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T R Breitman

Publications and source records attributed to T R Breitman.

At least 55 records · Page 3Linked to original sources
PubMed1986

Arabinofuranosyl-5-azacytosine: antitumor and cytotoxic properties.

Arabinofuranosyl-5-azacytosine (ara-AC), a nucleoside combining the structural elements of 5-azacytidine and arabinofuranosylcytosine, exhibited unusually wide therapeutic activity against several murine leukemias and all three human xenografts of the National Cancer Institute tumor panel. Activity was observed following either a daily or an intermittent regimen of treatment in the i.p. L1210 model. However, when multiple doses were administered on each treatment day, a greater therapeutic effect was produced and the total dose was reduced. Extensive necrosis was observed by light and electron microscopy in P388 tumors treated with ara-AC. Following s.c. administration, ara-AC caused regression of the mammary and lung xenografts (MX-1 and LX-1) and a 93% inhibition of the human colon tumor (CX-1); other analogues of this drug failed to demonstrate a comparably broad spectrum of activity. Morphological assessment of treated xenografts revealed a general loss of cell-to-cell contact and abundant necrosis 24 h after the administration of ara-AC. In culture, the 50% inhibitory concentrations of ara-AC for P388 and L1210 cells at 24 h were 1.9 and 4.5 microM, respectively, and the decline in replication rates was dependent on drug concentration. The cytocidal nature of the drug was demonstrated by cloning experiments in which it was observed that ara-AC abolished the clonogenicity of lymphoblasts but was only minimally cytotoxic to normal murine bone marrow progenitor cells. As adjudged by flow cytometry, the drug induced a distinct slowing of cell cycle traverse through S phase. Induction of the differentiation of HL-60 cells in culture was another cytotropic effect of this drug. At 44% differentiation (10 microM ara-AC), 50% of the cultured cells were viable. Its broad spectrum antitumor activity, its selective toxicity to tumor cells, and its ability to produce cytodifferentiation render ara-AC of interest as a potential antineoplastic agent in humans.

Animals↗
PubMed1986

A combination of a T cell-derived lymphokine differentiation-inducing activity and a physiologic concentration of retinoic acid induces HL-60 to differentiate to cells with functional chemotactic peptide receptors.

The human acute promyelocytic leukemia cell line HL-60 is induced by retinoic acid (RA) and N,N-dimethylformamide (DMF) to differentiate into cells having many of the functional and morphologic characteristics of mature granulocytes. With normal human phagocytic cells there is both superoxide anion (O2-) production and chemotaxis in response to chemoattractants such as N-formyl-methionyl-leucyl-phenylalanine (FMLP). We have now found that although HL-60 cells induced with RA alone produce O2- in response to 12-0-tetradecanoyl-phorbol-13-acetate (TPA) they are deficient in FMLP-stimulated O2- production and chemotaxis. In contrast, HL-60 induced either with DMF or with a combination of 10 nmol/L RA and a T cell-derived lymphokine, differentiation-inducing activity (DIA), produce O2- and exhibit chemotaxis in response to FMLP. The basis for these results appears to be the concentration of cell surface chemotactic peptide receptors. Thus, untreated HL-60 and HL-60 induced with either RA alone or DIA alone do not have measurable levels of FMLP receptors, whereas HL-60 induced with a combination of RA and DIA has 5,400 receptors per cell. HL-60 induced with RA and DIA plus 1 mumol/L dexamethasone have 25,000 receptors per cell and have greater chemotactic activity than HL-60 induced with the combination of RA and DIA. Thus, differentiation of HL-60 to cells with many properties of normal phagocytes can be induced in vitro by physiologic substances.

Cell Adhesion↗
PubMed1985

Induction of functional differentiation of a human monocytic leukemia cell line (THP-1) by retinoic acid and cholera toxin.

The human monocytic leukemia cell line, THP-1, is induced to differentiate into more functionally mature monocyte (macrophage)-like cells by incubation with retinoic acid at concentrations of 10nM or higher. There is no apparent morphological change accompanying this functional maturation. These induced cells show increases in nitroblue tetrazolium reduction, immunoerythrophagocytosis, hexose monophosphate shunt activity, and 5'-nucleotidase and NAD+-glycohydrolase activities. Prostaglandin E2, dibutyryl cyclic adenosine 3':5'-monophosphate, or T-lymphocyte-derived differentiation-inducing activity, all inactive or less active alone, increase the extent of differentiation of THP-1 in combination with 10nM retinoic acid. THP-1 is also induced to differentiate by 0.1nM or higher concentrations of cholera toxin. Furthermore, 24,24-difluoro-1 alpha,25-dihydroxyvitamin D3 induces less differentiation of THP-1 compared to retinoic acid. Dimethyl sulfoxide and 12-O-tetradecanoylphorbol-13-acetate show no induction of functional differentiation. THP-1 thus joins the list of leukemic myelomonocytic cell lines (e.g., the promyelocytic HL-60 and the monoblast-like U-937) that are blocked at a relatively late stage of maturation and which differentiate in response to retinoic acid.

5'-Nucleotidase↗
PubMed1984

Isolation and characterization of a T lymphocyte-derived differentiation inducing factor for the myeloid leukemic cell line HL-60.

Mitogen-stimulated mononuclear blood cells produce differentiation inducing factors (DIFs) for the promyelocytic cell line HL-60. We report that DIF is produced constitutively by a malignant T lymphocyte line HUT-102. DIF was purified 7,000-fold from HUT-102 conditioned media by utilizing ion-exchange chromatography with DEAE-Sepharose, gel chromatography, Blue-Sepharose chromatography, and preparative SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The final preparation is susceptible to protease treatment, has a molecular weight of 46,000, as determined by SDS-PAGE and approximately 55,000 by gel filtration, has an isoelectric point of approximately 5.2, does not adhere to lectin-Sepharose and is resistant to periodate oxidation, and is free of colony-stimulating factor. DIF induced maturation of HL-60 into phagocytizing nitro blue tetrazolium reducing cells with the morphological characteristics of myelomonocytic or monocyte-like cells. An activity, co-chromatographing with DIF, acts synergistically with retinoic acid to induce maturation not only of HL-60, but also of the monoblast-like cell line U-937 (measured as percentage of cells reducing NBT).

Cell Line↗
PubMed1983

Structure-activity relationships of a new series of retinoidal benzoic acid derivatives as measured by induction of differentiation of murine F9 teratocarcinoma cells and human HL-60 promyelocytic leukemia cells.

A new group of retinoids, which are 3-alkyl and 3-alkoxy derivatives of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]-benzoic acid (TTNPB), has been synthesized. They were tested in vitro for biological activity by measuring induction of terminal differentiation in both murine F9 teratocarcinoma cells and human HL-60 promyelocytic leukemia cells. In the F9 assay, TTNPB was significantly more active (dose effective in achieving a half-maximal response, 3 X 10(-9) M) than was all-trans-retinoic acid, while the 3-methyl derivative of TTNPB was not. However, in the HL-60 assay, the 3-methyl derivative of TTNPB was more active (dose effective in achieving a half-maximal response, 2 X 10(-8) M) than was all-trans-retinoic acid, while TTNPB was less active. 3-Ethyl and 3-propyl derivatives were much less active than was all-trans-retinoic acid in both assays. These new retinoids should be useful agents for experimental studies of both cancer prevention and treatment, as well as for investigation of the mechanism of action of retinoids in the control of cell differentiation.

Animals↗
PubMed1982

Agents with potential specificity against melanotic melanoma.

Agents were designed to exploit the high tyrosinase activity in melanotic melanoma relative to normal tissues. If specific tyrosinase activation of these agents occurred, the production of toxic metabolites in the melanoma cells would produce selective cell kill. Synthesis and antitumor activities of three new amino acids, 1a [beta-[(p-hydroxyphenyl)amino]alanine hydrochloride], 1b [N delta-(p-hydroxyphenyl)ornithine hydrochloride], and 1c [N delta-(m-hydroxyphenyl)ornithine dihydrochloride], were described. Compounds 1a and 1b were approximately 2-fold more active against the B-16 melanotic melanoma than the amelanotic melanoma cell line in vitro. Compound 1b was approximately 2-fold more potent than compound 1a against either cll line and was 8-fold more potent than L-glutamic acid gamma-(4-hydroxyanilide), a natural product isolated from mushroom. No significant growth inhibitory activity was found for the m-hydroxy analogue 1c at 100 micrometers, the highest concentration tested. Similarly, compound 1b exhibited better activity against P-388 (ED50 = 9.5 x 10(-6) M) than 1a (ED50 = 3.2 x 10(-5) M) and was about 30-fold more potent than 1c. Against human epidermoid carcinoma of the nasopharynx (KB), these agents showed modest inhibitory activity with ED50 values in the range of 1.2 to 3 x 10(-4) M. No in vivo activity against P-388 and B-16 at doses up to 150-200 mg/kg was observed. The biological results suggest that a nonspecific oxidation rather than a specific tyrosinase activation is involved in the biological action of these new compounds.

Animals↗
PubMed1982

Induction of differentiation of the human histiocytic lymphoma cell line U-937 by retinoic acid and cyclic adenosine 3':5'-monophosphate-inducing agents.

The monoblast-like human histiocytic lymphoma cell line, U-937, is induced to differentiate into monocyte-like cells by incubation with 0.1 to 1.0 microM retinoic acid (RA). These induced cells are phagocytic, reduce nitroblue tetrazolium, and show an increased hexose monophosphate shunt activity, consistent with monocyte-like cells. Prostaglandin E, cholera toxin, or dibutyryl cyclic adenosine 3':5'-monophosphate, all inactive alone, increased markedly the extent of RA-induced differentiation of U-937. These data suggest that the intracellular level of cyclic adenosine 3':5'-monophosphate is of importance for expression of the RA-induced effect. Responsiveness to RA seems to be limited to those leukemic myeloid cells blocked at a relatively late stage of maturation, like the promyelocytic HL-60 and the monoblast-like U-937 cell lines.

Bucladesine↗
PubMed1982

Priming of human myeloid leukemic cell lines HL-60 and U-937 with retinoic acid for differentiation effects of cyclic adenosine 3':5'-monophosphate-inducing agents and a T-lymphocyte-derived differentiation factor.

The human cell lines HL-60 (acute promyelocytic leukemia) and U-937 (histiocytic monoblast-like lymphoma) differentiate to functionally mature cells by incubation with retinoic acid (RA). This differentiation is potentiated by agents known to increase intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels. The present study shows that these cells can be primed for differentiation by treatment for approximately one day with RA followed by exposure to a cAMP-inducing agent. The reverse sequence was ineffective. Thus, HL-60 could be primed by incubation for less than 20 hr with 10 nM RA to respond by differentiation to the addition of 10 nM prostaglandin E2 or 1 nM cholera toxin, whereas 10 nM RA alone was almost inactive. RA-primed HL-60 also responded with differentiation to a concentration of T-lymphocyte-derived differentiation-inducing factor which alone was inactive. U-937 primed by incubation for 24 hr with 100 nM RA responded to cAMP-inducing agents and differentiation-inducing factor, which alone were inactive on this cell line. Priming of these cell lines does not depend on the normal rate of protein synthesis, as it occurs even better in the presence of a concentration of cycloheximide that inhibits growth completely, suggesting that a decrease in synthesis of some protein(s) favors RA-induced differentiation. Cycloheximide alone produced some priming of HL-60 but not of U-937. HL-60, but not U-937, primed with RA responded to adenosine triphosphate and other nucleoside triphosphates, consistent with the notion that modulation of the RA effect may be mediated through protein kinase activity at the plasma membrane. The finding that myeloid cell lines, like HL-60 and U-937, blocked at a late stage of maturation can be primed by RA to respond to cAMP-inducing agents and differentiation-inducing factor may improve our understanding of the arrest in maturation typical of some forms of leukemia.

Cell Differentiation↗
PubMed1982

Terminal differentiation of the human promyelocytic leukemia cell line, HL-60, in the absence of cell proliferation.

Induction of differentiation of the human promyelocytic leukemia cell line, HL-60, by dimethyl sulfoxide was analyzed for a requirement for cell replication. The ability of HL-60 cells to undergo terminal granulocytic differentiation as judged by nitroblue tetrazolium reduction, phagocytosis, and morphological criteria was not impaired by a total block in cellular proliferation. Retinoic acid, actinomycin D, and butyric acid also induced differentiation of HL-60 cells in the absence of cell growth. These results and the earlier demonstration that phorbol ester-induced macrophage differentiation of HL-60 occurred independently of DNA synthesis indicate that in these leukemic cells there is a dissociation of proliferation and maturation. The ability of retinoic acid to enhance differentiation of HL-60 cells was not altered in the presence of various growth-inhibiting concentrations of two clinically useful chemotherapeutic agents: hydroxyurea and 1-beta-D-arabinofuranosylcytosine. These results suggest that combination therapy in a program aimed at both inhibiting proliferation and inducing differentiation of leukemia cells could be beneficial.

Cell Cycle↗
PubMed1981

Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid.

The recent finding that retinoic acid induces terminal granulocytic differentiation of the human promyelocytic leukemia cell line, HL-60, prompted an investigation of the sensitivity to this inducer of human myelocytic leukemia cells in primary suspension culture. Of the 21 leukemic specimens, only cells from the two patients with acute promyelocytic leukemia differentiated in response to retinoic acid. After an incubation period of 5--7 days in 1 microM retinoic acid, the cells from these two patients showed extensive morphological and functional maturation. Thus, because it appears that retinoic acid specifically induces granulocytic differentiation of leukemic promyelocytes, this compound may have therapeutic utility in the treatment of acute promyelocytic leukemia.

Adolescent↗
PubMed1981

New facts and speculations on human myeloid leukemias.

The Hl-60 cell line, derived from a patient with acute promyelocytic leukemia, proliferates continuously in suspension culture and consists predominantly of promyelocytes. These cells can be induced to differentiate to morphologically and functionally mature granulocytes by incubation with a wide variety of compounds, including butyrate and hypoxanthine and polar planar compounds such as dimethylsulfoxide and hexamethylene bisacetamide. However, these compounds are either nonphysiological or induce HL-60 at concentrations that are markedly greater than physiological. We have now found that retinoic acid is the most potent inducer of granulocytic differentiation of HL-60. This compound induces differentiation at concentrations 1/10(3) to 1/10(6) the concentration of other inducers and at concentrations that are physiological. These findings prompted an investigation of the sensitivity to retinoic acid of fresh human myelocytic leukemia cells in primary suspension culture. Of 21 leukemic specimens, only cells from the 2 patients with acute promyelocytic leukemia differentiated in response to retinoic acid. Thus, as with HL-60, it appears that retinoic acid specifically induces granulocytic differentiation of leukemic promyelocytes and may have therapeutic utility in the treatment of acute promyelocytic leukemia. In addition, our results suggest that retinoic acid may also be involved in the differentiation of certain hematopoietic cells.

Cell Differentiation↗
PubMed1980

Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.

The HL-60 cell line, derived from a patient with acute promyelocytic leukemia, proliferates continuously in suspension culture and consists predominantly (greater than 90%) of promyelocytes. These cells can be induced to differentiate to morphologically and functionally mature granulocytes by incubation with a wide variety of compounds, including butyrate and hypoxanthine and polar planar compounds such as dimethyl sulfoxide and hexamethylene bisacetamide. We have now found that retinoic acid (all-trans-retinoic acid) induces differentiation (as measured morphologically and by the ability to reduce nitroblue tetrazolium) of HL-60 at concentrations as low as 1 nM. Maximal differentiation (approximately 90%) occurs at 1 micro M, a concentration 1/500th to 1/160,000th the concentrations of butyrate (0.5 mM) and dimethyl sulfoxide (160 mM) that promote a similar increase in differentiation. Continuous exposure to retinoic acid is necessary for optimal differentiation, with the percentage of mature cells in the culture directly related to the length of time of exposure to retinoic acid. Retinoic acid and 13-cis-retinoic acid are equally effective in inducing differentiation of HL-60. Retinol (vitamin A), retinal, and retinyl acetate are approximately 1/1000th less potent. This study suggests that retinoids could provide a therapeutic tool in the treatment of acute myeloid leukemia, a disease that has been looked upon as primarily involving a block in myeloid differentiation, and indicates that retinoids, in addition to their well-characterized involvement in epithelial cell differentiation, may also be involved in the differentiation of certain hematopoietic cells.

Cell Differentiation↗