tretinoin and Lymphoma

The beginning of this century was marked, in our specialty as in other, by two revolutions: the routine use of molecular biology tools for a better prognosis of the disease (flt3 receptor duplication in AML, mutational profile of Ig genes in CLL, gene expression profile with ARN chips in aggressive lymphomas.), and the discovery of "intelligent" molecules, targeting the tumoral cell. In this category, the most appealing is the STI571 (Gleevec , Novartis), targeting the molecular abnormality of the cells expressing bcr-abl protein: CML, ALL Ph1(+). Other molecules targeting signal transduction proteins (ras farnesylation inhibitors for example) are already in clinical trials. The increasing therapeutic use of monoclonal antibodies is also to be cited, with a special mention concerning the rituximab, used in several B lymphoid pathologies, from lymphoma to autoimmune diseases. His very good tolerance permits his use in ambulatory patients, and his combination with chemotherapy or his linkage with radioactive elements render this molecule indispensable. The other side of these molecules is their incredibly high cost, explaining the uncontrolled expenses in 2001 of hospitals hosting hematology as well as oncology activities.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Immunotoxins; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Lymphoma; Myelodysplastic Syndromes; Piperazines; Pyrimidines; Tretinoin

Treatment failure in drug sensitive malignancies is a complex phenomenon resulting from both drug resistance and from the rapid regrowth of malignant cells ('regrowth resistance'). Attempts to overcome regrowth resistance during the treatment of the aggressive lymphomas by increasing the frequency of cytotoxic therapy appears to have failed. An alternative approach of significant potential would be to administer biologically active agents to directly slow the regrowth of neoplastic cells between courses of full dose cytotoxic therapy. To facilitate this approach a new system for classifying treatment failure in the leukemias and lymphomas is needed so that the extent of regrowth resistance and the effects of treatment on regrowth resistance can be directly assessed. Accordingly, a new classification system is proposed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance; Genes, myc; Genes, p53; Humans; Interferons; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lymphoma; Treatment Failure; Tretinoin

Damage to the gastrointestinal tract during graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. In the current study, we identified a critical role for the retinoic acid (RA) signaling pathway in the induction and propagation of gastrointestinal GVHD. The administration of exogenous RA significantly increased expression of the gut-homing molecules, CCR9 and α4β7, on donor T cells in mesenteric lymph nodes, and augmented the accumulation of proinflammatory CD4(+) and CD8(+) T cells within the gut mucosa, leading to a selective exacerbation of colonic GVHD and increased overall mortality. Conversely, depletion of RA in recipient mice by vitamin A deprivation resulted in a dramatic reduction of gut-homing molecule expression on donor T cells after HSCT. Significantly, absence of the RA receptor-α on donor T cells markedly attenuated the ability of these cells to cause lethal GVHD. This observation was attributable to a significant reduction in pathological damage within the colon. These findings identify an organ-specific role for RA in GVHD and provide evidence that blockade of the RA signaling pathway may represent a novel strategy for mitigating the severity of colonic GVHD.

Topics: Animals; Bone Marrow Transplantation; Cells, Cultured; Colon; Gastrointestinal Diseases; Graft vs Host Disease; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Organ Specificity; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Severity of Illness Index; Signal Transduction; Tretinoin

The occurrence of acute promyelocytic leukemia (APL) in HIV-infected patients has been reported in only five cases. Due to a very small number of reported HIV/APL patients who have been treated with different therapies with the variable outcome, the prognosis of APL in the setting of the HIV-infection is unclear. Here, we report a case of an HIV-patient who developed APL and upon treatment entered a complete remission. A 25-years old male patient was diagnosed with HIV-infection in 1996, but remained untreated. In 2004, the patient was diagnosed with primary central nervous system lymphoma. We treated the patient with antiretroviral therapy and whole-brain irradiation, resulting in complete remission of the lymphoma. In 2006, prompted by a sudden neutropenia, we carried out a set of diagnostic procedures, revealing APL. Induction therapy consisted of standard treatment with all-trans-retinoic-acid (ATRA) and idarubicin. Subsequent cytological and molecular ana?lysis of bone marrow demonstrated complete hematological and molecular remission. Due to the poor general condition, consolidation treatment with ATRA was given in March and April 2007. The last follow-up 14 months later, showed sustained molecular APL remission. In conclusion, we demonstrated that a complete molecular APL remission in an HIV-patient was achieved by using reduced-intensity treatment.

Topics: Adult; Anti-Retroviral Agents; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Bisexuality; Brain; Brain Neoplasms; HIV Infections; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukemia, Radiation-Induced; Lymphoma; Male; Remission Induction; Tretinoin

Hematological malignancies such as leukemia or lymphoma are mainly treated by hospitalization or in outpatient clinics. Therefore, home care and home nursing are not so intensively done in the treatment of these malignancies. However, G-CSF administration against neutropenia after chemotherapy and administration of narcotics or opioids against severe pain have been performed sometimes during home care, and have been contributing to better QOL of the patients.

Topics: Analgesics, Opioid; Granulocyte Colony-Stimulating Factor; Home Care Services, Hospital-Based; Humans; Leukemia; Lymphoma; Multiple Myeloma; Myelodysplastic Syndromes; Neutropenia; Pain; Quality of Life; Tretinoin

Retinyl palmitate (RP) is frequently used as an ingredient in cosmetics and other retail products. We previously reported that, under UVA light irradiation, RP is facilely decomposed into multiple products, including anhydroretinol (AR) and 5,6-epoxyretinyl palmitate (5,6-epoxy-RP). We also determined that combined treatment of mouse lymphoma cells with RP and UVA irradiation produced a photomutagenic effect. In this study, we evaluated the photomutagenicity of AR and 5,6-epoxy-RP, in L5178Y/Tk+/- mouse lymphoma cells. Treatment of cells with AR or 5,6-epoxy-RP alone at 10 and 25 microg/mL for 4 h did not show a positive mutagenic response. However, because these doses did not induce the required amount of cytotoxicity for mouse lymphoma assay, we are unable to determine whether or not these two compounds are mutagenic. Treatment of cells with 1-25 microg/mL AR or 5,6-epoxy-RP under UVA light (315-400 nm) for 30 min (1.38 mW/cm2) produced a synergistic photomutagenic effect. At 10 microg/mL (37.3 microM) AR with UVA exposure, the mutant frequency (MF) was about 3-fold higher than that for UVA exposure alone, whereas the MF for 25microg/mL (46.3microM) of 5,6-epoxy-RP + UVA was approximately 2-fold higher than that for UVA exposure alone. Compared with previous results for RP + UVA treatment, the potency of the induced phototoxicity and photomutagenicity was AR > RP > 5,6-epoxy-RP. To elucidate the underlying photomutagenic mechanism, we examined the loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 for mutants induced by AR or 5,6-epoxy-RP. Most mutants lost the Tk+ allele, and more than 70% of the chromosome damage extended to 38 cM in chromosome length. AR + UVA induced about twice as many mutants that lost all four microsatellite markers from the chromosome 11 carrying the Tk+ allele as RP + UVA or 5,6-epoxy-RP + UVA. These results suggest that two of RP's photodecomposition products are photomutagenic in mouse lymphoma cells, causing events that affect a large segment of the chromosome.

Topics: Animals; Cell Line, Tumor; Loss of Heterozygosity; Lymphoma; Mice; Molecular Structure; Mutagenicity Tests; Mutagens; Palmitates; Photochemistry; Signal Transduction; Tretinoin; Ultraviolet Rays; Vitamin A

To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries.. The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients.. Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years.. tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Belgium; Breast Neoplasms; Child; DNA Topoisomerases, Type II; Female; France; Humans; Leukemia, Promyelocytic, Acute; Leukemia, Radiation-Induced; Lymphoma; Male; Middle Aged; Retrospective Studies; Spain; Treatment Outcome; Tretinoin

We have previously described a microarray of cluster of differentiation (CD) antibodies that enables concurrent determination of more than 60 CD antigens on leukocytes. This procedure does not require protein purification or labeling, or a secondary detection system. Whole cells are captured by a microarray of 10 nL antibody dots immobilized on a nitrocellulose film on a microscope slide. Distinct patterns of cell binding are observed for different leukemias or lymphomas. These haematological malignancies arise from precursor cells of T- or B-lymphocytic, or myeloid lineages of hematopoiesis. The dot patterns obtained from patients are distinct from those of peripheral blood leukocytes from normal subjects. This microarray technology has recently undergone a number of refinements. The microarray now contains more CD antibodies, and a scanner for imaging dot patterns and software for data analysis provide an extensive immunophenotype sufficient for diagnosis of common leukemias. The technology is being evaluated for diagnosis of leukemias with parallel use of conventional diagnostic criteria.

Topics: Antibodies; Antigens, Surface; Collodion; HL-60 Cells; Humans; Leukemia; Leukocytes; Lymphoma; Tretinoin

FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone; FR901228, depsipeptide] is a novel histone deacetylase inhibitor that shows therapeutic efficacy in Phase I trials of patients with malignant lymphoma. However, its mechanism of action has not been characterized. In this study, we examined the in vitro and in vivo effects of FK228 on human lymphoma U-937 cells. FK228 very strongly inhibited the growth of U-937 cells with an IC(50) value of 5.92 nM. In a scid mouse lymphoma model, mice treated with FK228 once or twice a week survived longer than control mice, with median survival times of 30.5 (0.56 mg/kg) and 33 days (0.32 mg/kg), respectively (vs. 20 days in control mice). Remarkably, 2 out of 12 mice treated with FK228 (0.56 mg/kg once or twice a week) survived past the observation period of 60 days. The apoptotic population of U-937 cells time-dependently increased to 37.7% after 48 hr of treatment with FK228. In addition, FK228 induced G1 and G2/M arrest and the differentiation of U-937 cells to the CD11b(+)/CD14(+) phenotype. Expression of p21(WAF1/Cip1) and gelsolin mRNA increased up to 654- and 152-fold, respectively, after 24hr of treatment with FK228. FK228 caused histone acetylation in p21(WAF1/Cip1) promoter regions, including the Sp1-binding sites. In conclusion, (i) FK228 prolonged the survival time of scid mice in a lymphoma model, and (ii) the beneficial effects of FK228 on human lymphoma may be exerted through the induction of apoptosis, cell cycle arrest, and differentiation via the modulation of gene expression by histone acetylation.

Topics: Acetylation; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle; Cell Differentiation; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Depsipeptides; Disease Models, Animal; Gelsolin; Histone Deacetylase Inhibitors; Histones; Humans; Leukemia; Lymphoma; Mice; Mice, SCID; Neoplasm Transplantation; Peptides, Cyclic; Promoter Regions, Genetic; RNA, Messenger; Tretinoin; U937 Cells; Xenograft Model Antitumor Assays

A 44-year-old female patient was admitted to our department with diagnosis of malignant lymphoma. The abdominal USG and CT showed multiple liver lesions with partial portal vein thrombosis, moderately increased alfa-fetoprotein (AFP), ASAT, ALAT (2x normal value), serology was negative for HBV and HCV. Liver transplantation was suggested but refused because of portal vein thrombosis. ATRA (45 mg/m2/day orally) was given on the basis of the assumption that HCC and acute promyelocytic leukaemia share similar oncogenic pathway (alter the RAR alpha and beta receptors). She was gained 15 kg-s and has resumed her work as a teacher for the last 20 months. Abdominal CT showed a complete regression of the intrahepatic tumour.

Topics: Adult; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Lymphoma; Tomography, X-Ray Computed; Tretinoin; Ultrasonography

Natural killer (NK) cells are well established as fundamental elements in the early eradication of aberrant cells potentially leading to neoplasia. Moreover, it has also long been known that inbred strains of laboratory mice, as well as human individuals, demonstrate a wide range of NK cell-mediated immune response even to the same tumor. In the present study, various parameters which could lead ultimately to high, or low, NK cell-mediated functional activity have been assessed. Mice of the A/J strain demonstrate very low NK cell tumor-lytic activity and correspondingly high incidence of lymphoma. By contrast, C57B1/6 mice demonstrate relatively high NK cell activity and virtually never develop lymphomas. The results of this study have revealed that the absolute numbers of splenic NK cells were significantly lower in A/J vs C57B16/mice. Furthermore, the blood of A/J mice contained significantly fewer (30%) NK cells than did that of C57B1/6 mice. However, no significant difference between the 2 strains was found in the numbers of lymphocytic cells from NK cell-enriched fractions from the spleens, which possessed either the homing receptor MEL-14, or the integrin Mac-I, both essential surface molecules for transendothelial migration of lymphocytic cells from the circulation into organ parenchyma. Moreover, NK cells from both strains responded similarly to the NK cell stimulants, ATRA, indomethacin and interleukin-2. Finally, there was no significant difference between the 2 strains, in the numbers of lymphocytic cells in the bone marrow (including NK cells), which were radiolabelled with the DNA synthetic precursor, 3H-thymidine, indicative, thus, of equivalent levels of lymphocyte production by the bone marrow in the 2 strains. The observations collectively suggest that the low peripheral (spleen, blood) levels of NK cell-mediated functional activity found in the A/J strain of mouse at least, reflects either post-production, large-scale NK cell abortion/death, or a bone marrow-based microenvironmental deficiency which inhibits NK cells' exit from the bone marrow birth site.

Topics: Animals; Bone Marrow Cells; Cytotoxicity, Immunologic; Indomethacin; Interleukin-2; Killer Cells, Natural; L-Selectin; Lymphocyte Count; Lymphoma; Macrophage-1 Antigen; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Species Specificity; Spleen; Tretinoin; Tumor Cells, Cultured

Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid-induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-alpha, -beta, and -gamma or retinoid X receptor (RXR)-alpha into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-alpha is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-alpha with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-alpha lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-alpha. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-alpha retinoid receptors.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Animals; Antigens, CD; Antigens, Differentiation; Benzoates; Chromans; DNA, Antisense; DNA, Complementary; Female; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Lymphoma; Male; Membrane Glycoproteins; Mice; Mice, Inbred Strains; Mice, Transgenic; N-Glycosyl Hydrolases; Neoplasm Proteins; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Signal Transduction; Transcription Factors; Tretinoin

Annexin VIII is a calcium- and phospholipid-binding protein with anticoagulant activity. Annexin VIII mRNA was found to be specifically expressed in acute promyelocytic leukemia (APL) cells; it was not found in other types of acute myeloid leukemia (AML) nor in lymphoid malignancies. Using Northern blot analysis we investigated annexin VIII expression in 142 continuous human leukemia and lymphoma cell lines at the mRNA level. While the only APL cell line, NB-4, was indeed positive, other cell lines also displayed annexin VIII mRNA: 4/22 myeloid cell lines, 8/23 monocytic cell lines, 2/8 megakaryoblastic cell lines, 5/26 lymphoma-derived cell lines, 2/10 myeloma cell lines and 1/44 lymphoid leukemia cell lines. The strongest expression was seen in NB-4 and in the Hodgkin's disease derived cell line HDLM-2. Treatment of NB-4 cells with all-trans retinoic acid (ATRA) or the phorbol ester TPA induced terminal differentiation and down-regulated annexin VIII mRNA expression rapidly within a few hours; vitamin D3 was ineffective in this regard; the protein kinase C activator Bryostatin 1 up-regulated the expression. A panel of initially negative cell lines could not be induced by any of these biomodulators to transcribe annexin VIII. The half-life (T1/2) of annexin VIII mRNA was about 3-4 h using actinomycin D as transcription inhibitor. Treatment with ATRA or TPA prior to exposure to actinomycin shortened the T1/2 to 2 h while Bryostatin 1 extended it to 6h. As 21/141 non-APL cell lines were positive, annexin VIII cannot be used as a marker gene for APL cells; however, it might be associated with myelomonocytic or erythro-megakaryoblastic precursor cells. Annexin VIII gene expression might play a unique role in the proliferation and/or differentiation of leukemic cells and could be associated with the particular abnormal hemostasis of some leukemias.

Topics: Annexins; Blotting, Northern; Bryostatins; Cell Differentiation; Cholecalciferol; Dactinomycin; Gene Expression Regulation, Neoplastic; Half-Life; Humans; Lactones; Leukemia; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Lymphoma; Macrolides; RNA, Messenger; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

Topics: Brain Neoplasms; Child; Clinical Trials as Topic; Humans; Lymphoma; Neoplasms; Tretinoin

The neoplastic Hodgkin's Reed-Sternberg (H-RS) cells in Hodgkin's disease are surrounded in vivo by abundant reactive cells, the function of which may be attributed in part to their elaboration of various cytokines. Thus, a study of the interaction of H-RS cells with exogenous cytokines may provide information as to the mechanism of the clinical and histopathologic changes observed in Hodgkin's disease. This study examined the effect of various cytokines, and of phorbol ester (TPA) and retinoic acid, on the differentiation and proliferation of cultured H-RS cells (cell lines HDLM-1 and KM-H2). In addition, it was determined whether these cells were able to secrete cytokines after being treated with exogenous cytokines. The cytokines used included various types of interleukins (1, 2, and 3), colony-stimulating factors (GM, G, and M), interferons (alpha, beta, and gamma), and tumor necrosis factor (alpha). It was found that these cytokines, used alone or in combination, were not effective in modulating the proliferation and differentiation of cells, or the production of cytokines, in cultured H-RS cells. In contrast, this study revealed that retinoic acid can potentiate TPA-induced growth inhibition in cultured H-RS cells. Retinoic acid, when used alone, exhibited a minimal effect on cell differentiation. No synergistic effects of cytokines and retinoic acid on H-RS cells were observed. The failure of cultured H-RS cells to respond to exogenous cytokines suggests that, during the course of neoplastic transformation, of progression of disease, or of establishment of the cells in culture, H-RS cells lose their dependence on cytokines, although they retain the capacity to produce various cytokines.

Topics: Aged; Biological Factors; Cell Line; Cell Transformation, Neoplastic; Colony-Stimulating Factors; Cytokines; Hodgkin Disease; Humans; Interferons; Interleukins; Lymphoma; Male; Phorbol Esters; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Necrosis Factor-alpha

Two lymphokines that contribute to induction of cell differentiation in promyelocytic HL-60 leukemia cells by human T-cell lymphoma HUT-102 cells were identified previously. The lymphokines identified in the differentiation-inducing preparation were interferon-gamma (IFN-gamma) and lymphotoxin. To determine the remaining component(s) of this differentiation-inducing activity, we used gene-cloned (recombinant) forms and antibodies of lymphokines. The differentiation-inducing activity of the HUT-102 cells was not completely neutralized by the antibodies, suggesting that an additional lymphokine(s) is involved. Granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with retinoic acid induced differentiation of the HL-60 cells in a dose-dependent manner. Furthermore, the activity of the differentiation-inducing factors was partially inhibited by anti-GM-CSF antibody and completely inhibited by the combination of antibodies to lymphotoxin, IFN-gamma, and GM-CSF. These results indicate that, in addition to IFN-gamma and lymphotoxin, GM-CSF is the third major component released by HUT-102 cells for inducing differentiation of HL-60 cells.

Topics: Cell Differentiation; Chromatography, Ion Exchange; Colony-Stimulating Factors; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Interferon-gamma; Interleukin-1; Leukemia, Promyelocytic, Acute; Lymphoma; Lymphotoxin-alpha; Neutralization Tests; Recombinant Proteins; T-Lymphocytes; Tretinoin; Tumor Cells, Cultured

Topics: Animals; Female; Lymphoma; Mice; Mice, Inbred DBA; T-Lymphocytes, Cytotoxic; Tretinoin; Tumor Cells, Cultured

Sixteen patients - 12 with cutaneous T cell lymphoma (CTCL), 1 with Sézary syndrome, 1 with actinic reticuloid, and 2 with parapsoriasis variegata - were treated with either a new, potent arotinoid alone or with combined etretinate (Tigason) and PUVA therapy (Re-PUVA). 92% of all patients showed a minor up to a distinct response of their skin lesions within 12.6 +/- 7.4 weeks. More than 50% of the skin lesions cleared in 67% of the patients. After discontinuation of the retinoid therapy, relapses occurred in all cases within 3-10 weeks. There was no difference between the therapeutic efficacy of arotinoid alone and the Re-PUVA regimen, but the latter was less toxic.

Topics: Antineoplastic Agents; Benzoates; Combined Modality Therapy; Humans; Isotretinoin; Lymphoma; PUVA Therapy; Retinoids; Skin Neoplasms; T-Lymphocytes; Tretinoin

Retinoic acid (RA) is teratogenic in rodent embryos. Several teratogens have been shown to induce the synthesis of a subset of heat shock proteins (stress proteins) in Drosophila. To determine if RA induces the synthesis of these proteins in rodent embryos, pregnant ICR mice were dosed with 100 mg/kg RA on Day 11 of gestation. Forelimb buds were removed from embryos 2.5 hr post-RA-treatment and nuclei were isolated, stained, and sorted from stages of the cell cycle. Nuclear proteins were extracted and analyzed by two-dimensional polyacrylamide gel electrophoresis. Nuclear proteins with molecular weights of approximately 84 and 25 kDa were synthesized in embryos in the G0 + G1 phase after pregnant dams were treated with RA. Isoelectric points, molecular weights, immunochemical blotting, and polypeptide mapping demonstrated that these proteins are indistinguishable from stress proteins isolated under a variety of conditions from rat submaxillary glands and mouse lymphoma cells. These results suggest that treatment with RA induces the synthesis of a subset of stress proteins; the role of these proteins in the teratogenic effects of RA is not known.

Topics: Animals; Autoradiography; Cell Cycle; Cell Nucleus; Electrophoresis, Polyacrylamide Gel; Forelimb; Heat-Shock Proteins; Isoelectric Focusing; Lymphoma; Mice; Mice, Inbred ICR; Molecular Weight; Rats; Submandibular Gland; Tretinoin

The aim of the study was to analyze the incidence of spontaneous thymic lymphomas in AKR mice kept on a diet with normal and excess retinoid content. The mice whose diet was supplemented with 13-cis-retinoic acid (250 mg per kg chow) developed less lymphomas than those kept on a standard diet (15 mg per kg chow). The effect of cyclophosphamide on the early stage of lymphomogenesis was tested using a single dose (100 mg per kg body weight), injected intraperitoneally to AKR mice. Increased incidence of lymphoma following cyclophosphamide administration was observed as result of a) low sensitivity of prelymphoma and lymphoma cells and/or b) immunosuppressive effect of cyclophosphamide.

Topics: Animals; Cocarcinogenesis; Cyclophosphamide; Diet; Female; Injections, Intraperitoneal; Isotretinoin; Lymphoma; Male; Mice; Thymus Neoplasms; Tretinoin

Untreated and retinoic acid (RA) treated human leukemia-lymphoma cell lines reflecting hematopoietic cells at various stages of differentiation, were examined electron microscopically for their surface negative charge distribution using cationized ferritin (CF), an electron dense label of anionic sites. The results indicate that there is a correlation between the CF labeling density/distribution and the stage of lymphoid cell differentiation. Viable unfixed null cell lines show a low CF labeling density with few and small CF patches. A gradual increase in CF labeling density and increase in size and number of CF patches correlates with the stage of differentiation on cell lines of both T or B origin. Treatment of viable unfixed cells with 10(-5) MRA for 10 days seems to prevent the CF-induced formation of CF patches, resulting in a continuous and even distribution of the CF label, similar to that observed on the surface of cells fixed before CF labeling. Some correlation between the distribution of surface anionic sites and the malignant potential of the human leukemic lines could be detected.

Topics: Anions; Cell Differentiation; Cell Line; Ferritins; Humans; Leukemia; Lymphocytes; Lymphoma; Surface Properties; Tretinoin

1 alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] and retinoic acid (RA) induce a high-phagocytic phenotype in the macrophage-like tumor cell line P388D1. A concurrent cultivation of P388D1 cells in the presence of suboptimal concentrations of both agents led to an extent of induction of phagocytic activity that surpassed the additive effect of either of the agents alone; i.e., 1,25(OH)2D3 and RA synergistically induce the phagocytic capability of P388D1 cells. Dexamethasone and 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (TPA) did not induce a high-phagocytic phenotype in P388D1 cells and affected differentially the high-phagocytic phenotype induced by RA and 1,25(OH)2D3. Dexamethasone inhibited the phagocytic activity induced by RA (80% at 24 h), while it had small suppressive effects on that induced by 1,25(OH)2D3. TPA suppressed the phagocytic activity induced by RA (60% within 96 h) while potentiating the expression of the high-phagocytic phenotype induced by 1,25(OH)2D3 (50% increase with 96 h). The observed effects did not involve modulation of prostaglandin synthesis or intracellular cyclic adenosine 3':5'-monophosphate. Expression of transglutaminase activity in P388D1 cells was also modulated differentially by the four agents; 1,25(OH)2D3 treatment had no effect on enzyme level, RA and TPA suppressed it, and dexamethasone increased it. The data suggest that: 1,25(OH)2D3 and RA act via disparate mechanisms that can operate simultaneously; the elements induced in P388D1 cells by 1,25(OH)2D3 and RA, and which are responsible for the phagocytic activity, differ in their sensitivity to dexamethasone and TPA; and transglutaminase activity in P388D1 cells is readily manipulable, but there seems to be no straightforward correlation between the level of its activity and the phagocytic capability of the cells or their rate of proliferation.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Acyltransferases; Animals; Calcitriol; Cell Differentiation; Cell Line; Dexamethasone; Drug Synergism; Lymphoma; Mice; Phagocytosis; Phenotype; Phorbols; Prostaglandins; Tetradecanoylphorbol Acetate; Transglutaminases; Tretinoin

Both human beta-interferon (IFN-beta) and retinoic acid (RA) are able to induce the differentiation of the human histiocytic lymphoma cell line U937, but neither one alone can effectively eliminate the leukemic cells. When U937 cells are incubated with a combination of IFN-beta (200 units/ml) and RA (0.1-1.0 microM), extensive cell death can be observed as early as day 3 posttreatment, and IFN-beta alone at a concentration as high as 10(4) units/ml is ineffective. These data suggest that there is a strong synergistic cell killing effect between IFN-beta and RA against the U937 cells. This effect is so highly selective that similar enhancement has not been detected using a closely related cell line, HL-60, and RA enhances neither IFN-alpha nor IFN-gamma in the killing of U937 cells. The mechanism of such synergism is unknown in the present study, but it appears that cytostasis or promotion of differentiation alone cannot account for this phenomenon since neither activity is enhanced to any appreciable extent.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Cell Line; Cell Survival; Drug Synergism; Humans; Interferon Type I; Leukemia, Myeloid, Acute; Lymphoma; Tretinoin

The aim of the study was to analyze the incidence of X-ray induced lymphomas in C57B1/10W mice kept on diet with varying retinoid content. The mice whose diet was supplemented with 13-cis retinoic acid (300 mg per kg of chow) developed less lymphomas than those kept on Vitamin A deficient diet as well as on a standard diet (15 mg per kg of chow). Mice subjected to Vitamin A deficient diet displayed a shortening of the latency period.

Topics: Administration, Oral; Animals; Female; Isotretinoin; Leukemia, Radiation-Induced; Lymphoma; Mice; Mice, Inbred Strains; Thymus Neoplasms; Tretinoin

Topics: Humans; Isotretinoin; Lymphoma; Skin Neoplasms; T-Lymphocytes; Tretinoin

Three human myeloid leukemic cell lines (HL60, KG1, and ML3) and one histiocytic lymphoma line (U937) were induced to differentiate terminally to mature myelomonocytic cells with either 12-O-tetradecanoylphorbol-13-acetate (TPA) or lymphocyte-conditioned medium (LCM), which is known to contain differentiation-inducing factors. HL60 cells were also forced to differentiate along the myeloid series with retinoic acid (RA) or dimethyl sulfoxide (DMSO). The striking morphologic changes and the expression of differentiated markers on the induced cells (whether macrophage- or granulocyte-like) were always associated with an acquired or dramatically increased ability to stimulate proliferation and natural killer cell (NK) activity in human lymphocytes. Like HL60 cells after granulocytic differentiation, granulocytes freshly separated from the peripheral blood of healthy donors were also strong inducers of mixed lymphocyte reaction (MLR) responses. Analysis of the expression of HLA-DR antigens on the surface of undifferentiated and mature cells with two monoclonal antibodies directed against HLA-DR monomorphic determinants, indicated that 1) upon differentiation induced with RA, DMSO, and TPA the cells never acquired surface DR antigens, and 2) normal peripheral blood granulocytes lacked these antigens. In contrast, treatment with LCM always resulted in the expression of high levels of DR antigens on the differentiated macrophage-like cells. Taken together, these findings indicate that all mature myelomonocytic cells, either freshly separated from peripheral blood or obtained after forced in vitro differentiation of leukemic cells, express MLR stimulatory antigens that appear to be unrelated to DR determinants. The possibilities discussed are that such antigens are associated with other molecules encoded by the D region or with new surface structures unrelated to Ia but dependent on the stage of differentiation.

Topics: Cell Differentiation; Cell Division; Cell Line; Dimethyl Sulfoxide; Granulocytes; Histiocytoma, Benign Fibrous; Histocompatibility Antigens Class II; HLA-DR Antigens; Humans; Killer Cells, Natural; Leukemia, Myeloid; Lymphoma; Tetradecanoylphorbol Acetate; Tretinoin

Twelve patients with various types of lymphoma were treated with etretinate. The diagnosis included parapsoriasis en plaque, epidermotropic lymphoma (diffuse chronic erythroderma with atypical mononuclear cells, Sézary syndrome or MF tumours) and non-epidermotropic lymphoma. The patients received etretinate in a dose of 0.8 to 1.0 mg/kg/day for 2 to 14 months. No additional therapy was given. Patients with epidermotropic lymphomas stage I and II had a favourable clinical and histological response whereas those with deeply infiltrating tumours remained unresponsive. Patients with parapsoriasis en plaque and poikiloderma showed little response. Of the four patients who discontinued the treatment, three had recurrences after 3 to 4 months but one remained clear. The results obtained with etretinate may equal those obtained with more aggressive treatments.

Topics: Aged; Etretinate; Female; Humans; Lymphoma; Male; Middle Aged; Parapsoriasis; Skin Neoplasms; Tretinoin

A 77-year-old woman developed a diffuse nodular eruption with histologic, ultrastructural, and biologic evidence of cutaneous T-cell lymphoma (CTCL) limited to the skin. She was treated with a new aromatic retinoid Ro 10-9359 (1 mg/kg/day). After 34 days, the lesions flattened completely and the mononuclear cell infiltrate decreased significantly. No clinical recurrences occurred after a 4-month survey. Discontinuation of the aromatic retinoid led to a relapse with identical clinical and histologic features.

Topics: Aged; Etretinate; Female; Humans; Lymphoma; Skin Neoplasms; T-Lymphocytes; Tretinoin

12-O-tetradecanoyl-phorbol-13-acetate (TPA), a potent tumour promoter, was tested for its effects on the proliferation of the human Burkitt lymphoma cell line, Namalwa, and the synthesis of interferon by these cells. At nanomolar concentrations, TPA blocked thymidine incorporation into cellular DNA by more than 90% within 24 h. TPA-treated cells produced about 20-fold more interferon in response to Sendai virus than did untreated controls and simultaneous treatment with TPA and sodium n-butyrate gave a further two- to three-fold enhancement. Neither of these effects of TPA was reversed on removal of the compound; furthermore, exposure of Namalwa cells to TPA for only 1 h was sufficient for full activity. 4-O-methyl-TPA, a compound only marginally active as a tumour promoter, showed effects similar to TPA, but only at concentrations 300-fold higher. In contrast to its effects on Namalwa cells, TPA did not affect synthesis of interferon in response to Sendai virus in two other Burkitt lymphoma lines (Raji and Daudi) nor in the Epstein-Barr virus (EBV)-negative lymphoma line, BJAB; it inhibited interferon production in the human myeloid cell line, HL-60.

Topics: Burkitt Lymphoma; Butyrates; Cell Line; DNA; Humans; Interferons; Lymphoma; Melitten; Parainfluenza Virus 1, Human; Phorbols; Tetradecanoylphorbol Acetate; Tretinoin