tretinoin and Hematologic-Neoplasms

Despite enormous global investment, translational medical research faces considerable challenges and patients, and their doctors are frequently frustrated by the apparent lack of research activity or progress. Understanding the factors that prevent innovative research discoveries from making it to clinical trials is a multifaceted problem. However, one question that must be addressed is whether the nature of current research activity and the factors that influence the conduct of pre-clinical research, permit, or hamper the timely progression of laboratory-based observations to proof of concept (PoC) clinical trials. Inherent in this question is to what extent a deep mechanistic understanding of a potential new therapy is required before commencing PoC studies, and whether patients are better served when mechanistic and clinical studies progress side by side rather than in a more linear fashion. Here we address these questions by revisiting the historical development of hugely impactful and paradigm-changing innovations in the treatment of hematological cancers. First, we compare the history and route to clinical PoC, of two molecularly-targeted therapies that are BCR:ABL inhibitors in chronic myeloid leukaemia and all-trans retinoic acid (ATRA) in acute promyelocytic leukaemia (APL). We then discuss the history of arsenic trioxide as additional APL therapy, and the repurposing of thalidomide as effective multiple myeloma therapy. These stories have surprising elements of commonality that demand debate about the modern-day hard and soft governance of medical research and whether these processes appropriately align the priorities of advancing scientific knowledge and the need of patients.

Topics: Arsenic Trioxide; Arsenicals; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Oxides; Thalidomide; Translational Research, Biomedical; Tretinoin

The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche, where they endure chemotherapy, survive as minimal residual disease (MRD), and eventually prevail at relapse. Powerful morphogens, such as retinoids, Wnt/βcatenin, Notch, and Hedgehog, control stem cell fates across tissues, including normal and malignant hematopoiesis. The molecular conversations between these pathways and the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence suggesting that cytochrome P450 (CYP26), the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche, with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.

Topics: Antineoplastic Agents; beta Catenin; Cytochrome P450 Family 26; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplastic Stem Cells; Receptors, Notch; Signal Transduction; Stem Cell Niche; Tretinoin; Tumor Microenvironment

Topics: Annexin A2; Antineoplastic Agents; Asparaginase; Cytokines; Disseminated Intravascular Coagulation; Drug Interactions; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Thalidomide; Thrombomodulin; Tretinoin; Venous Thromboembolism

The same progress in the recent therapeutic strategy for older adults with hematological malignancies has also been seen in younger adults. The standard initial therapy for elderly acute promylocytic leukemia is the combination with all-trans retinoic acid and anthracyclines. For other acute myeloid leukemias (AML), many trials of combination chemotherapy have not improved the outcome of elderly patients. Gemtuzumab ozogamicin,which is an immunoconjugate binding to CD 33 on the surface of AML blasts, has produced good results for elderly patients in either monotherapy or in combination with conventional chemotherapeutic drugs. One of the BCR-ABL tyrosine kinase inhibitors, imatinib mesylate, is active for elderly Philadelphia-positive leukemia including acute lymphoblastic leukemia and chronic myeloid leukemia. In the treatment of elderly diffuse large B cell lymphoma, combination of rituximab and cyclophosphamide+doxorubicin+vincristine+prednisone (CHOP) has become the therapy of choice based upon a Groupe d'Etude des Lymphomes de l'Adulte (GELA) trial even though there are some other trials for elderly patients such as dose-dense CHOP therapy. For follicular lymphoma, combination therapies of rituximab and cytotoxic drugs such as R-CHOP and R-CVP are also considered as promising therapies. For the management of multiple myeloma, high-dose chemotherapy, mainly melphalan with autologous stem cell transplantation, has become the standard treatment even for elderly patients less than 65 years of age.

Topics: Aged; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Gemtuzumab; Hematologic Neoplasms; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Multiple Myeloma; Prednisone; Rituximab; Survival Rate; Tretinoin; Vincristine

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Benzamides; Clinical Trials as Topic; ErbB Receptors; Fusion Proteins, bcr-abl; Gefitinib; Hematologic Neoplasms; Humans; Imatinib Mesylate; Intracellular Signaling Peptides and Proteins; Neoplasms; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Quinazolines; Rituximab; Signal Transduction; Trastuzumab; Tretinoin

Topics: Antineoplastic Agents; Benzamides; Enzyme Inhibitors; Gene Targeting; Hematologic Neoplasms; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Tretinoin

Arsenic trioxide (As(2)O(3)) for leukaemia treatment was described a century ago. Recent resurgence in the use of arsenic trioxide is related to its high efficacy in acute promyelocytic leukaemia (APL). Most arsenic trioxide preparations are intravenous, although an oral formulation is similarly efficacious. Side effects of arsenic trioxide are usually minor, including skin reactions, gastrointestinal upset, and reversible increases in transaminases. During therapy, a leukocytosis occasionally occurs, which may be complicated by fluid accumulation and pulmonary infiltration. Arsenic trioxide causes an asymptomatic QT prolongation in most patients. However, if concomitant cardiopulmonary diseases or electrolyte disturbances are present, more sinister arrhythmias may develop. Therefore, before commencement of arsenic trioxide therapy, a full cardiac assessment and avoidance of drugs that prolong QT interval should be instituted. Arsenic trioxide is partly renally excreted and, therefore, dose adjustment is required when renal function is impaired. In addition to its use in APL, arsenic trioxide is now tested in other malignancies, notably multiple myeloma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Oxides; Remission Induction; Salvage Therapy; Tretinoin

Acute promyelocytic leukemia (APL), once considered the most devastating subtype of acute myeloid leukemia, is now the most treatable of all subtypes as a result of intensive research into its molecular pathogenesis. This research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid (ATRA) has proven to be effective first-line treatment for inducing complete remission. Arsenic trioxide (ATO) is currently used to treat relapsed disease, further enhancing survival rates in a patient population for which limited salvage options exist. This review discusses the molecular mechanisms responsible for development of APL and the evolution of treatment options over the last three decades, including the major advances using ATRA and ATO in the last 12 years. The mechanism of action of ATO is also described in view of this agent's potential for broader therapeutic application in a variety of hematologic malignancies.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Multiple Myeloma; Myelodysplastic Syndromes; Oxides; Recurrence; Remission Induction; Survival Analysis; Treatment Outcome; Tretinoin

Proteasomes are the main non lysosomal proteolytic structures of the cells. They correspond to the major system eliminating abnormal proteins, short half-life proteins and proteins controlling the cell cycle. They are essential for the production of peptides subsequently presented by the MHC-I. They are formed by a proteolytic core (the 20S proteasome) made of 4 rings of 7 proteic subunits associated with regulatory complexes (namely the 19S complex forming the 26S proteasome). Using classical cell biology techniques (cytometry, immunofluorescence microscopy, Western blot) our group has particularly studied the proteasome expression of leukaemic cell lines (U937 and CCRF-CEM) during in vitro differentiation induced by PMA and Vitamin D plus retinoïc acid. During differentiation, the level of proteasome expression and its localization vary. The various monoclonal antibodies used provided different patterns according to the different subunits. There was a general trend to a disappearance of nuclear proteasome and to a decrease in their cytoplasmic expression. In contrast, proteosomal antigens were increased on the cell membrane and in culture supernatants. We derived an ELISA test to measure plasma proteasome concentrations. Preliminary results showed differences between patients with haemopoietic malignancies or solid tumors and normal donors. Proteasome levels varied under treatment. They were correlated with LDH levels. Taken together, these results argue in favor of a role for cellular proteasomes in malignant differentiation process, and emphasize the qualitative changes in proteasome expression. Plasma proteasomes do not only reflect tumor cell mass and could play a role in addition to their proteolytic activity. They seem to be a relevant tool for diagnosis, prognosis and therapeutic monitoring.

Topics: Biomarkers, Tumor; Cell Differentiation; Cell Membrane; Cell Nucleus; Cell Transformation, Neoplastic; Cysteine Endopeptidases; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Hematologic Neoplasms; Humans; L-Lactate Dehydrogenase; Leukemia-Lymphoma, Adult T-Cell; Multienzyme Complexes; Neoplasm Proteins; Neoplasms; Proteasome Endopeptidase Complex; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured; U937 Cells; Vitamin D

The oral antitumor drugs against hematological malignancies are summarized. Sobuzoxane, a topoisomerase II inhibitor, is useful for the treatment of lymphoma, especially adult T cell leukemia/lymphoma. Sobuzoxane has an effect to protect against doxorubicin cardiotoxicity. Cytarabine ocfosfate, a derivative of cytosine arabinoside, is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL. The JALSG AML 92 study for APL with all-trans retinoic acid resulted in a 89% CR rate in 196 and 64% 4-year DFS in CR cases. Hydroxycarbamide is can control the WBC in CML. This agent is also effective for other myeloproliferative disorders, such as acute leukemia and MDS. Oral administration of 50 mg etoposide daily showed a good outcome in old patients with malignant lymphoma. For old patients and those with refractory hematological malignancies, oral administration of these agents can offer a new form of palliative therapy to allow them to remain at home while maintaining a high quality of life.

Topics: Administration, Oral; Antineoplastic Agents; Cytarabine; Etoposide; Hematologic Neoplasms; Humans; Hydroxyurea; Leukemia-Lymphoma, Adult T-Cell; Piperazines; Prodrugs; Tretinoin

Topics: Antineoplastic Agents; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Allografts; B-Lymphocytes; Chronic Disease; Female; Gene Expression Regulation, Neoplastic; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Interferon Regulatory Factors; Male; Middle Aged; Neoplasm Proteins; Receptor, Notch2; Receptors, Antigen, B-Cell; Signal Transduction; Tretinoin

A series of α-branched α,β-unsaturated ketones were prepared via boron trifluoride etherate mediated reaction between arylalkynes and carboxaldehydes. The evaluation of the antiproliferative activity over hematological (NB4) and solid cancer (A549, MCF-7) cell lines provided a structure-activity relationship. 5-Parameter QSAR equations were built which were able to explain 80%-92% of the variance in activity. The resulting selective lead compound showed IC50 value 0.6 μM against the hematological cell line and did not cause apoptosis, but blocked cell cycle in G0/G1. Moreover, it was demonstrated that this compound enhances and accelerates retinoic acid induced granulocytic differentiation.

Topics: Cell Line, Tumor; Cell Proliferation; Hematologic Neoplasms; Humans; Ketones; Neoplasms; Quantitative Structure-Activity Relationship

Retinoids triggers differentiation of acute promyelocytic leukemia (APL) blasts by transcriptional regulation of myeloid regulatory genes. Using a microarray approach, we have identified a novel retinoid-responsive gene (CXXC5) encoding a nuclear factor, retinoid-inducible nuclear factor (RINF), that contains a CXXC-type zinc-finger motif. RINF expression correlates with retinoid-induced differentiation of leukemic cells and with cytokine-induced myelopoiesis of normal CD34(+) progenitors. Furthermore, short hairpin RNA (shRNA) interference suggests for this gene a regulatory function in both normal and tumoral myelopoiesis. Interestingly, RINF localizes to 5q31.3, a small region often deleted in myeloid leukemia (acute myeloid leukemia [AML]/myelodysplasia [MDS]) and suspected to harbor one or several tumor suppressor gene.

Topics: Amino Acid Sequence; Carrier Proteins; DNA-Binding Proteins; Gene Expression Profiling; Gene Expression Regulation; Granulocyte Precursor Cells; Hematologic Neoplasms; HL-60 Cells; Humans; Intracellular Signaling Peptides and Proteins; K562 Cells; Models, Biological; Molecular Sequence Data; Myelopoiesis; Oligonucleotide Array Sequence Analysis; Sequence Homology, Amino Acid; Transcription Factors; Tretinoin; Tumor Cells, Cultured

Recent progress in molecular biology has led to an increase of prognostic markers and development of molecular-targeted therapy in pediatric malignancies. Previous treatment including stem cell transplantation showed a remarkable cure rate, however, some patients are resistant to such therapy. Recently, all-trans retinoic acid (ATRA) for acute promyeloblastic leukemia, imatinib for chronic myeloid leukemia, and rituximab for B-cell malignant lymphoma serve to improve the clinical outcome of these patients. Furthermore, molecular-targeted therapies including tyrosine kinase inhibitor, farnesyl transferase inhibitor, methylation inhibitor, and histone deacetyl enzyme inhibitor, were applied for clinical study. For pediatric malignancies, in addition to molecular-targeted therapy against leukemia, molecular-targeted therapies, mainly tyrosin kinase inhibitors, were applied to neuroblastoma and various types of sarcomas. Recent progress in prognostic molecular marker and molecular-targeted therapy against pediatric malignancies was here reviewed.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzamides; Biomarkers, Tumor; Child; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Hematologic Neoplasms; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Loss of Heterozygosity; Piperazines; Prognosis; Protein-Tyrosine Kinases; Pyrimidines; Quinolones; Rituximab; Tretinoin

The aim of this study was to evaluate the effect of all-trans retinoic acid (ATRA) on cell adhesion molecule expression and adhesion capacity of bone marrow stromal cells (BMSC) in patients after conditioning treatment for peripheral blood stem cell transplantation (PBSCT). BMSC of 27 patients before and after conditioning treatment for PBSCT were cultured in vitro. After treated with ATRA at 0.01, 0.1, or 1 micromol/L, expression of intercellular adhesion molecule-1 (ICAM-1) protein and vascular adhesion molecule-1 (VCAM-1) protein were detected by flow cytometry, and soluble ICAM-1 (sICAM-1) protein was determined by using radioimmunoassay. Then BMSC was co-cultured with CD34+ cells, and adhesion rate of BMSC to CD34+ cells was measured. The results showed that after pretreatment with conditioning regimen for PBSCT, the expressions of ICAM-1 and VCAM-1 proteins in BMSC and the expression level of sICAM-1 protein in supernatant of BMSC culture were down-regulated, and the adhesion rate of BMSC to CD34+ cells was decreased, after administration of ATRA, the expression of ICAM-1 protein in BMSC, sICAM-1 protein in culture medium and adhesion rate of BMSC to CD34+ cells all increased significantly, but expression of VCAM-1 protein changed no significantly. It is concluded that the ATRA can partly restore adhesion function of BMSC injured by pretreatment for PBSCT and contribute to hematopoietic reconstitution.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Agents; Bone Marrow Cells; Cell Adhesion; Cell Adhesion Molecules; Child; Coculture Techniques; Hematologic Neoplasms; Humans; Middle Aged; Peripheral Blood Stem Cell Transplantation; Stromal Cells; Tretinoin; Tumor Cells, Cultured; Vascular Cell Adhesion Molecule-1