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Biomedical subjects

Z Estrov

Publications and source records attributed to Z Estrov.

At least 37 records · Page 2Linked to original sources
PubMed2000

Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins.

The antiapoptotic proteins, Bcl-2 and Bcl-X(L), are expressed in most cases of acute myeloid leukemia (AML) and may contribute to drug resistance in AML. We tested the hypothesis that down-regulation of Bcl-2 alone by antisense oligodeoxynucleotides (Bcl-2-AS) induces apoptosis, even in the presence of other antiapoptotic genes. We tested Bcl-2-AS in myeloid leukemic HL-60 cells, in Bcl-2 and Bcl-X(L) overexpressing HL-60-DOX cells, and in primary AML samples. Down-regulation of Bcl-2 by Bcl-2-AS reduced the viability of HL-60 cells and, less effectively, HL-60-DOX cells and increased ara-C cytotoxicity in both cell lines. Incubation of primary AML blasts with Bcl-2-AS decreased Bcl-2 expression in CD34(+) blast cells after induction of apoptosis and enhancement of ara-C cytotoxicity in 11 of 19 primary AML samples. In 8 samples in which Bcl-2-AS did not induce apoptosis, baseline Bcl-2 levels were found to be strikingly high. The expression of other antiapoptotic proteins (Bcl-X(L), Bag-1, A1, and Mcl-1) did not prevent Bcl-2-AS-induced apoptosis. Bcl-2-AS also inhibited colony formation of AML progenitor cells. Low concentrations of Bcl-2-AS induced significant increases in S-phase cells (P =.04). Results establish Bcl-2 as a critical target for AS strategies in AML in which the baseline levels predict response to Bcl-2-AS. Bcl-2 exerts both antiapoptotic and antiproliferative functions in AML. Because early normal hematopoietic stem cells do not express Bcl-2, Bcl-2-AS therapy should be highly selective for AML cells. (Blood. 2000;95:3929-3938)

Acute Disease↗
PubMed2000

Studies of minimal residual disease in acute lymphocytic leukemia.

During the past 2 decades, there has been considerable progress made in the treatment of childhood and adult lymphocytic leukemia (ALL). Currently, 70% to 90% of adults achieve a complete remission, and 25% to 50% of these patients may experience prolonged disease-free survival and may be cured of their disease. Unfortunately, most adults with ALL will ultimately experience a recurrence and die of their leukemia. Although most children with ALL may now be cured with current therapeutic regimens, the ability to distinguish good-risk patients from those who are likely to relapse has important clinical implications. Relapse, in most pediatric and adult cases, is thought to result from residual leukemia cells that remain following achievement of "complete" remission but are below the limits of detection using conventional morphologic assessment of the bone marrow. Sensitive techniques are now available to detect subclinical levels of residual leukemia, termed minimal residual disease.

Adolescent↗
PubMed2000

Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients.

Bcr-Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a major substrate of the Bcr-Abl tyrosine kinase. CRKL can also bind via its first SH3 domain [SH3(1)] to specific sequences in Bcr-Abl. Cell-penetrating peptides were developed that bind with high affinity and selectivity to the SH3(1) domain of CRKL. They disrupt Bcr-Abl-CRKL complexes and strongly reduce the proliferation of primary CML blast cells and cell lines established from Bcr-Abl-positive patients. Activation-specific antibodies against phosphorylated MAP kinase (MAPK) showed that MAPK activity is down-regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude that the Bcr-Abl-CRKL complexes are largely dependent on the CRKLSH3(1) domain, that the central mitogenic cascade is down-regulated as a consequence of the disruption of CRKLSH3(1) interactions, and that CRKL therefore contributes to the proliferation of CML blast cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

CA 125: a clinically useful tumor marker in the management of colorectal carcinoma metastatic to the liver in patients with normal carcinoembryonic antigen.

Two patients with colon carcinoma metastatic to the liver had normal plasma carcinoembryonic antigen (CEA) levels (<1.0 ng/ml) but elevated CA 125 levels. Treatment of the metastatic disease with chemotherapy, plus surgery in one case, led to declines in the CA 125 levels. These decreases were associated with tumor regression, as confirmed by clinical and radiologic evidence. These findings lead us to conclude that the measurement of CA 125 for patients with normal CEA levels is useful in the management of colorectal carcinoma.

Adult↗
PubMed2000

Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia.

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) represents the most common cytogenetic abnormality in adult ALL. It is found in 15% to 30% of patients, and its incidence increases with age. As in children, prognosis in Ph-positive adult ALL is poor. No therapeutic approach has had substantial impact on its unfavorable course. We analyzed the characteristics and outcome of newly diagnosed adults with Ph-positive ALL treated at the M. D. Anderson Cancer Center between 1980 and 1997. The diagnosis of patients was based on typical morphological and immunophenotypic criteria of marrow aspirate and biopsy specimens. Cytogenetic and molecular studies were also performed. A total of 67 patients were included in this study. From 1980 until 1991, 38 patients with Ph-positive ALL were treated with vincristine, Adriamycin, and dexamethasone (VAD), or with acute myeloid leukemia (AML)-like induction protocols. Since 1992 a total of 29 patients received induction therapy with an intensified treatment protocol, called "hyper-CVAD". The outcome of patients treated with standard and intensified treatment regimens was compared and results of our institution contrasted with data obtained from other centers. Ph-positive ALL was present in 67 of 498 patients with newly diagnosed ALL (13%). Patients with Ph-positive ALL had a higher median age (44 versus 34, P=0.007), higher median white blood cell (WBC) counts at presentation (25 versus 8, P=0.0002), and higher peripheral median percentage of blast counts (63 versus 40, P=0.023). FAB subtype L2 (70% versus 49%, P=0.001) and CALLA-positive pre-B immunophenotype (75% versus 37%, P<0.001) predominated among Ph-positive ALL. Myeloid marker coexpression was more frequent in Ph-positive ALL when compared with Ph-negative ALL (52% vs. 27% for CD13, P<0.001, and 44% vs. 27% for CD33, P=0.005). Among patients treated with hyper-CVAD, the complete remission (CR) rate was 90% versus 55% (P=0.002) with pre-hyper-CVAD regimens (VAD and AML-like induction protocols), the median CR duration was 43 weeks versus 32 weeks (P>0.5), median disease-free survival (DFS) was 42 weeks versus 29 weeks (P=0.008), and median survival was 66 weeks versus 45 weeks (P>0.5). Patients with hyperdiploid Ph-positive ALL on hyper-CVAD therapy achieved significantly longer CR duration and DFS than hypo- and pseudodiploid cases (59 weeks versus 42 and 31 weeks, P=0.02 and 0.04, respectively). In contrast, patients treated with regimens prior to hyper-CVAD had significantly shorter CR duration (21 weeks versus 33 and 29 weeks, P=0.03) and DFS with hyperdiploid karyotypes when compared to pseudodiploid and hypodiploid cases (16 weeks versus 30 and 13 weeks, P=0.008). In conclusion, our results demonstrate improved response rate and DFS with current intensive regimens (hyper-CVAD) in patients with Ph-positive ALL, but no advantage in overall survival.

Adult↗
PubMed2000

Clinical significance of minimal residual disease in leukemia.

Considerable progress has been made in the treatment of acute and chronic leukemias. Remission rates are generally high and cure rates of up to 80% can be achieved in children with acute lymphoblastic leukemia (ALL). However, in many patients the disease will ultimately recur. In most if not all of these patients, relapse is thought to result from subclinical levels of residual leukemia, termed minimal residual disease (MRD). Therefore, the study of MRD holds a significant potential to understand the biology of relapse and remission and to design new therapies to improve the cure rate of patients. A major goal of these studies is to be able and identify patients at a defined risk of relapse which can lead to risk-adapted therapy approaches. Laboratory assays such as polymerase chain reaction (PCR) and multicolor flow cytometry are sensitive enough to detect one leukemic cell in up to 104-105 normal cells and have become ideal tools to monitor MRD. Especially PCR has been used extensively. Although a wealth of data has been generated, some questions remain as to the impact of monitoring MRD on clinical outcome and are the object of this review.

Acute Disease↗
PubMed2000

E1A-mediated paclitaxel sensitization in HER-2/neu-overexpressing ovarian cancer SKOV3.ip1 through apoptosis involving the caspase-3 pathway.

HER-2/neu-overexpressing breast cancer cells are more resistant to the chemotherapeutic agent paclitaxel (Taxol) than low-HER-2/neu-expressing breast cancer cells, and the adenoviral type 5 EIA can down-regulate HER-2/neu overexpression. Therefore, in this study, we asked (a) whether EIA might sensitize response to paclitaxel in human HER-2/neu-overexpressing ovarian cancer cells, and, if so, what is the mechanism responsible; and (b) whether this enhanced chemosensitivity would translate into a therapeutic effect in an ovarian cancer xenograft model. Consequently, we demonstrated that: (a) adenovirus type 5 E1A could enhance the sensitivity of paclitaxel in paclitaxel-resistant HER-2/neu-overexpressing human ovarian cancer cells in vitro by inducing apoptosis, (b) this induction was heavily dependent on activation of the caspase-3 pathway, and (c) nude mice bearing i.p. HER-2/neu-overexpressing human ovarian cancer cells and treated with both paclitaxel and E1A gene therapy survived significantly longer than did mice treated only with paclitaxel or E1A gene therapy. Thus, we concluded that the E1A gene enhanced both the in vitro and in vivo sensitivity of paclitaxel in paclitaxel-resistant HER-2/ neu-overexpressing ovarian cancer SKOV3.ipl cells. Because a Phase I clinical trial using E1A gene targeted to HER-2/neu down-regulation has recently been completed, the current study also provided a scientific basis to further develop a novel therapy that combines paclitaxel and E1A gene therapy and its testing in a Phase II trial.

Adenovirus E1A Proteins↗
PubMed2000

BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia.

Previously, we demonstrated that the level of BCL2 expression is prognostic in acute myelogenous leukemia (AML). High levels of BCL2 correlate with an adverse outcome when associated with favorable and intermediate prognosis cytogenetics (FIPC), whereas low levels portend an adverse outcome when associated with unfavorable cytogenetics (UC). Because BCL2 function can be modulated by dimerization with family members, like BAX, or by phosphorylation by protein kinase C alpha (PKCalpha), we hypothesize that the relative expression of these proteins in primary leukemic cells might alter the prognostic impact of BCL2 expression. We therefore measured BAX and PKCalpha protein levels in peripheral blood mononuclear cell lysates from 165 newly diagnosed AML patients and correlated the expression of these proteins with BCL2 expression, patient survival, and remission induction success. Expression levels of BAX and PKCalpha were normalized against a control cell line, K562. BAX and PKCalpha expression levels were heterogeneous and did not correlate with the percentage of blasts in the sample (R2 = 0.01 and <0.01). The median expression of both was similar across FAB groups but the range was greater for M4. A similar distribution of expression was observed in all cytogenetic groups, except that patients with inversion 16 demonstrated lower levels of BAX. Individually, neither PKCalpha nor BAX expression was prognostic of response to induction therapy or survival. A similar outcome was obtained when patients were stratified by cytogenetics into FIPC and UC groups. However, the ratio of either BCL2:BAX (B2:BX) or PKCalpha*B2:BX (PK*B2:BX) was highly prognostic. Patients with FIPC and a lower ratio (less than median) of either B2:BX or PK*B2:BX had a significantly higher remission induction rate (88 versus 69%, P = 0.04) and longer survival (median: 141 versus 80.5 weeks, P = 0.007) compared with those with ratios more than median. For patients with UC, values of either B2:BX or PK*B2:BX below the median had an inferior response rate to induction therapy (35 versus 78%, P = 0.0006) and inferior survival outcomes (median survival: 11 versus 53 weeks, P = 0.00002). Interestingly, FIPC and UC patients with antiapoptotic ratios (defined as B2:BX or PK*B2:BX more than median) had identical response rates and survival outcomes. In multivariate analyses, the compound variables of cytogenetics and B2:BX, or PK*B2:BX were independent predictors of survival. These results suggest that expression levels of proteins that affect the functional status of BCL2 modify the prognostic impact of BCL2 and suggest that the role of apoptosis in different cases of AML varies independently in the different cytogenetic subgroups.

Adolescent↗
PubMed1999

Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia.

Vascular endothelial growth factor (VEGF) is a potent mitogen for vascular endothelial cells. It has been associated with angiogenesis, growth, dissemination, metastasis, and poor outcome in solid tumors. To assess cellular VEGF levels and their prognostic significance in newly diagnosed acute myeloid leukemia (AML), we used a radioimmunoassay (RIA) to quantify VEGF levels in stored samples obtained before treatment from 99 patients with newly diagnosed AML treated at the MD Anderson Cancer Center from 1996 to 1998. Outcome in the 99 patients was representative of that observed in all patients seen at this institution with this diagnosis during these years, but the 99 patients had higher white blood cell (WBC) and blast counts than the other patients. Results of the RIA were confirmed by Western blot. There was a relationship between increasing VEGF levels and shorter survival (P =.01), as well as shorter disease-free survival, both from start of treatment and from complete response (CR) date. In contrast, there was no relationship between VEGF level and WBC or blast count, or between VEGF level and such established prognostic factors as age, cytogenetics, performance status, or presence of an antecedent hematologic disorder, and multivariate analysis indicated that VEGF was still prognostic for the above outcomes after accounting for these factors, as well as treatment. Our results suggest that at least in AML patients with higher WBC and blast counts, cellular VEGF level is an independent predictor of outcome.

Acute Disease↗
PubMed1999

Phenylarsine oxide blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, and induces apoptosis of acute myelogenous leukemia cells.

Arsenic compounds have recently been shown to induce high rates of complete remission in patients with acute promyelocytic leukemia (APL). One of these compounds, As(2)O(3), induces apoptosis in APL cells via a mechanism independent of the retinoic acid pathway. To test the hypothesis that arsenic compounds may be effective against other forms of acute myelogenous leukemia (AML), we studied the membrane-permeable arsenic compound phenylarsine oxide (PAO). Because interleukin-1beta (IL-1beta) plays a key role in AML cell proliferation, we first tested the effect of PAO on OCIM2 and OCI/AML3 AML cell lines, both of which produce IL-1beta and proliferate in response to it. We found that PAO inhibited the proliferation of both OCIM2 and OCI/AML3 cells in a dose-dependent fashion (0.01 to 0.1 micromol/L) and that IL-1beta partially reversed this inhibitory effect. We then measured IL-1beta levels in these cells by using an enzyme-linked immunosorbent assay and Western immunoblotting and found that PAO almost completely abolished the production of IL-1beta in these AML cells, whereas it did not affect the production of IL-1 receptor antagonist. Because PAO inhibits activation of the transcription factor NF-kappaB and because NF-kappaB modulates an array of signals controlling cellular survival, proliferation, and cytokine production, we also studied the effect of PAO on NF-kappaB activation in AML cells and found that PAO suppressed the IL-1beta-induced activation of NF-kappaB. Because inhibition of NF-kappaB may result in cellular apoptosis, we also tested whether PAO may induce apoptotic cell death in AML cells. We found that PAO induced apoptosis in OCIM2 cells through activation of the cystein protease caspase 3 and subsequent cleavage of its substrate, the DNA repair enzyme poly (ADP-ribose) polymerase. The PAO-induced apoptosis was caspase dependent, because it was completely blocked by the caspase inhibitor Z-DEVD-FMK. Finally, we tested the effect of PAO on fresh AML marrow cells from 7 patients with newly diagnosed AML and found that PAO suppressed AML colony-forming cell proliferation in a dose-dependent fashion. Taken together, our data showing that PAO is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.

Acute Disease↗
PubMed1999

Chronic myelogenous leukemia: biology and therapy.

Chronic myelogenous leukemia is a myeloproliferative disorder. It is characterized by a biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase. On a cytogenetic and molecular level, most patients with chronic myelogenous leukemia demonstrate BCR-ABL fusion genes in hematopoietic progenitor cells, which result from a reciprocal translocation between chromosomes 9 and 22; this translocation leads to a shortened chromosome 22, called the Philadelphia chromosome. Translation of the fusion products yields chimeric proteins of variable size that have increased tyrosine kinase activity. Conventional chemotherapy with hydroxyurea or busulfan can achieve hematologic control but cannot modify the natural disease course, which inevitably terminates in a rapidly fatal blastic phase. Since its introduction in the 1980s, allogeneic stem-cell transplantation has provided the groundwork for a cure of chronic myelogenous leukemia. However, few patients are eligible for this treatment because of donor availability and age restrictions. Therapy with interferon-alpha alone or in combination with cytarabine suppresses the leukemic clone, produces cytogenetic remissions, and prolongs survival. It is an effective alternative first-line treatment for patients ineligible for transplantation. New drugs active against chronic myelogenous leukemia may show increased activity in the transformed phases of the disease. Novel therapies and concepts are developing rapidly; targeted molecules are tyrosine kinases, ras, and messenger RNA through antisense oligonucleotides. Alternative transplantation options, such as stem cells from autologous sources and matched unrelated donors, are expanding. Immunomodulation by adoptive immunotherapy and vaccine strategies hold significant promise for the cure of chronic myelogenous leukemia.

Blast Crisis↗
PubMed1999

Autocrine interleukin-1beta production in leukemia: evidence for the involvement of mutated RAS.

Interleukin (IL)-1beta is constitutively expressed in many leukemias and operates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic leukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-1beta and have mutations in the K-RAS and N-RAS genes, respectively. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1beta promoter elements [nuclear factor (NF)-IL6/CREB, NFB1, NFkappaB, and NF-IL6], consistent with the activation of an upstream signaling pathway. To determine whether activated Ras was involved, two structurally distinct classes of farnesyltransferase (FTase) inhibitors (the monoterpenes and a peptidomimetic) and an adenoviral vector expressing antisense targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a concentration-dependent decrease in both NF-IL6/CREB binding to the IL-1beta promoter and IL-1beta protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21Ras and IL-1beta protein levels. Growth suppression was observed after FTase inhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1beta to the cultures. Our observations suggest that mutated RAS genes may mediate autocrine IL-1beta production in some leukemias by stimulating signal transduction pathways that activate the IL-1beta promoter.

Alkyl and Aryl Transferases↗
PubMed1999

Expression and function of leptin receptor isoforms in myeloid leukemia and myelodysplastic syndromes: proliferative and anti-apoptotic activities.

The receptor for the gene product of the obesity gene, leptin, was recently reported to be expressed on murine and human hematopoietic progenitor cells. Therefore, we studied the expression of the leptin receptor, OB-R, in normal myeloid precursors, human leukemia cell lines, and primary leukemic cells using reverse-transcriptase polymerase chain reaction. In normal hematopoiesis, OB-R was expressed in CD34(+) cells. Normal promyelocytes (CD34(-)33(+) and CD34(-)13(+)) expressed only very low levels of the short, presumably nonsignaling isoform. Both the long and short isoforms of OB-R were expressed in 10 of 22 samples from patients with newly diagnosed primary or secondary acute myeloid leukemia (AML), with a higher incidence of the long isoform in primary AML (87.6% v 28.6%; P =.01). The incidence of OB-R expression was higher in recurrent than in newly diagnosed AML (P <.001), and samples from four patients with refractory AML showed strong expression of both isoforms. Both OB-R isoforms were also expressed in newly diagnosed and recurrent acute promyelocytic leukemia cells but were essentially absent in samples of chronic or acute lymphocytic leukemia. In vitro growth of myeloid leukemic cell lines and of blasts from 14 primary AMLs demonstrated that recombinant human leptin alone induced low level proliferation, significantly (P <.05) increased proliferation induced by recombinant human granulocyte colony-stimulating factor, interleukin 3, and stem cell factor in a subset of AML and increased colony formation (P <.005). Also, leptin reduced apoptosis induced by cytokine withdrawal in MO7E and TF-1 cells. Serum leptin levels correlated only with body mass index (P <. 001) and gender (P =.03). Results confirm the reported expression of leptin receptor in normal CD34(+) cells and demonstrate the frequent expression of leptin receptors in AML blasts. While normal promyelocytes lack receptor expression, leukemic promyelocytes express both isoforms. We also demonstrate proliferative effects of leptin alone and in combination with other physiologic cytokines, and anti-apoptotic properties of leptin. These findings could have implications for the pathophysiology of AML.

Apoptosis↗
PubMed1999

Correlation between lower c-mpl protein expression and favorable cytogenetic groups in acute myeloid leukemia.

The gene for the thrombopoietin receptor, c-mpl, has been shown to be overexpressed at the mRNA level in acute myeloid leukemia (AML) and myelodysplastic syndrome. A recent study reported c-mpl mRNA overexpression in 60% of a small sample of AML patients, and this overexpression correlates with shorter complete remission but not with karyotype group. We quantified c-mpl protein expression in 107 cases of AML and 24 normal bone marrow and 12 normal peripheral blood samples by using Western blot analysis and radioimmunoassay (RIA). Western blot analysis revealed no detectable level of c-mpl protein in the normal samples, whereas trace amounts were detected by RIA. c-mpl protein expression was increased (> or = twice normal) in 65% of the AML cases. c-mpl protein expression was correlated with cytogenetic groups (P = 0.0009, Kruskal-Wallis test in rejecting the hypothesis that c-mpl expression was the same in different groups). Specifically, patients with favorable cytogenetic groups (t(8;21), inv16, and t(15;17)) had lower c-mpl protein expression (median 1.7 times normal), whereas patients with unfavorable abnormalities (+8, -5 or -7, and del(11)(q23)) and normal cytogenetics had high expression (3.1 and 2.85 times normal, respectively). The findings were the same when only the 61 untreated AML patients were considered. No statistically significant correlation between c-mpl expression and age or antecedent hematologic disorder was found. These results suggest that c-mpl protein overexpression in AML may play a role in the aggressiveness of this disease.

Blotting, Western↗
PubMed1999

Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid.

The expression of Bcl-2 family members was examined in normal and leukemic hematopoietic cells. Immature hematopoietic progenitor cells (CD34+/33-/13-) did not express Bcl-2 but Bcl-XL, the majority of CD34 cells expressed Bcl-2, Bcl-XL and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-XL, while leukemic CD34+progenitors and promyelocytes expressed these anti-apoptotic proteins. In AML, Bcl-2 expression was higher on CD34+ than on all AML cells, however, expression of Bcl-2 or Bcl-XL did not predict achievement of complete remission. Surprisingly, low Bcl-2 content was associated with poor survival in a group of patients with poor prognosis cytogenetics. The anti-apoptotic BAD protein was found to be expressed in AML, but was phosphorylated in 41/42 samples. Phosphorylation was found at both sites, Ser 112 and Ser 136. During induction chemotherapy, Bcl-2 levels of CD34 cells increased significantly. In the context of evidence for small numbers of leukemic CD34+ cells expressing very high levels of Bcl-2 prior to therapy, this finding is interpreted as a survival advantage of Bcl-2 overexpressing progenitors and rapid elimination of cells with low Bcl-2. Bcl-2 and Bcl-XL were both expressed in minimal residual disease cells. Downregulation of Bcl-2 mRNA and protein was observed by ATRA and the combination of Ara-C, followed by ATRA, resulted in markedly increased cytotoxicity in HL-60 cells, as compared to Ara-C alone or ATRA followed by Ara-C. Implications of these findings for the development of new therapeutic strategies for AML are discussed.

Acute Disease↗