tretinoin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Component Transfusion; Child; Child, Preschool; Female; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tretinoin

Topics: Evidence-Based Medicine; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA Antigens; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Tretinoin

Acute leukemia is classified broadly as either acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL). The main treatments remain remission induction therapy and postremission chemotherapy. The advances in chemotherapy for pediatric patients with ALL have been dramatic, with some 95% achieving complete remission, and long-term survival is 60-80%. Among adults, high long-term survival rates due to improvements in chemotherapy for B-cell type ALL and core binding factor leukemias have been reported. For adult leukemias overall, however, long-term survival rates have stalled at 15-40% despite the high remission rate attained. In most cases this is due to a recurrence. Among the prognostic factors reported for acute leukemia, chromosome type may be cited as the currently most reliable. Acute leukemia patients are classified based on chromosome type, and the postremission therapeutic strategy is considered in terms of an appropriate combination of chemotherapy and hematopoietic stem cell transplant. This accounts for an important part of the treatment given today. Target-based therapies such as all-trans-retinoic acid (ATRA) for AML have brought dramatic improvements in treatment results. The effect of imanitib against Philadelphia chromosome positive ALL, for which the prognosis is poor, is also attracting attention. Moreover, promising new treatment strategies that have been developed, including cord blood transplant, mini-transplant, antibody therapy, and immunotherapy, Clinical studies of PCR and other means to reveal small residual lesions and estimate prognosis are also making progress. In the future it will be possible to identify prognostic factors in genetic tests such as DNA microarrays and single nucleotide polymorphisms, so that the optimum treatment can be selected for individual patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Combined Modality Therapy; Female; Humans; Leukemia, Myeloid, Acute; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Stem Cell Transplantation; Survival Rate; Survivors; Tretinoin

Malignancies in childhood occur with an incidence of 13-14 per 100,000 children under the age of 15 years. Acute lymphoblastic leukaemia with an incidence of 29% is the most common paediatric malignancy, whereas acute myeloid leukaemias account for about 5%. The treatment of acute leukaemias consists of sequential therapy cycles (induction, consolidation, intensification, maintenance therapy) with different cytostatic drugs over a time period of up to 1.5-3 years. Over the last 25 years of clinical trials, a significant rise in the rate of complete remissions as well as an increase in long-term survival has been achieved. Therefore, growing attention is now focused on the long-term effects of antileukaemic treatment. Several cytostatic drugs administered in the treatment of acute leukaemia in childhood are known to cause long-term adverse effects. Anthracyclines may induce chronic cardiotoxicity, alkylating agents are likely to cause gonadal damage and secondary malignancies and the use of glucocorticoids may cause osteonecrosis. Most of the long-term adverse effects have not been analysed systematically. Approaches to minimising long-term adverse effects without jeopardising outcome have included: the design of new drugs such as a liposomal formulation of anthracyclines, the development of anthracycline-derivates with lower toxicity, the development of cardioprotective agents or, more recently, the use of targeted therapy;alternative administration schedules like continuous infusion or timed sequential therapy; and risk group stratification by the monitoring of minimal residual disease. Several attempts have been made to minimise the cardiotoxicity of anthracyclines: decreasing concentrations delivered to the myocardium by either prolonging infusion time or using liposomal formulated anthracyclines or less cardiotoxic analogues, or the additional administration of cardioprotective agents. The advantage of these approaches is still controversial, but there are ongoing clinical trials to evaluate the long-term effects. The use of new diagnostic methods, such as diagnosis of minimal residual disease, which allow reduction or optimisation of dose, offer potential advantages compared with conventional treatment in terms of reducing the risk of severe long-term adverse effects. Most options for minimising long-term adverse effects have resulted from theoretical models and in vitro studies, but only some of the modalities such as the use of dexrazoxane, the con

Topics: Alkylating Agents; Anthracyclines; Antimetabolites; Antineoplastic Agents; Asparaginase; Asparagine; Cardiovascular Diseases; Child; Clinical Trials as Topic; Glucocorticoids; Gonadal Disorders; Humans; Leukemia; Leukemia, Myeloid, Acute; Osteonecrosis; Podophyllotoxin; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tretinoin; Vinca Alkaloids

Therapy-related MDS and AML are complications of intensive chemotherapy regimens. Traditionally, patients exposed to topoisomerase II inhibitors are reported to develop secondary AML with abnormalities of chromosome 11q23. We evaluated the long-term hematologic toxicity of topoisomerase II-intensive high-dose mitoxantrone-based chemotherapy in 163 newly diagnosed acute leukemia patients treated over an 8 year period. Nine (5.5%) patients developed new cytogenetic abnormalities. Four patients developed MDS with progression to AML, three patients developed new abnormalities at the time of relapse, and three patients (including one of the former patients) had changes that were not associated with hematologic disease. The abnormalities most frequently involved chromosomes 7q, 20q, 1q, and 13q. Despite the use of topoisomerase II-intensive treatment, no patient developed an abnormality involving chromosome 11q23. Spontaneous resolution of some changes and prolonged persistence of others in the absence of hematologic disease indicates that some cytogenetic changes are not sufficient to promote leukemogenesis.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Chromosomes, Human, Pair 11; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cytarabine; Disease Progression; Disease-Free Survival; Enzyme Inhibitors; Etoposide; Female; Humans; Idarubicin; Incidence; Karyotyping; Leukemia, Myeloid; Life Tables; Male; Middle Aged; Mitoxantrone; Myelodysplastic Syndromes; Neoplasm Proteins; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Remission Induction; Retrospective Studies; Topoisomerase II Inhibitors; Treatment Outcome; Tretinoin

This review briefly summarizes literature noteworthy in the field of adult acute leukemia published during 1999. The relationship between specific cytogenetic abnormalities and response to treatment was explored within a clinical framework. In particular, detailed analyses of the abnormalities seen in acute promyelocytic leukemia were examined. Two case reports of special interest were published: one shed light on the role of histone deacetylase inhibitors in combination with all-trans retinoic acid, and the other, on the role of granulocyte colony-stimulating factor in this disease. The clinical activity of arsenic was also reported and its mechanism of action explored. In acute lymphoblastic leukemia, attention was focused on occult translocations, and the importance of minimal residual disease was again emphasized. Lastly, results of early clinical trials using an anti-CD19 antibody were reported, with provocative results.

Topics: Acute Disease; Adolescent; Adult; Antibodies, Monoclonal; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Chromosome Aberrations; Clinical Trials as Topic; Combined Modality Therapy; DNA, Neoplasm; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Infant; Leukemia; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Middle Aged; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Randomized Controlled Trials as Topic; Treatment Outcome; Tretinoin

Topics: Adult; Aged; Bone Marrow Transplantation; Child; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Cytarabine; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic; Tretinoin

Topics: Gene Rearrangement; Humans; Infant; Myeloid-Lymphoid Leukemia Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tretinoin

Despite the success achieved in the treatment of acute lymphoblastic leukemia (ALL), the search for new drugs featuring selectivity against leukemia cells and effectiveness to prevent relapsed ALL is still highly desirable. Here, we described the synthesis of several novel 3-substituted and 3,6-disubstituted-2-carboalkoxy indoles followed by the elucidation of their mechanism of action and in vivo anti-leukemia efficacy. The synthesis of 3-substituted-2-carboalkoxy indoles relied on two Heck arylations of methyl acrylate and methyl cinnamates respectively, to generate β,β-disubstituted acrylates followed by an efficient Cadogan-Sundberg reaction of these latter intermediates. The method developed led to the synthesis of twenty-one novel functionalized indoles. Of these, indole 20 showed selective cytotoxicity against leukemia cells at the nanomolar scale, and, therefore, it was selected for the investigation of its mechanism of action. Indole 20 was found to target tubulin leading to G2/M cell cycle arrest, DNA damage and apoptosis. Indole 20 decreased β-tubulin protein in leukemia cells in a time-dependent manner and induced depolymerization of the microtubule network in Hela cells, thus fully characterizing its microtubule destabilizer activity. The connectivity map analysis of HL60 promyelocytic leukemia cells treated with indole 20 revealed a transcriptional profile similar to that of cells treated with prostaglandins, apparently due to the induction of cellular differentiation as addressed by the expression of CD11 and CD14 markers. Finally, indole 20 given intraperitoneally, at 10 mg/kg, 5x/week significantly prolonged the overall survival of NOD/SCID mice transplanted with RS4; 11 B-ALL cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cinnamates; G2 Phase Cell Cycle Checkpoints; HeLa Cells; HL-60 Cells; Humans; Indoles; Leukemia, Promyelocytic, Acute; Mice, Inbred NOD; Mice, SCID; Precursor Cell Lymphoblastic Leukemia-Lymphoma

1,25-Dihydroxyvitamin D3 (1,25D) induces differentiation of myeloid leukemia cells, but resistant cells are also encountered. We studied the mechanistic basis for the resistance in a model system using enhancers of 1,25D, the antioxidant carnosic acid and a kinase inhibitor SB202190. Knock-down (KD) of JNK2p54 unexpectedly increased the intensity of differentiation induced by the 1,25D, carnosic acid and SB202190 (DCS) combination. This was associated with upregulation of activated JNK1p46, and the transcription factors regulated by the JNK pathway, c-Jun, ATF2 and JunB, as well as C/EBP beta. In contrast, KD of JNK1p46 reduced the intensity of DCS-induced differentiation, and partially abrogated activation of c-Jun/AP-1 transcription factors.

Topics: Abietanes; Antioxidants; Cell Differentiation; Cell Division; Drug Resistance, Neoplasm; Enzyme Inhibitors; HL-60 Cells; Humans; Imidazoles; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 9; Plant Extracts; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-jun; Pyridines; RNA, Small Interfering; Transcription Factor AP-1; Tretinoin

The innate immune system produces a number of effector molecules that are important for protection against bacterial infections. Neutrophils and antimicrobial peptides are major components of innate defense with the capacity of rapid bacterial killing. Patients with severe congenital neutropenia (SCN) experience recurrent and chronic infections despite recombinant G-CSF-mobilized neutrophils. We have shown previously that these neutrophils are deficient in that they lack the antimicrobial peptide LL-37. Here, we show that pro-LL-37 mRNA is not expressed in neutrophil precursors from patients with SCN, although the gene and promoter region for pro-LL-37, CAMP, does not display any mutations. The hormonal form of vitamin D3 [1,25(OH)2D3] induced the expression of pro-LL-37 in isolated neutrophil progenitors and in EBV-transformed B cells from patients with SCN, whereas all-trans retinoic acid only induced expression in transformed B cells. These results demonstrate that myeloid cells of patients with SCN can produce pro-LL-37, suggesting that other pathways are impaired.

Topics: Antimicrobial Cationic Peptides; Calcitriol; Cathelicidins; Cell Differentiation; Child; Cholecalciferol; Humans; Neutropenia; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Siblings; Transcription, Genetic; Tretinoin

Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Clone Cells; Cytotoxins; Hematopoietic Stem Cells; Humans; Immunophenotyping; In Vitro Techniques; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tretinoin

Leukemias are differentially sensitive to histone deacytelase inhibitor (HDI)-induced apoptosis, but molecular reasons for this remain unclear. We here show that BCR/ABL-, but not FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-transformed 32D cells or primary acute myeloid leukemia (AML) blasts undergo apoptosis after treatment with the HDI valproic acid (VPA) plus all-trans retinoic acid (VPA/ATRA). A particular VPA/ATRA responsiveness of Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) was confirmed in a therapy-refractory patient in vivo. HDI-stimulated apoptosis in Ph+ cells was caspase dependent, but independent from Akt pathway inhibition. Conversely, separate blockage of the Akt/mTor-signaling pathway was a prerequisite for overcoming apoptosis resistance to VPA/ATRA in FLT3-ITD cells, and primary AML blasts (n = 9). In conclusion, constitutive Akt activation causes apoptosis resistance to VPA/ATRA in AML, but not in Ph+ leukemia. This warrants the application of HDI-based therapies in poor-risk Ph+ ALL, and the use of Akt/mTor inhibitors to overcome HDI resistance in AML.

Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Fusion Proteins, bcr-abl; Histone Deacetylase Inhibitors; Humans; Leukemia, Myelomonocytic, Acute; Mutation; Oncogene Protein v-akt; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Tretinoin; Tumor Cells, Cultured; Valproic Acid

The retinoic acid receptor alpha (RARA) gene is disrupted by PML/RARA fusion in acute promyelocytic leukemia (APL). The P2 promoter of RARA, controlling the RARalpha2 isoform, contains an RA-responsive element and may be targeted in APL. To test whether aberrant methylation of P2 was involved, 47 APL at diagnosis, 16 APL at first relapse, 50 acute myeloid leukemia (AML) and 22 acute lymphoblastic leukemia (ALL) were tested by methylation-specific polymerase chain reaction. RARA P2 methylation was highly associated with APL (APL: 25/63 vs AML/ALL: 2/75, P<0.0001). P2 methylation occurred at similar frequencies in APL at diagnosis and relapse, suggesting it was an initiating leukemogenic event. In the APL line NB4, RARalpha2 was not expressed, with the untranslocated RARA shown to be P2 methylated. 5-Azacytadine treatment of NB4 led to progressive P2 demethylation and re-expression of RARalpha2, confirming that RARA methylation collaborated with PML/RARA in totally suppressing RARalpha. In APL, RARA P2 methylation was unrelated to gender, age, presenting leukocyte counts and additional cytogenetic aberrations. For APL patients receiving all-trans retinoic acid for induction, P2 methylation did not affect the complete remission rates and survivals. RARA is the first myeloid-specific transcription factor shown to be dysregulated by both translocation and aberrant methylation.

Topics: Acute Disease; Biological Transport; DNA Methylation; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Receptors, Retinoic Acid; Recurrence; Remission Induction; Retinoic Acid Receptor alpha; Survival Rate; Tretinoin

Acute promyelocytic leukemia (APL) is invariably associated with chromosomal translocation to retinoic acid receptor alpha (RARalpha) locus. In a vast majority of cases, RARalpha translocates to and fuses with the promyelocytic leukemia (PML) gene. It was thought that the fusion protein PML-RARalpha acts as a double dominant negative mutant to inhibit the PML and RARalpha signaling. In an attempt to study the physiological role of retinoic acid in mammary gland development, we created a transgenic model system expressing a dominant negative RARalpha under the regulation of murine mammary tumor viral promoter. We found that the transgene was also targeted to the lymphoid system in addition to mammary gland. Here we showed that dominant negative RARalpha induced acute lymphoblastic leukemia and lymphoma development in the transgenic mice. Retinoic acid blocked tumor development ex vivo through induction of apoptosis. Thus, our results suggested that disruption of RARalpha signaling was the first essential step in the development of APL in vivo.

Topics: Acute Disease; Animals; Apoptosis; Cell Proliferation; Female; Gene Expression Regulation; Genes, Dominant; Humans; Male; Mammary Tumor Virus, Mouse; Mice; Mice, Transgenic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Survival Rate; Tretinoin; Tumor Cells, Cultured

Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate (HS) synthesis. Reduced HS production can be reversed by the use of a DNA demethylating agent. Furthermore, the re-introduction of EXT1 into cancer cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g. reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Heparitin Sulfate; Humans; Leukemia, Promyelocytic, Acute; Mice; Mice, Nude; Mutation, Missense; N-Acetylglucosaminyltransferases; Neoplasms, Experimental; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Skin Neoplasms; Transplantation, Heterologous; Tretinoin

Topics: Adult; Aged; Amsacrine; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Cytarabine; Daunorubicin; Female; Heart; Heart Failure; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tretinoin

To investigate whether apoptosis occurs in vivo in patients with acute leukemia during induction chemotherapy and its significance.. Apoptotic effect on peripheral blood of 20 patients with different types of acute leukemia prior to and during routine chemotherapy was studied by cell morphology, DNA electrophoresis and FCM-DNA analysis.. After chemotherapy, with falls in WBC and blast count, no apoptotic cell appeared on smears of peripheral blood, nor did ladder pattern of DNA on electrophoresis and subdiploid peak on FCM.. Although anticancer drugs have been shown to induce apoptosis in vitro, circulating apoptotic cells are hardly detected probably due to their rapid clearance from the circulation. It is more difficult to study apoptosis in vivo than in vitro.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Tretinoin; Vincristine

We have previously proposed a novel mechanism for the coupled regulation of glucocorticoid receptor (GR) and c-jun transcription in triamcinolone acetonide (TA)-treated AtT-20 cells. This involved transcriptional interference of AP-1 (Fos/Jun)-driven gene transcription by the formation of inactive GR/Jun heterodimers. To further elucidate the molecular mechanism for GR autoregulation, the expression of GR and c-jun mRNA and protein levels were examined in both mouse L929 fibroblast cells and human CEM-C7 acute lymphoblastic leukemia cells. A rapid down-regulation of both GR and c-jun mRNA and protein levels occurs in TA-treated L929 cells. All-trans-retinoic acid (RA) treatment of Jun-deficient, mouse F9, teratocarcinoma cells causes the induction of c-jun expression. The increased expression of both c-jun mRNA and protein is accompanied by the induction of GR expression. These data further suggest that functional cJun is needed for the expression of the GR and c-jun genes in F9 cells. CEM-C7 cells undergo apoptosis after exposure to glucocorticoids. There is a parallel up-regulation of GR and c-jun mRNA levels in TA-treated CEM-C7 cells. This is accompanied by a concomitant increase in GR and cJun protein levels. Dose-response analyses reveal the expected coordinate regulation of both GR and c-jun mRNA and protein in L929 cells (decreasing) and in CEM-C7 cells (increasing). However, approximately 20-fold less TA is required for the inhibition of GR and c-jun expression as compared to that required for the stimulation of these two genes. These data demonstrate that the coordinate regulation of GR and c-jun gene expression is dose-dependent and cell type-specific. These results, along with previously reported data, suggest that GR complex formation with itself or with another transcription factor is important for the coordinate up- and down-regulation, respectively, of the GR and c-jun genes.

Topics: Animals; Cell Line; Down-Regulation; Gene Expression Regulation; Homeostasis; Kinetics; L Cells; Mice; Pituitary Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-jun; Receptors, Glucocorticoid; RNA, Messenger; Time Factors; Transcription, Genetic; Tretinoin; Triamcinolone Acetonide; Tumor Cells, Cultured; Up-Regulation

We studied 18 patients with acute promyelocytic leukaemia and 13 with relapsed APL. We found a significantly elevated EGF in acute leukaemia, especially in APL, being 418.59 +/- 19.2 micrograms in the 24-h urine that was much higher than that of the normal controls. When eight APL patients achieved complete remission by RA treatment, the EGF value decreased to 149.9 +/- 27.3 micrograms in the 24-h urine near to normal. In 13 patients with relapsed APL, EGF rose to 446.9 +/- 82.6 micrograms in the 24-h urine. Most interestingly, this elevated EGF could be detected before the relapse by 5 +/- 0.84 months in seven out of eight APL with relapse. We suggest that the unaccountably elevated EGF during remission period may be an indicator of the occurrence of relapse.

Topics: Acute Disease; Adult; Aged; Base Sequence; Biomarkers, Tumor; Cell Differentiation; Epidermal Growth Factor; Female; Humans; Immunologic Factors; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Molecular Sequence Data; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm, Residual; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tretinoin

Bone marrow transplantation procedure has emerged as an effective treatment for hematological malignancies. However, recurrence of leukemia is still the major cause of treatment failure. Subsequent treatment in this category of patients, generally considered incurable, has not been yet standardized. At our institution, 13 patients, 7 with acute non lymphoid leukemia (ANLL) and 6 with acute lymphoid leukemia (ALL), were treated at relapse after bone marrow transplantation either autologous or allogeneic (AuBMT 8, ABMT 4) performed in complete remission (CR). The interval between BMT and relapse was less than 9 months in 6 patients (2 ABMT and 4 AuBMT) and more than 9 months in 7 patients. Early relapsed patients showed no response to treatment and died at a median of 5.5 months (range 1-13) after relapse. Late relapse after BMT was characterized by a high percentage of response (5 CR and 1 PR), particularly after intensive chemotherapy and by a longer survival (median 14 months; range 2-36). Chemotherapy after transplantation should be carefully evaluated in patients relapsed after BMT in order to select a population that can achieve long term disease free survival.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Female; Humans; Idarubicin; Italy; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Middle Aged; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Analysis; Treatment Outcome; Tretinoin; Vincristine

The effects of TPA (12-0-tetradecanoylphorbol-13-acetate) and RA (retinoic acid) were investigated on the cell lines HL60 (acute promyelocytic leukemia) and K562 (erythroleukemia) and on cells from patients with several kinds of leukemia. There were 14 cases of acute lymphocytic leukemia (ALL), 2 cases of chronic lymphocytic leukemia (CLL), 23 cases of acute myeloid leukemia (M1-M7), 5 cases of chronic myelocytic leukemia in blast crisis (CML-BC) and 2 mixed leukemias. In almost all of the cases examined, after TPA exposure cells from patients with proven myeloid leukemia became adherent to the substrate, while lymphoid leukemia cells remained in suspension, allowing the differentiation of lymphoid from myeloid blasts. The only exception was in one case of CLL, which had cells that became adherent with long filamental projections. In addition, increased phagocytosis following TPA exposure permitted characterization of M7 as this was the only myeloid leukemia negative for phagocytosis. Further discrimination between the subtypes of myeloid leukemia could be based on the increased lysozyme production seen after TPA in M4 and M5. Esterase positivity allowed the discrimination of M1 cells, which were negative before and after TPA treatment. In agreement with the results of other authors, TPA and RA led to independent ways of differentiation, granulocytic-like lineage and monocytic-like cells being favored by RA and TPA, respectively. The capacity of the same cell to differentiate into more than one lineage, depending on whether RA or TPA was used, was only seen in the present study with M3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cell Transformation, Neoplastic; Diagnosis, Differential; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetradecanoylphorbol Acetate; Tretinoin

The in vitro induced differentiation of a number of human leukemia cell lines by chemical inducers not only provides a valuable model system for the study on the mechanism of hematopoietic cell proliferation and differentiation at both cellular and molecular levels, but also reveals a new prospect in the treatment of leukemia. In order to find out the possibility of applying inducing agents to the patients with various types of leukemia, the bone marrow cells in primary culture from 50 patients with leukemia were tested for their inducibility in response to the inducers. Only M3 leukemia bone marrow cells can be markedly induced by retinoic acid to the myeloid terminal cells with positive NBT reduction while the cells of other types respond with uncertainty. TPA is able to cause a macrophage-like differentiation in bone marrow cells of all types of leukemia except M1. However, the leukemic cells of chronic myelogenous leukemia in lymphocytic blast crisis will lose response to TPA. The cultured bone marrow cells of acute lymphocytic leukemia respond neither to retinoic acid nor to TPA. Homoharringtonine, a chemotherapeutic drug used in the so-called HOAP regimen for acute nonlymphocytic leukemia, seems to possess the capability of inducing HL-60, the promyelocytic leukemia cell line, to NBT positive myeloid terminal cells, although the inducing effect is weaker than retinoic acid.

Topics: Adolescent; Adult; Aged; Bone Marrow; Child; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

Topics: Biological Transport; Cell Differentiation; Cytarabine; Deoxycytidine Kinase; Dipyridamole; Humans; Inosine; Leukemia, Promyelocytic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tetradecanoylphorbol Acetate; Thioinosine; Tretinoin; Tumor Cells, Cultured

HL-60 cells were incubated with [32P]-Pi in order to label endogenous phosphoproteins in situ. These were then resolved via two-dimensional electrophoresis and autoradiograms were made from the gels. A comparison of autoradiograms made from retinoic-acid-differentiated cells with those made from control cells revealed a small number of phosphoproteins whose labeling was enhanced in differentiated cells. Incubating HL-60 cells with [35S]-methionine revealed that RA induced the synthesis of one of these proteins, (53 kDa, pl 4.8) although not to a degree sufficient to account for the increased phosphate labeling observed in differentiated cells. Difluoromethylornithine (DFMO), which arrests HL-60 cell proliferation without inducing differentiation, had no effect on endogenous protein phosphorylation. Treatment of DFMO-arrested cells with retinoic acid, however, increased the phosphorylation of the proteins and resulted in differentiation of the cells. Densitometric analysis of autoradiograms made from two-dimensional gels revealed that the phosphorylation of the 53-kDa, pl 4.8 protein was significantly elevated in cells exposed to RA for as little as 12 hours, i.e., before the cells were committed to differentiate and before a significant increase in the number of phenotypically mature cells was observed. It therefore appears that this protein may be an intermediate in the retinoic-acid-induced differentiation process.

Topics: Cell Line; Humans; Isoelectric Point; Molecular Weight; Phosphoproteins; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteins; Tretinoin