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PubMed2004

Measurement of Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine in human plasma protein by stable-isotope-dilution tandem mass spectrometry.

BACKGROUND: N(epsilon)-(Carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL) are two stable, nonenzymatic chemical modifications of protein lysine residues resulting from glycation and oxidation reactions. We developed a tandem mass spectrometric method for their simultaneous measurement in hydrolysates of plasma proteins. METHODS: CML and CEL were liberated from plasma proteins by acid hydrolysis after addition of deuterated CML and CEL as internal standards. Chromatographic separation was performed by gradient-elution reversed-phase chromatography with a mobile phase containing 5 mmol/L nonafluoropentanoic acid as ion-pairing agent. Mass transitions of 205.1-->84.1 and 219.1-->84.1 for CML and CEL, respectively, and 209.1-->88.1 and 223.1-->88.1 for their respective internal standards were monitored in positive-ion mode. RESULTS: CML and CEL were separated with baseline resolution with a total analysis time of 21 min. The lower limit of quantification was 0.02 micromol/L for both compounds. Mean recoveries from plasma samples to which CML and CEL had been added were 92% for CML and 98% for CEL. Within-day CVs were <7.2% for CML and <8.2% for CEL, and between-day CVs were <8.5% for CML and <9.0% for CEL. In healthy individuals (n = 10), mean (SD) plasma concentrations of CML and CEL were 2.80 (0.40) micromol/L (range, 2.1-3.4 micromol/L) and 0.82 (0.21) micromol/L (range, 0.5-1.2 micromol/L), respectively. In hemodialysis (n = 17) and peritoneal dialysis (n = 9) patients, plasma concentrations of CML and CEL were increased two- to threefold compared with controls, without significant differences between dialysis modes [7.26 (1.36) vs 8.01 (3.80) micromol/L (P = 0.89) for CML, and 1.84 (0.39) vs 1.71 (0.42) micromol/L (P = 0.53) for CEL]. CONCLUSIONS: This stable-isotope-dilution tandem mass spectrometry method is suitable for simultaneous analysis of CML and CEL in hydrolysates of plasma proteins. Its robustness makes it suitable for assessing the value of these compounds as biomarkers of oxidative stress resulting from sugar and lipid oxidation.

Biomarkers↗

PubMed1998

The effect of interferon-alpha on beta-1 integrin mediated adhesion and growth regulation in chronic myelogenous leukemia.

There is considerable interest in understanding the mechanisms by which interferon-alpha can induce hematological and cytogenetic remissions and prolong survival in patients with chronic myelogenous leukemia (CML). There is evidence that the selective expansion and growth advantage of malignant hematopoietic progenitors in CML may be related, at least in part, to their deficient responsiveness to normal negative regulation by the marrow stromal microenvironment and that interferon-alpha may restore normal hematopoiesis in CML by restoring normal microenvironmental regulation of malignant CML progenitor proliferation. In normal hematopoiesis, beta1 integrin receptors mediate progenitor adhesion to stroma. Stimulation of beta1 integrin receptors on normal progenitors results in transmission of proliferation inhibitory signals. CML progenitors demonstrate defective beta1 integrin receptor-mediated adhesion and regulation of proliferation. We have shown that interferon-alpha can restore both beta1 integrin mediated adhesion as well as integrin-mediated proliferation inhibition of CML progenitors. Interferon-alpha enhances CML integrin function through direct effects on CML progenitors as well as indirect effects on stroma. Restored beta1 integrin-mediated regulation of malignant CML progenitor proliferation may result in restoration of normal hematopoiesis in CML patients treated with interferon-alpha. There is evidence that abnormal integrin mediated signaling in CML progenitors may result from abnormalities in integrin-cytoskeletal interactions induced by the p210BCR/ABL tyrosine kinase. Although the exact mechanisms by which interferon-alpha restores normal integrin signaling in CML are not known, preliminary studies indicate that this may at least partly be related to the restoration of normal integrin-cytoskeletal interactions. The above studies offer some insights into the mechanisms of abnormal hematopoietic regulation in CML and the mechanisms by which interferon-alpha may restore normal hematopoiesis, in this disease.

Antineoplastic Agents↗

PubMed2000

Topotecan-based combination chemotherapy in patients with transformed chronic myelogenous leukemia and advanced myelodysplastic syndrome.

BACKGROUND: Patients with transformed chronic myelogenous leukemia(CML) and advanced myelodysplastic syndrome(MDS) have poor prognosis. The aim of this study is to evaluate the feasibility of second chronic phase induction in accelerated phase(CML-AP) or blastic crisis of CML(CML-BC) and remission induction in advanced MDS by combining topoisomerase I inhibitor (topotecan) with topoisomerase II inhibitor(mitoxantrone). METHODS: Twenty-four evaluable patients were entered on this study with a median age of 34 years. Eighteen patients with transformed CML(7 CML-AP, 11 CML-BC) and 6 patients with advanced MDS were treated. Topotecan was administered as 1.5 mg/m2/day by continuous infusion over 24 hours daily for 5 days every 4 to 8 weeks until remission. To enhance the tumoricidal effects, mitoxantrone(12 mg/m2/day, Days 1-3) was added. RESULTS: Eight patients(33%) achieved a complete remission(CR). Four of 7 patients with CML-AP(57%), 2 of 4 patients with CML-lymphoid blastic crisis (-LBC)(50%) and 2 of 6 patients with advanced MDS(33%) had CR lasting more than 45 days(45 to 400 days). There was no CR in the patients with CML-myeloid blastic crisis(-MBC). The dose level of 1.5 mg/m2/day(7.5 mg/m2/course) of topotecan was well tolerated in all patients. Mucositis occurred in 69% of patients (severe in 5%) and diarrhea in 67%(severe in 8%). In addition, there were no new or unexpected toxicities in the patients who were treated at this dose(7.5 mg/m2/course). In patients who recovered their neutrophil count, the absolute neutrophil count(ANC) remained below 500/microL for a period of 13 to 58 days(median 21 days) and the time to ANC recovery was associated with pretreatment severity of bone marrow fibrosis(mainly CML patients). Likewise, in the patients who recovered unsupported platelets, the platelets remained below 20,000/microL for a period of 0 to 37 days (median 19 days). CONCLUSION: The combination of topotecan-mitoxantrone has shown modest activity in CML-AP, CML-LBC and advanced MDS with acceptable toxicities.

Adult↗

PubMed2005

[Overexpression of Shp-2 is associated with the unlimited growth and apoptosis resistance of p210 bcr-abl-mediated chronic myeloid leukemia].

OBJECTIVE: To investigate the expression level of Shp-2 tyrosine phosphatase in chronic myeloid leukemia (CML) and its relationship with the unlimited growth and apoptosis resistance of p210 bcr/abl-induced malignant cells. METHODS: In this study, p210 bcr/abl positive leukemia cell specimens were obtained from 25 CML cases, meanwhile, bone marrow and peripheral blood cell samples from 8 non-tumor individuals and 10 normal individuals were used as p210 bcr/abl negative controls. K562 and KU812 leukemia cells were used as p210 bcr/abl positive controls, and KG-1 leukemia cell line was used as Shp-2 positive control. Specimens of peripheral blood and bone marrow of 25 adult patients of chronic myelocytic leukemia, 15 males and 10 females, aged 28-64, were collected. Specimens of bone marrow of 8 basically healthy adult volunteers and specimens of peripheral blood of 10 healthy adult volunteers were used as controls. The total cell protein was collected and the expression of Shp-2 was examined by Western blotting. Human leukemia cells of the line K562 were cultured. Shp-2 specific sense and antisense oligonucleotides were added into the culture fluid respectively. The cell apoptosis was detected by flow cytometry (FCM). STI571, specific inhibitor of p210 bcr/abl was added into the cultured fluid of K562 cells, then Western blotting and FCM were used to detect the protein expression of Shp-2 and p210 bcr/abl, and cell apoptosis. RESULTS: Phosphorylated Shp-2 (pShp)-2 protein was overexpressed in 92% (23/25) of the CML cells, but lowly expressed or not expressed in the normal hematopoietic cells. The mean pShp-2 protein/beta-actin ratio of the primary CML leukemia cells was 0.91 +/- 0.62, significantly higher than those of the normal bone marrow cells and peripheral blood hematopoietic cells (0.16 +/- 0.09 and 0.03 +/- 0.05 respectively, both P < 0.01). The apoptotic rates of the CML cells treated by Shp-2 specific antisense oligonucleotide of the concentrations of 1 micromol/L and 4 micromol/L respectively for 72 h was 7.98% and 20.29% respectively, both significantly higher than that of the control group (4.06%, P < 0.01). The number of clone of CML cells treated by 0.25 micromol/L and 1.0 micromol/L Shp-2 specific antisense oligonucleotide for 7 days were 67% (37/60) and 11.9% (5/42) that of the control group. Twenty-four and 48 hours after the stimulation of STI571 the expression level of Shp-2 protein in the CML cells decreased time-dependently and the CML cell apoptotic rates were 31.15% and 38.69% respectively, both lower than that of the control group (33.6%). The number of clone of CML cells effected by 0.25 micromol/L and 1.0 micromol/L Shp-2 specific antisense oligonucleotide for 7 days was 67% (37/60) and 11.9% (5/42) that of the control group. Twenty-four and 48 hours after the stimulation of STI571 the expression level of Shp-2 protein in the CML cells decreased time-dependently and the CML cell apoptotic rates were 31.15% and 38.69% respectively, both lower than that of the control group (33.6%). CONCLUSION: (1) The pShp-2 protein is overexpressed in CML cells, which is associated with the unlimited growth and apoptosis resistance of malignant cells. (2) Shp-2 is upregulated by p210 bcr/abl oncoprotein in CML.

Adult↗

PubMed1989

Adherent lymphokine-activated killer cells in chronic myelogenous leukemia: a benign cell population with potent cytotoxic activity.

We generated a homogeneous population of cells with cytotoxic activity termed "adherent lymphokine-activated killer" (ALAK) cells from the peripheral blood of nine patients in the chronic phase of Ph1 positive chronic myelogenous leukemia (CML). The selective enrichment of CML ALAK cells depended on their propensity to adhere to plastic and proliferate when cultured in the presence of recombinant interleukin-2 (rIL-2) for 14 days. Culture of peripheral blood mononuclear cells under these conditions resulted in growth of a uniform population of cells with morphologic characteristics of large granular lymphocytes. The NKH1+/CD3- phenotype associated with IL-2-stimulated natural killer (NK) cells was present on 79% +/- 9% of cells. Absence of colony formation in conditions promoting the growth of CFU-GEMM indicated that the CML ALAK population was not contaminated with viable hematopoietic progenitors. Cytogenetic analysis of the CML ALAK population revealed 119/120 Ph1 negative metaphases and l/120 Ph1 positive metaphase in six patients. Southern blot analysis of CML ALAK failed to demonstrate a bcr gene rearrangement in seven patients known to have a bcr gene rearrangement in myeloid cells. Comparison of ALAK populations derived from peripheral blood of CML patients and normals revealed similar cytotoxicity against the NK-sensitive K562 cell line (104 +/- 36 LU v 88 +/- 19 LU; P = NS) and the NK-resistant Raji cell line (93 +/- 26 LU v 98 +/- 28 LU; P = NS). The proliferative capacity of CML ALAK cells (101 +/- 33 fold expansion) exceeds the growth potential of the normal ALAK cells (22.3 +/- 3 fold expansion; P = .02). Direct comparison of equal numbers of CML ALAK cells and a CML LAK cell population produced by incubation of peripheral blood mononuclear cells in rIL-2 for 14 days without adherence revealed that the CML LAK population had significantly lower lytic activity against K562 and Raji cell lines. We are able to expand CML peripheral blood mononuclear cells to provide a population of ALAK cells with potent cytotoxic activity. The CML ALAK population is relatively homogeneous, not contaminated with viable stem cells, not derived from a malignant lineage, and more cytotoxic than equal numbers of CML LAK cells. Further studies are underway to determine if this ALAK population may be effective in autologous killing of chronic myelogenous leukemia stem cells.

Azure Stains↗

PubMed1992

A differential sensitivity to recombinant human interferon-alpha 2a between normal and chronic myeloid leukaemic peripheral blood granulocyte-macrophage colony-forming units.

The sensitivity to recombinant human interferon-alpha 2a (IFN) of peripheral blood granulocyte-macrophage colony-forming units (PB CFU-GM) from patients with chronic myeloid leukaemia (CML) was studied in a semi-solid clonogenic assay, and compared with normal PB CFU-GM. Like normal PB CFU-GM, the growth of CML PB CFU-GM in vitro was found to be dependent on the plating concentration used. The optimal CFU-GM growth occurred when CML PB mononuclear cells (MNC) were plated at low concentrations in the range of 0.01-0.1 x 10(5)/ml, compared to the range of 0.3-3.0 x 10(5)/ml optimal for CFU-GM growth in normal subjects. The optimal plating concentration for CML PB CFU-GM was similar to that observed in PB collected from patients with ovarian carcinoma during haematological recovery following chemotherapy-induced myelosuppression (recovery phase). The recovery phase PB was used as a source of non-leukaemic cells with a higher incidence of CFU-GM similar to that of CML. IFN produced a dose-related inhibition of CFU-GM growth in normal, recovery phase ovarian carcinoma and CML, PB MNC. The IFN concentration required to inhibit 50% of the CFU-GM in culture (LD50) was found to be significantly influenced by the plating concentration. When cells were cultured at 1.0 x 10(5) MNC/ml the mean LD50 for 7 CML patients was similar to that in normal (n = 5) or recovery phase (n = 5) peripheral blood, 273 i.u./ml, 1047 i.u./ml and 795 i.u./ml, respectively. In contrast when CML cells were cultured at 0.03 x 10(5) MNC/ml the concentration for optimal CML CFU-GM growth, the mean LD50 was significantly lower than that in normal PB and recovery phase PB, 4 i.u./ml, 251 i.u./ml and 78 i.u./ml, respectively (p less than 0.05). This is the first report of a differential sensitivity to IFN between CML and non-CML progenitors using an optimized PB CFU-GM assay system and proposes that further study of the in vitro culture of CML progenitors may increase our understanding of the clinical effects of IFN.

Cells, Cultured↗

PubMed2000

Glycoxidative modification of AA amyloid deposits in renal tissue.

BACKGROUND: N(epsilon)-carboxymethyllysine (CML) is a product of the oxidative modification of glycated proteins, which damages proteins with ageing, diabetes, uraemia and Alzheimer's disease. In contrast, pyrraline is one of the advanced glycation end products, which is independent of oxidative processes. CML has been identified in beta-amyloid of Alzheimer's disease and beta(2)-microglobulin-associated amyloid. We investigated whether CML and pyrraline are formed in AA and AL amyloid of the kidney. METHOD: Renal specimens from 19 cases of AA amyloidosis and 14 cases of AL amyloidosis were investigated for immunolocalization of CML, pyrraline, collagen type IV and laminin in amyloid deposits. Renal biopsies of 10 age-matched cases with thin basement membrane disease and normal renal function were used as controls. The fractional areas of amyloid, CML, laminin and collagen IV in glomeruli and interstitium (%amyloid, %CML, %laminin and %collagen, respectively) were calculated using the point counting method. The correlation between these parameters was evaluated using Spearman's rank correlation test. RESULTS: CML colocalized with AA amyloid, but not AL amyloid, except in two cases of the latter with a long history of nephropathy exceeding 14 years. In contrast, pyrraline was not observed in either type of amyloid. Mean %CML in AA amyloid was significantly higher than %collagen and %laminin in glomeruli and interstitium, indicating that AA amyloid is modified by CML independent of colocalized extracellular matrix. %CML significantly correlated with %amyloid both in glomeruli and interstitium in AA amyloidosis. AL amyloid cases with a long history of nephropathy showed positive staining for CML in glomeruli and interstitium but no staining for collagen IV and laminin in amyloid deposits. CONCLUSION: CML modification may occur in amyloid deposits of AA amyloidosis, independent of extracellular matrix components. Glycoxidative modification may have a functional link to AA amyloid deposition in renal tissues.

Adult↗

PubMed2005

Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors.

Imatinib has impressive activity against chronic myeloid leukaemia (CML), but does not appear to completely eradicate the disease. Although responses to interferon-alpha (IFN) are slower and less dramatic than those to imatinib, they can be durable even after discontinuation of the drug. Unlike imatinib, the specific mechanisms responsible for IFN's clinical activity in CML are unknown. We found that IFN induced a G1 cell cycle arrest, as well as terminal differentiation, of the CML cell line KT-1 and CML CD34+ cells from clinical specimens. Myeloid growth factors augmented the antileukaemic activity of IFN, and neutralising antibodies directed against myeloid growth factors inhibited IFN's antileukaemic activity. We next directly compared the effects of imatinib and IFN against differentiated and primitive CML progenitors from newly-diagnosed patients. Although less active against CML granulocyte-macrophage colony forming units than imatinib, IFN was significantly more toxic to primitive CML progenitors responsible for the maintenance of long-term cultures. Imatinib and IFN appear to have divergent effects on CML progenitors at different stages of maturation, with imatinib more active against differentiated CML progenitors and IFN more active against primitive CML progenitors. The different target cells for these agents may explain the disparities in the kinetics and durability of their clinical responses. At least part of the clinical effect of IFN in CML appears to result from its ability to differentiate primitive CML progenitors.

Adult↗

PubMed1997

Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging.

N(epsilon)-(Carboxymethyl)lysine (CML), a major product of oxidative modification of glycated proteins, has been suggested to represent a general marker of oxidative stress and long-term damage to proteins in aging, atherosclerosis, and diabetes. To investigate the occurrence and distribution of CML in humans an antiserum specifically recognizing protein-bound CML was generated. The oxidative formation of CML from glycated proteins was reduced by lipoic acid, aminoguanidine, superoxide dismutase, catalase, and particularly vitamin E and desferrioxamine. Immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries provided evidence for an age-dependent increase in CML accumulation in distinct locations, and acceleration of this process in diabetes. Intense staining of the arterial wall and particularly the elastic membrane was found. High levels of CML modification were observed within atherosclerotic plaques and in foam cells. The preferential location of CML immunoreactivity in lesions may indicate the contribution of glycoxidation to the processes occurring in diabetes and aging. Additionally, we found increased CML content in serum proteins in diabetic patients. The strong dependence of CML formation on oxidative conditions together with the increased occurrence of CML in diabetic serum and tissue proteins suggest a role for CML as endogenous biomarker for oxidative damage.

Adult↗

PubMed2004

Treatment patterns, outcomes and costs among elderly patients with chronic myeloid leukaemia: a population-based analysis.

BACKGROUND AND OBJECTIVE: Chronic myeloid leukaemia (CML) affects approximately 3000-5000 Americans each year, with the American Cancer Society expecting 4600 new cases in 2004. The incidence of CML increases with age; median age at diagnosis is 67 years. Long-term data on the economic burden associated with CML among the elderly are sparse. To fill this void, our study uses population-based data to evaluate longer-term treatment patterns, outcomes and costs among elderly Medicare beneficiaries following their diagnosis of CML. PATIENTS AND METHODS: This retrospective cohort analysis used linked data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute and Medicare claims. Study cohorts included 567 patients aged > or = 65 years newly diagnosed with CML between 1991 and 1993 in a SEER registry and followed for 5 years or until death, whichever occurred first. In addition, 567 control patients without CML matched 1 : 1 by age and sex (average age 78 years, 52% male) were included. The costs of care were based on total Medicare payments (in constant 1998 dollars). Groups were generally similar in terms of nonmatched variables. RESULTS: Five years following diagnosis, 13% of CML patients were still alive versus 68% of the control patients (median survival: 14 months vs > 60 months, respectively). The average total Medicare payments were USD35,785 for CML patients versus USD21,161 for control subjects (monthly payments: USD1688 vs USD428, respectively; p < 0.001). Approximately 25% of CML patients underwent Medicare-covered cancer treatment (11% outpatient chemotherapy, 6% inpatient chemotherapy and 8% outpatient interferon-alpha therapy). Younger patients and those diagnosed in the later years were most likely to be treated. Costs for treated patients were higher, and they lived longer. CONCLUSION: Our findings suggest low treatment rates, and substantial excess mortality and costs associated with CML among the elderly. The recent introduction of imatinib has dramatically changed the treatment of CML, which is likely to cause important changes to the economic burden of CML. Our results can be used as a baseline for evaluating the impact of such new therapies as data from clinical trials become available. Further work is needed to characterise this disease and the complex factors that influence treatment decisions and associated health outcomes in elderly patients.

Aged↗

PubMed1999

Significance of FHIT expression in chronic myelogenous leukemia.

Loss or reduced expression of the fragile histidine triad (FHIT) gene, a tumor suppressor gene localized at chromosome 3p14.2, is common in several solid and hematological cancers and has been associated with tumor progression and worse prognosis. The role of the FHIT gene in the pathogenesis of chronic myelogenous leukemia (CML) or its progression from a chronic phase to the accelerated and blastic phases is not known. The aim of this study was to evaluate whether Fhit protein expression is altered in CML, and whether it plays any role in CML progression, disease responsiveness to therapy, or prognosis. A total of 195 patients with Philadelphia chromosome-positive CML were evaluated, including 129 patients in early chronic phase (time from diagnosis to study, 12 months or less), 30 patients in late chronic phase, and 36 patients in the accelerated and blastic phases. The levels of cellular Fhit protein expression were determined using Western blot analysis and solid-phase RIA and compared to the levels in 31 normal marrows. The median Fhit expression in normal marrows was assigned a value of 1, and the levels in CML samples were normalized to the median of the normal control. Fhit levels in CML samples were evaluated in relation to CML phase and patient characteristics and prognosis in the early chronic phase. The median Fhit value in CML samples was 0.89 (range, 0.34-2.62). Eight of the 195 (4%) CML samples showed Fhit levels <0.5 and lacked detectable Fhit protein by Western blot. There was no difference in the levels of Fhit expression by different CML phases. In early chronic phase, reduced Fhit expression tended to be associated with leukocytosis (P = 0.04) and lower platelet counts (P = 0.01), but not with poorer-risk groups. No differences in response to IFN-alpha therapy or in survival were observed by different Fhit levels. Lack of Fhit protein expression was detected in 4% of CML cases, and reduced expression occurred in a subpopulation of patients. However, reduced Fhit expression is not associated with progression, response to therapy, or prognosis in CML.

Acid Anhydride Hydrolases↗

PubMed2000

[In vitro induction of autologous T cell killing by heat treated human chronic myelogenous leukemia cells].

OBJECTIVE: To investigate the potential of autologous T cell killing of heat treated chronic myelogenous leukemia (CML) cells (autologous tumor killing, ATK). METHODS: (51)Cr release assay was used to measure the ATK activity of autologous T cells against CML cells treated with 42 degrees C for 30 minutes (heat) or 37 degrees C for 30 minutes (non-heat). The phenotypes of T cells and heat shock protein 70 (HSP70) expression of CML cells were measured by flow cytometry (FCM). T cells from the CML patients were stimulated and expanded by autologous mixed lymphocyte/tumor cell cultures (MLTC). RESULTS: ATK activity of autologous T cells to the non-heated and heated CML cells were found in 4 (19.05%) and 10 (47.62%) of the 21 cases, respectively. The ATK activity of interleukin-2 (IL-2) stimulated autologous T cells against heated CML cells was markedly higher than that of unstimulated autologous T cells against non-heated CML cells (P < 0.001). FCM analysis showed that no HSP70 was expressed on the CML cell membranes whether heated or non-heated, but intracellular HSP70 expressions were (83.42 +/- 5.65)% and (78.34 +/- 6.32)% pre- and post-heated, respectively. The phenotypes of T cells stimulated and expanded in MLTC were TCRgammadelta - CD(3)(+), mostly CD(8)(+), with some activation markers (CD(25) and HLA-DR) expression. The ATK activities of these T cells against the heated and non-heated CML cells and K562 cells were (51.25 +/- 4.26)%, (36.52 +/- 3.83)% and (2.92 +/- 1.19)%, respectively. CONCLUSIONS: ATK activity of autologous T cells against CML cells could be induced or enhanced by heat treatment of the CML cells particularly of T cells stimulated with IL-2. This ATK activity was not associated with gammadelta T cells or HSP70 expression of CML cells.

Adolescent↗

PubMed2001

[Expression of Vascular Endothelial Growth Factor in the Bone Marrow Cells from Adult Chronic Myelogenous Leukemia]

Vascular endothelial growth factor (VEGF) is one of the main angiogenic cytokines and plays an important role in the development of human solid tumors. However, it is not clarified whether VEGF governs the progress of the chronic myelogenous leukemia (CML). This study is to estimate VEGF expression in the bone marrow cells from normal and adult CML patients and various leukemic cell lines. Reverse transcription-polymerase chain reaction (RT-PCR) was used for detection of VEGF mRNA. VEGF concentrations in the cell cultural supernatant and the plasma from normal and CML patient bone marrows were determined by enzyme linked immunosorbent assay (ELISA). VEGF mRNA was positive in 67 of 72 cases of bcr/abl(+) CML patient bone marrow cells (93.1%), in 5 of 10 CML patients post Allo-BMT bone marrow cells (50%), and in 6 of 10 normal bone marrow cells (60%), the expression rate of VEGF mRNA in CML patients bone marrow cells was higher than that in CML patients post Allo-BMT and normal bone marrow cells. VEGF mRNA also expressed in the HL-60, K562, CEM, KG1a, NB4, and Nalm6 cells, but not in the Jurkat cells. The mean VEGF concentration in the plasma (380.6 pg/ml) from 22 untreated CML patients was 9 folds higher than that from 9 CML patients post Allo-BMT (38.0 pg/ml). The mean VEGF concentration in the cultural supernatant (499.8 pg/ml) of 17 newly diagnosed CML bone marrows was 2.5-folds higher than that in 11 normal donors (141.3 pg/ml). The CML marrow cells secrete more VEGF than normal marrow cells do. Our results suggest that the abnormality of VEGF transcription and translation expression may play an important role in the development of CML.

Journal Article↗

PubMed1993

Chronic myelogenous leukemia: biology and therapy.

There is remarkable recent progress in our understanding of the biology of chronic myelogenous leukemia (CML). First, the BCR/ABL rearrangement was identified as the molecular basis of the disease. Second, animal models support the notion that the BCR/ABL gene product causes a syndrome similar to CML. Third, recent advances in understanding the functions of the normal ABL protein have given clues to the mechanism(s) of ABL-induced leukemias and approaches to blocking this process. Extrapolating these findings to humans seems reasonable. The challenge now is to determine how the BCR/ABL gene product causes chronic phase CML. Also unresolved is whether BCR/ABL also plays a role in the acute phase of the disease. Finally, the relationship between the two common forms of BCR/ABL, the P190 and P210 configurations, and different disease phenotypes, like CML and Philadelphia (Ph1)-chromosome positive acute lymphoblastic leukemia (ALL), needs to be clarified. There is also substantial progress in treating CML. Bone marrow transplants have emerged as the preferred therapy. These result in long-term leukemia-free survival in more than one-half of appropriately selected subjects. How transplants cure CML is complex and controversial. Some data suggest high-dose treatment is the dominant factor whereas other data implicate antileukemia effects of the immune system. Interferon treatment has also proven effective in CML. Whether it prolongs survival of persons with CML remains to be determined, as does its mechanism of action. Certainly the most important and difficult challenge in CML therapy is determining how to use knowledge about the causes CML to treat the disease. These and other issues in the biology and therapy of CML were the subject of a recent meeting of basic and clinical scientists. The meeting, third in a series begun in 1987, was held on Martha's Vineyard, Cape Cod, Massachusetts, USA from 4-7 April, 1992. Four major topics were considered in five sessions: molecular biology, cell biology, Ph1-chromosome positive ALL, and therapy of CML. This report summarizes meeting highlights.

Animals↗

PubMed1998

Abnormal levels of proinflammatory cytokines in serum and monocyte cultures from patients with chronic myeloid leukemia in different stages, and their role in prognosis.

Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), primarily monocyte-derived cytokines, form a group of proinflammatory cytokines with related and overlapping spectra of activities. The role of these cytokines in chronic myeloid leukemia (CML) has been investigated. A distinctive pattern of cytokine secretion has been found in chronic myeloid leukemia in chronic phase (CML-CP), in blastic crisis (CML-BC) and in normal subjects. Serum IL-6 levels in CML-CP and CML-BC were significantly raised compared with normal controls (p = 0.0026 for CML-CP and p = 0.0011 for CML-BC). IL-6 was significantly elevated in blastic crisis of CML (103.5 +/- 20.77 pg ml-1) compared with CML-CP (37.35 +/- 10.88 pg ml-1; p = 0.014). IL-6 serum levels were found to correlate significantly with peripheral blood monocyte counts and bone marrow blast and basophil counts. We have analysed monocyte/macrophage function with respect to their ability to produce IL-1, IL-6 and TNF-alpha, spontaneously as well as in response to LPS, in comparison with normal controls. A direct correlation of IL-6 levels in unstimulated and stimulated cultures with bone marrow blast and basophil counts has been observed. From these results it is inferred that the monocyte function is impaired in CML patients, and the cytokine secretion is deficient. Our limited data suggest that serum IL-6 levels may play an important role as a prognostic marker for CML.

Blast Crisis↗

PubMed2002

Neutrophilic-chronic myeloid leukemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course.

BACKGROUND: Neutrophilic-chronic myeloid leukemia (CML-N) has been described as a CML variant associated both with a distinctive molecular defect of the Philadelphia chromosome and with a more benign clinical course than classic CML. The translocation (9;22) in CML-N results in the transcription of an e19/a2 type BCR/ABL mRNA that codes for a 230-kD BCR/ABL protein (p230). The indolence of the clinical course of patients with CML-N has been disputed. METHODS: The objectives of this study were to quantify and correlate with clinical outcome the p230 mRNA and protein in patients with CML-N, to describe six new patients and the follow-up (with molecular analysis) of five previously reported patients with CML-N, and to review characteristics of all patients with CML-N and p230 BCR/ABL reported to date in the literature. RESULTS: Quantitative polymerase chain reaction assays on specimens from the great majority of patients with CML-N revealed minimal numbers of molecules of p230 BCR/ABL transcripts per total RNA. This also was associated with a lack of detectable p230 BCR/ABL protein in patient specimens, even in one patient who was followed for 16 years after diagnosis. This may explain the milder leukemic phenotype in most patients with CML-N. A review of all 23 patients who had an e19/a2 type BCR/ABL translocation suggested that the low level of p230 BCR/ABL mRNA and the lack of detectable p230 BCR/ABL protein in patients with no additional cytogenetic abnormalities may predict their indolent clinical course. CONCLUSIONS: Patients with p230 positive CML-N have indolent course, probably as a result of low p230 mRNA and protein levels. This supports the need to conduct additional molecular studies, even if cytogenetic studies have revealed t(9;22), because of the prognostic importance of the molecular findings.

Adult↗

PubMed2003

Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia.

BACKGROUND: General and site-specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML. METHODS: One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML. Decitabine was given at 100 mg/m(2) over 6 hours every 12 hours x 5 days (1000 mg/m(2) per course) in the first 13 patients, 75 mg/m(2) in the subsequent 33 patients, and 50 mg/m(2) in the remaining 84 patients. RESULTS: A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph-negative CML, four (57%) had objective responses. There was no evidence of a dose-response effect. The estimated 3-year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50-75 mg/m(2), the median time to granulocyte recovery above 0.5 x 10(9)/L was about 4 weeks. Myelosuppression-associated complications included febrile episodes in 37% and documented infections in 34%. CONCLUSIONS: Decitabine appears to have significant anti-CML activity. Future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases.

Adolescent↗

PubMed2003

Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

BACKGROUND: Older age is a consistent poor prognostic factor in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Whether this is related to an intrinsic worse disease biology or to inadequate drug delivery or excessive treatment-associated toxicity is unknown. The availability of imatinib mesylate, a selective, Bcr-Abl-targeted therapy that is administered orally with minimal side effects, may clarify whether older age would remain an adverse factor (thus, implying a different age-related CML biology). METHODS: Seven hundred forty-seven patients in different phases of Ph-positive CML who were treated with imatinib from 1999 until the time of last follow-up were evaluated. Among them, 187 patients had newly diagnosed, early chronic phase CML; 351 patients had chronic phase CML after interferon alpha (IFN) failure; 133 patients had accelerated phase CML; and 76 patients had blastic phase CML. The imatinib daily dose varied from 400 mg to 800 mg orally, according to the protocol design. Patients were categorized into a group of older patients (age 60 years or older) or younger patients (age younger than 60 years). Their characteristics, responses to therapy, and survival were compared by univariate and multivariate analyses. RESULTS: One hundred eighty-seven patients had newly diagnosed CML, and 49 patients (26%) were in the older age group. Older patients had similar cytogenetic response rates and survival compared with younger patients. Among 351 patients with late chronic phase CML after IFN failure, 120 patients (34%) were in the older age group. Although the older patients had a lower incidence of achievement of complete cytogenetic response (Ph, 0%) by univariate analysis (56% vs. 44%; P = 0.05), age was not found to be an independent poor prognostic factor in the multivariate analysis. Similarly, older age was not an adverse poor prognostic factor for survival. Forty-two of 133 patients (32%) with accelerated phase CML were older. The incidence of any cytogenetic response was lower in older patients (53% vs. 33%; P = 0.04), but age was not significant in the multivariate analysis. Older patients also had a trend toward worse survival (P = 0.09) that was not significant in the multivariate analysis. Twenty-eight of 76 patients (37%) evaluated in blastic phase were older. Older age was not a significant prognostic factor either for achieving response or for survival. CONCLUSIONS: With imatinib therapy, older age appears to have lost much of its prognostic relevance. This suggests that the previous poor prognosis observed with older age was related to treatment-associated factors (e.g., toxicity with allogeneic transplantation or with IFN therapy) rather than to an intrinsic, different disease biology of CML in older patients.

Administration, Oral↗