and differentiation of Bcr-Abl-positive human leukemic cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Troponin T as a first-line test: the Royal Liverpool and Broadgreen University Hospital experience.

Many hospital laboratories are unable to offer a cardiac troponin service because of the cost of providing this assay in addition to existing cardiac enzyme profiles: we circumvented this problem by withdrawing the conventional cardiac enzyme service and substituting cardiac troponin T. By ensuring that only one specimen for cTnT is analysed per episode of chest pain. substantial financial savings have been achieved.

Chemistry, Clinical↗
PubMed2001

Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl-positive human acute leukemia cells.

Bcr-Abl tyrosine kinase inhibitor STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p190 Bcr-Abl) and K562 (with endogenous expression of p210 Bcr-Abl) cells (Blood, 96: 2246-2253, 2000). Cotreatment with STI-571 partially overcomes the resistance to antileukemic drug-induced apoptosis of HL-60/Bcr-Abl and K562 cells. Tumor necrosis factor (TNF) alpha-related apoptosis-inducing ligand (Apo-2L/TRAIL), after binding with its signaling death receptors (DR4 and DR5), triggers the intrinsic "mitochondrial" pathway of apoptosis more efficiently in the cancer than do normal cells. In the present studies, we compared the apoptotic effects of Apo-2L/TRAIL, with or without cotreatment with STI-571, in HL-60/neo, HL-60/Bcr-Abl, and K562 cells. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells are relatively resistant to Apo-2L/TRAIL-induced apoptosis. In HL-60/Bcr-Abl and K562 versus HL-60/neo cells, Apo-2L/TRAIL caused less cytosolic accumulation of cytochrome c and the processing of caspase-9 and -3. This was also associated with decreased processing of caspase-8, c-FLIP(L) and Bid. Reduced effects of Apo-2L/TRAIL in Bcr-Abl-positive leukemic cells were not attributable to diminished expression of DR4 and DR5, or higher expressions of the decoy receptors DcR1 and -2 or c-FLIP(L). Cotreatment with STI-571 significantly enhanced Apo-2L/TRAIL-induced apoptosis (P < 0.01) as well as increased the processing of caspase-9 and -3 and XIAP, without affecting the levels of DR4, DR5, decoy receptors, or c-FLIP(L). Cotreatment with STI-571 did not enhance Apo-2L/TRAIL-induced apoptosis of HL-60/neo cells. These studies suggest that a combined treatment with STI-571 may be an effective strategy to selectively sensitize Bcr-Abl-positive leukemic blasts to Apo-2L/TRAIL-induced apoptosis.

Annexin A5↗
PubMed2000

Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells.

In present studies, treatment with tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 microg/mL of Apo-2L (95.0% +/- 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53(wt) function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L-induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L-induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-x(L). Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L-induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L-induced apoptosis. (Blood. 2000;96:3900-3906)

Acute Disease↗
PubMed1999

CS exposure--clinical effects and management.

The number of people exposed to CS spray presenting to accident and emergency departments is on the increase. Its effects, though usually minor and short lived, involve several systems and can occasionally be life threatening. It is therefore important that staff are able to manage these patients and know when and how to protect themselves and others from further contamination.

Digestive System↗