Mechanisms of resistance to apoptosis in human AML blasts: the role of differentiation-induced perturbations of cell-cycle checkpoints.

Alterations in the response of leukaemic cells to apoptosis-inducing stimuli may account for resistance to chemotherapy and treatment failure, either by disruption of the apoptotic pathway itself or by altered DNA repair; quiescent cells and those with disrupted cell-cycle checkpoints may also display decreased apoptosis. Quiescence can be induced by the differentiation of myeloid cells, and this led us to investigate whether the modulation of drug-induced apoptosis associated with differentiation might be a model for quiescence-associated resistance generally. We have demonstrated that resistance to idarubicin-induced apoptosis increased with greater duration of incubation of HL60 and U937 cells with ATRA and 1,25(OH)2 D3 and that this protective effect correlated with the degree of G0/G1 accumulation. In addition, the cytoprotective effects held for other classes of cytotoxic drugs with different mechanisms of action to idarubicin. Prolonged exposure to idarubicin or vinblastine was associated with diminution of the protective effect and re-entry of cells into cycle. The full cytoprotective effect was restored by resupplementation with ATRA or 1,25(OH)2 D3 during exposure to idarubicin, with concomitant persistence of G0/G1 accumulation. Differentiating agents prevented the accumulation of leukaemic cells at the G2/M checkpoint in response to low concentrations of idarubicin. Understanding how differentiating agents modulate these cell-cycle checkpoints, and how quiescent cells evade apoptosis, may allow the development of therapeutic strategies to limit such apoptosis-inhibiting effects and maximise cell kill from chemotherapy.

Haemopoietic growth factors.

Haemopoietic growth factors are involved in the production of the various blood cells from progenitors in the bone marrow, making them useful in a range of clinical situations. The genes for several of them have been cloned and their production engineered by recombinant technology, making them widely available. Myeloid growth factors are used to support patients in the aftermath of chemotherapy and bone marrow transplantation and have potential application in the treatment of infectious diseases. Erythropoietin is widely used for patients with anaemia due to failure of marrow production, having established its effectiveness in chronic renal failure. Thrombopoietin has recently been described and may provide a means to alleviate thrombocytopenia. Current indications and areas of recent reappraisal are addressed in this review.

Non-inpatient parenteral antibiotic therapy in febrile adults.

Non-inpatient care is becoming an increasingly attractive option in many therapeutic areas, including the treatment of infections in patients with haematological malignancies. The choice of antibiotics for this care is governed by infection patterns and experience within particular institutions. There is an increase in infections caused by Gram-positive pathogens due to the long-term use of tunnelled catheters and intensive, punishing chemotherapy regimens. Patients suitable for non-inpatient care include both long- and short-term patients who fulfil specific clinical and social criteria. Haematological malignancy patients are often suitable for this type of care. Benefits for patients include improved quality of life, while benefits for the clinician include effective, safe care as well as reduced costs and greater bed availability. The glycopeptide teicoplanin has been assessed for use in non-inpatient care, and is particularly suitable due to its long half-life, no need for monitoring and its activity against Gram-positive pathogens. A comparative study of a teicoplanin-ciprofloxacin combination was conducted in inpatients, followed by a cohort study in non-inpatients. This combination was found to be clinically and microbiologically effective, suitable for non-inpatient administration and generated cost savings due to early discharge. The organization of a non-inpatient service demands dedicated team members, with well-defined roles and a designated treatment area. The day ward is the focus of care, which can then take place in the day ward or in the patient's home. Good communication between immediate and wider team members, and patient education are cornerstones of a successful service.

Non-inpatient Treatment of Febrile Episodes in Patients with Hematological Malignancy.

Infection related to indwelling central venous catheters is associated with considerable morbidity and inconvenience to patients, and has traditionally required admission for intravenous antibiotics in an attempt to salvage the line. We report the successful usage of an outpatient regimen consisting of alternate day teicoplanin with oral ciprofloxacin, which resulted in line salvage in 74% of cases, achieved satisfactory serum levels of teicoplanin and avoided the need for admission to hospital, with concomitant cost savings.

Teicoplanin and oral ciprofloxacin as outpatient treatment of infective episodes in patients with indwelling central venous catheters and haematological malignancy.

Central venous catheters are often the focus of microbial colonization which may cause bacteraemia (or fungal septicaemia) in both neutropenic and non-neutropenic patients. Such episodes are associated with considerable morbidity and may require admission to hospital or replacement of the central line. We have used the combination of intravenous teicoplanin and oral ciprofloxacin to treat such episodes as outpatients, achieving a salvage rate of 74%. Seven of thirty-five episodes resulted in removal of the line. The treatment was well tolerated and well-suited to the day ward setting.

Haematological splenectomy. Changing indications and complications.

Review of splenectomies carried out for haematological disease over a ten-year period, at a district hospital, shows that the indications for splenectomy have changed substantially over this time. Fewer patients with idiopathic thrombocytopenic purpura now require splenectomy, however its role in the management of lymphoproliferative disorders has expanded. Splenectomy remains an important therapeutic option for a range of haematological disorders: this series shows it to be a safe and effective operation in selected patients, although it is not without both short and long-term sequelae.

Modulation of idarubicin-induced apoptosis in human acute myeloid leukemia blasts by all-trans retinoic acid, 1,25(OH)2 vitamin D3, and granulocyte-macrophage colony-stimulating factor.

The relationship between differentiation of human myeloid cells and apoptosis remains unclear. Recent studies have shown that terminal differentiation need not necessarily lead to the apoptotic demise of myeloid cells, while other studies have shown that induction of differentiation is associated with increased resistance to apoptosis-inducing agents, such as chemotherapy and gamma-irradiation. Such results are pertinent to the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome, where differentiating agents and hemopoietic growth factors are being combined with chemotherapy to enhance response and limit toxicity. To elucidate the factors governing apoptosis in human AML blasts, we have studied the cytotoxic effect of idarubicin on HL60, U937 and KG1 cells, after incubation with all-trans retinoic acid (ATRA), 1, 25(OH)2 D3, and granulocyte-macrophage colony-stimulating factor (GM-CSF ). We show that prior incubation of human myeloid leukemic cells with ATRA or 1,25(OH)2 D3 induced resistance to idarubicin-induced apoptosis, which was modulated by coincubation with GM-CSF. The altered chemosensitivity of cells depended on the degree of G0/G1 cell-cycle arrest induced by incubation with ATRA, 1, 25(OH)2 D3, and GM-CSF and was independent of differentiation status or Bcl-2 oncoprotein expression. These findings suggest that cell-cycle arrest in human leukemic cells can be induced by exogenous agents and may promote drug resistance. Determining the mechanisms by which cell-cycle arrest is induced may permit understanding of the processes by which the cells escape cytotoxic drug-mediated apoptosis.