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M P Hacker

Publications and source records attributed to M P Hacker.

At least 37 records · Page 2Linked to original sources
PubMed1993

Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II.

We have examined the activities of two novel aza-anthracene-9,10-diones (aza), 1-aza and 2-aza, in HL-60 human leukemia cell lines containing type II topoisomerases with different sensitivities to inhibition by other intercalating agents. The sensitive line, HL-60, was sensitive to 2-aza but not to 1-aza, whereas the resistant HL-60/AMSA was sensitive to neither agent. Measurements of 1- and 2-aza-induced, topoisomerase II-mediated DNA cross-linking in the cells revealed patterns of resistance and sensitivity that paralleled the results in the cytotoxicity assays. However, measurements of drug-induced topoisomerase II-mediated DNA cross-linking using purified HL-60 and HL-60/AMSA topoisomerase II indicated that both agents could stabilize a covalent complex between DNA and the HL-60 enzyme. HL-60/AMSA topoisomerase II resisted stabilization by either agent. This suggests that the resistance of HL-60 cells to 1-aza is not due to the inability of this drug to inhibit topoisomerase II but rather to another, undefined mechanism.

Anthraquinones↗
PubMed1993

Nitric oxide modulates lymphocyte proliferation but not secretion of IL-2.

The objective of this study was to determine the effects of nitric oxide (NO) on lymphocyte proliferation and cytokine release. Bronchoalveolar lavage (BAL) cells served as the source of NO and were obtained from rats treated with a single, intratracheal dose of bleomycin (3.6 mg/kg). At the time of sacrifice, the spleens were removed and the lymphocytes separated. Co-cultures containing BAL cells, lymphocytes and concanavalin-A were established and incubated at 37 degrees C for 24 hours at which time proliferation, nitrite concentration and interleukin-2 (IL-2) production were measured. At ratios from 5:1 to 1:4 (BAL:lymphocyte) there was a significant reduction in lymphocyte proliferation. There was a significant, negative correlation between NO concentration and thymidine incorporation which was reversed when the NO synthase inhibitor NG-monomethyl-L-arginine (NMA) was added to the co-cultures. Despite marked inhibition of spleen lymphocyte proliferation by NO, released by BAL cells, there was no corresponding reduction in IL-2 production. These data demonstrate that macrophages, activated in vivo, produce NO which regulates lymphocyte growth but not necessarily functions such as the secretion of the cytokine IL-2. Further, the ability of IL-2-dependent CTLL-2 cells to proliferate in the presence of excess IL-2 was also inhibited by BAL cells, confirming that NO inhibits lymphocyte growth.

Amino Acid Oxidoreductases↗
PubMed1992

Formation of nitric oxide hemoglobin in erythrocytes co-cultured with alveolar macrophages taken from bleomycin treated rats.

Alveolar macrophages, taken from rats treated with a single intratracheal dose of bleomycin, release reactive nitrogen intermediates in the form of nitric oxide which are cytostatic to murine leukemia L1210 cells. When cultured in the presence of erythrocytes the cytostatic activity of alveolar macrophages was inhibited which corresponded with an increase in nitrosylated hemoglobin content when compared with erythrocytes cultured alone. These results suggest that erythrocytes inhibit alveolar macrophage cytostatic activity by preventing reactive nitrogen intermediates from reaching target cells because the hemoglobin serves as a sink for reactive nitrogen intermediates in the form of nitric oxide.

Animals↗
PubMed1992

Enhanced Ia expression by alveolar macrophages following intratracheal administration of bleomycin to rats.

Bleomycin is an important anticancer drug that causes severe, and sometimes life-threatening, pulmonary toxicity. Initially, there is an acute inflammation followed by an irreversible pulmonary fibrosis. Our studies have focussed on the effects of the acute pulmonary inflammation on the state of alveolar macrophage activation. To study this, we administered a single dose of 3.6 mg bleomycin/kg body weight intratracheally to rats and obtained alveolar macrophages at selected times thereafter. Ia expression was determined by fluorescent microscopy of cells labelled with a fluorochrome-tagged antibody against rat Ia molecules. We report that: 1.) alveolar macrophages have elevated Ia expression shortly after receiving intratracheally administered bleomycin; 2.) Ia expression is not limited to a specific subpopulation of alveolar macrophages; 3.) Ia expression is transient in nature returning to control levels 7-14 days after bleomycin administration; and, 4.) the degree of upregulation of Ia expression is directly related to the dose of bleomycin administered.

Animals↗
PubMed1991

Shikimic acid complexes of platinum. Preparation, reactivity, and antitumor activity of (R,R-1,2-diaminocyclohexane) bis(shikimato) platinum(II). Evidence for a novel rearrangement involving platinum-carbon bond formation.

The complex (R,R-1,2-diaminocyclohexane)bis(shikimato)platinum(II) (shikimato = the anion of 3R,4S,5R-trihydroxy-1-cyclohexene-1-carboxylic acid), I, has been synthesized and purified by high performance liquid chromatography (HPLC). The complex is only moderately stable in aqueous solution. Its major hydrolysis product, also purified by HPLC, is proposed to be a unique complex type in which a single shikimate group is coordinated through both the carboxylate oxygen and the C(2) vinylic carbon of the shikimate moiety [Pt(R,R-dach)(O,C-shikimato)], II. In vitro, complex I is active against L1210 leukemia and against an L1210 cell line with acquired resistance to cisplatin. In vivo, the complex is active against L1210, P388, and B16 melanoma; this activity is highly schedule-dependent. Complex II is also active against L1210 leukemia.

Animals↗
PubMed1991

Synthesis and antitumor evaluations of symmetrically and unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones and 1,4-bis[(aminoalkyl)amino]-5,8-dihydroxyanthracene-9,10-diones.

The ipso bis displacements of fluoride from 1,4-difluoroanthracene-9,10-dione (3) and 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione (4) by excess of a diamine (or a monoamine) in pyridine at room temperature lead to the symmetrically substituted 1,4-bis-substituted analogues 5 and 6, respectively. The ipso monodisplacements of fluoride from 3 and 4 can be accomplished by treatment with less than 1 molar equiv of a diamine (or a monoamine) to yield 7 and 8, respectively. Treatment of 7 or 8 with a different diamine leads to the unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones 9 and 10, respectively. Many of the synthetic unsymmetrical analogues have been evaluated for their antitumor activity against L1210 in vitro and in vivo. Cross resistance of analogue 10a with mitoxantrone (2) and doxorubicin was evaluated against MDR lines in vitro against human colon carcinoma LOVO and its subline resistant to DOXO (LOVO/DOXO). Potential mechanisms for the observed cytotoxicity are presented and discussed.

Animals↗
PubMed1990

Role of reactive nitrogen intermediate production in alveolar macrophage-mediated cytostatic activity induced by bleomycin lung damage in rats.

Bleomycin (BLM) is a useful anticancer agent sometimes associated with a diffuse pulmonary inflammation and fibrosis. Using an intratracheal model of BLM-induced pulmonary damage, we have further investigated alveolar macrophage (AM) activation following intratracheal BLM. From rats that had been treated with either a single, fibrogenic, intratracheal dose of BLM (BLM-AM) or a comparable volume of saline (C-AM), bronchoalveolar lavage fluid was collected, and AM were isolated using Percoll gradient centrifugation. Using a spectrophotometric assay, production of nitrites by AM was measured. C-AM released low levels of nitrites, whereas BLM-AM as well as C-AM activated in vitro with lipopolysaccharide released significant amounts of nitrites. The addition of N6-monomethylarginine, a substrate-specific inhibitor of the L-arginine-dependent effector mechanism in activated macrophages, reduced the amount of measurable nitrites released from both BLM-AM and activated C-AM. Similar results were observed when 12 x 10(6) RBC were added to the cocultures. In the presence of N6-monomethylarginine, BLM-AM had no effect on two consequences of BLM-AM-induced cytostatic activity, DNA synthesis inhibition and aconitase activity reduction in the L1210 target cell. These results suggest that reactive nitrogen intermediates measured as nitrites are important moieties in our in vivo model of macrophage activation. Further, the identification of this effector molecule presents possibilities for therapeutic and biochemical manipulations.

Aconitate Hydratase↗
PubMed1990

Effect of erythrocytes on alveolar macrophage cytostatic activity induced by bleomycin lung damage in rats.

Bleomycin (BLM) has been successfully used to treat a number of human neoplasms. The main toxicity associated with BLM therapy is an acute pulmonary inflammation that can culminate in diffuse chronic fibrosis. The effect of BLM-induced pulmonary inflammation on the cytostatic activity of alveolar macrophages (AM) was investigated using AM obtained from rats that had been previously treated with BLM. Bronchoalveolar lavage fluid was collected at selected time intervals following a single fibrogenic dose of intratracheally administered BLM (3.6 mg/kg). AM obtained 12 to 72 h following intratracheal BLM (BLM-AM) caused cytostasis of murine leukemia L1210 cells in co-culture, whereas AM obtained from saline-treated controls were not cytostatic. These results indicate that the growth-inhibitory activity of the AM was related to the pulmonary inflammation. Cytostatic activity in control AM could be induced by in vitro exposure to lipopolysaccharide (5 micrograms). When RBC were added to the AM-L1210 co-culture, the cytostatic activity of the BLM-AM was abrogated. The fact that chemical treatment of the RBC with sodium nitrite and potassium cyanide or N-ethylmaleimide did not alter the ability of the RBC to abrogate AM cytostatic activity suggests that the RBC is not acting as a scavenger of oxygen radicals. In contrast, the addition of FeSO4 to the AM-L1210 co-culture mimicked the effect of RBC addition. Aconitase, an iron-sulfur-containing enzyme necessary for mitochondrial respiration, is decreased in L1210 cells that have been co-cultured with BLM-AM but not when the co-cultures also contain RBC. These results suggest that (a) pulmonary inflammation induces cytostatic activity in AM, (b) the alteration of iron homeostasis plays an important role in this cytostatic process, and (c) RBC can prevent this cytostatic activity.

Aconitate Hydratase↗
PubMed1990

Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes.

The in vitro cytotoxicity and in vivo antitumor activity of bis(platinum) complexes of general formula [(PtX2-(L))2H2N(CH2)nNH2] (L = NH3, X = Cl or X2 = malonato or where L = py, X = Cl) is reported. Chloride complexes [(PtCl2(NH3]2H2N(CH2)nNH2] may exist as three possible isomers: those containing both coordination units in the cis configuration (2,2/c,c), both coordination units in the trans configuration (2,2/t,t), and the mixed cis,trans species (2,2/c,t), whose synthesis is reported here. The preparation of further complexes with sterically hindered diamine backbones, such as 2,5-dimethyl-2,5-hexanediamine, is exemplified. The biological activity of all complexes were compared. The 2,2/c,c complexes are particularly active in tissue culture in cells resistant both to cisplatin and its 1,2-diaminocyclohexane (dach) analogue. The inhibition of DNA synthesis in L1210/0 cells by the 2,2/c,c complexes is equivalent to that of cisplatin. The presence of at least one cis-[Pt(amine)2] unit appears necessary for activity in cell lines sensitive to cisplatin.

Animals↗
PubMed1989

Alteration of bronchoalveolar lavage cell populations following bleomycin treatment in mice.

Clinical use of the antitumor antibiotic bleomycin (BLM) is associated with the development of interstitial pulmonary fibrosis. Shortly after acute lung damage caused by intratracheal (it) administration of BLM to experimental animals there is an influx of inflammatory cells which are believed to modulate the process of fibrosis. This study was undertaken to determine what subpopulations of lymphocytes were in the bronchoalveolar lavage (BAL) cell population of C57BL/6J mice at various times after a single it dose of BLM and to determine whether BAL T-lymphocytes were activated after BLM treatment. The BAL lymphocyte population was analyzed by differential cell analysis and flow cytometry utilizing monoclonal antibodies specific for lymphocyte subpopulations. The majority of lymphocytes in the BAL of control and BLM-treated mice were T-lymphocytes, with less than 10% being B-cells. During the first 7 days after BLM the number of Lyt-2+ T-cells exceeded L3T4+ T-cells while in control mice the reverse was observed. The percentage of BAL lymphocytes expressing the IL-2 receptor did not change significantly at 3 and 7 days after BLM treatment, but was significantly decreased at Day 14. In contrast, the total number of lymphocytes expressing the IL-2 receptor was increased at all time points investigated. These results demonstrated that the majority of lymphocytes in the BAL were T-cells and that while the percentage of activated lymphocytes did not increase following BLM treatment, the absolute number did and this increased number of activated lymphocytes may be important in the disease process.

Animals↗
PubMed1989

Effect of cytotoxic monoclonal antibody depletion of T-lymphocyte subpopulations on bleomycin-induced lung damage in C57BL/6J mice.

Treatment of cancer patients with the antitumor antibiotic bleomycin (BLM) is associated with lung damage which can progress to pulmonary fibrosis. Shortly after intratracheal (it) administration of BLM to experimental animals there is an influx of inflammatory cells into the lung. These inflammatory cells, consisting primarily of polymorphonuclear cells, monocytes and lymphocytes, are believed to modulate the pathogenesis of pulmonary fibrosis. The objective of the present study was to determine the role of specific T-lymphocyte subpopulations in this disease process following a single it administration of BLM to C57BL/6J mice. Specific in vivo T-lymphocyte subpopulation depletion was accomplished by multiple intraperitoneal administrations of cytotoxic monoclonal antibodies to mice prior to and following BLM administration. Acute lung damage was assessed by measuring levels of angiotensin-converting enzyme and total protein in the bronchoalveolar lavage fluid 7 days after BLM treatment while chronic fibrosis was assessed by total lung hydroxyproline 28 days after BLM. Although we were able to deplete lymph nodes and BAL of specific T-lymphocyte subpopulations we were unable to detect a difference in the extent or severity of either the acute or chronic stage of BLM-induced lung damage. These results suggest that BLM lung disease progresses unabated in C57BL/6J mice despite virtually complete depletion of either L3T4+ or Lyt-2+ T-lymphocytes. Although a greater than 80% decrease in Thy-1.2+ T-lymphocytes was accomplished, there was a residual population of Thy-1.2+ lymphocytes resistant to the cytotoxic antibody. It is possible, therefore, that this population of cells does play a role in the development of BLM lung disease.

Animals↗
PubMed1989

Synthesis and antitumor activity of a series of (aminoethylpyrrolidine) platinum complexes.

A series of aminoethylpyrrolidine-platinum complexes were synthesized and partially characterized for chemical structure. The leaving groups in this series of complexes were varied in an attempt to identify cytotoxic, water-soluble aminoethylpyrrolidine-platinum complexes. The cytotoxic activity was tested in vitro against L1210 cells sensitive to cis-diamminedichloroplatinum(II) (L1210/0), L1210 cells resistant to cis-diamminedichloroplatinum(II) (L1210/DDP), and L1210 cells resistant to 1,2-diaminocyclohexane platinum (L1210/DACH). The complexes were also tested for in vivo antitumor activity against L1210/0 cells injected i.p. The results of these studies indicate that the aminoethylpyrrolidine-platinum complexes have moderate antitumor activity but are cross-resistant in L1210/DDP cells. The degree of antitumor activity was dependent on the characteristic leaving group of a given complex.

Animals↗
PubMed1989

Immobilized adriamycin: toxic potential in vivo and in vitro.

We report experiments which test the toxicity of a new potential therapeutic agent, agarose-bound adriamycin (ImA). In C57Bl/6N mice this preparation is almost completely devoid of untoward effects when administered intraperitoneally; ImA lacks all the usual toxic repercussions of free adriamycin including abdominal adhesions, inflammatory peritonitis, weight loss and cardiotoxicity. The immobilized adriamycin is also inactive in a fetal mouse heart model of cardiac toxicity. This lack of toxicity is not due to an intrinsic inactivity of the drug, however, since previous studies have shown that polymer-bound adriamycin can kill actively dividing cells. We also show here that the immobilized drug can undergo redox reactions and interact with enzymes from isolated respiratory chain preparations, so the lack of cardiac toxicity in vivo is most likely due to inaccessibility of the target. These results suggest that polymer immobilized adriamycin lacks the toxicity of the parent compound and may present a useful approach to regional chemotherapy.

Animals↗
PubMed1988

Overexpression of metallothionein confers resistance to anticancer drugs.

Resistance to antineoplastic agents is the major obstacle to curative therapy of cancer. Tumor cell lines with acquired resistance to the antineoplastic agent cis-diamminedichloroplatinum(II) overexpressed metallothionein and demonstrated cross-resistance to alkylating agents such as chlorambucil and melphalan. Human carcinoma cells that maintained high levels of metallothionein because of chronic exposure to heavy metals were resistant to cis-diamminedichloroplatinum(II), melphalan, and chlorambucil. Furthermore, cells transfected with bovine papilloma virus expression vectors containing DNA encoding human metallothionein-IIA were resistant to cis-diamminedichloroplatinum(II), melphalan, and chlorambucil but not to 5-fluorouracil or vincristine. Thus, overexpression of metallothionein represents one mechanism of resistance to a subset of clinically important anticancer drugs.

Animals↗
PubMed1987

Tumor vasculature in young and old hosts: scanning electron microscopy of microcorrosion casts with microangiography, light microscopy and transmission electron microscopy.

Tumor growth in vivo is dependent upon new blood vessel formation. When B16-F10 melanoma cells are implanted subcutaneously in young (3 mo) and old (24 mo) C57BL/6 mice the rate of growth is dependent on the age of the mice. This study involved a wide range of histological and microscopic techniques but was limited primarily to the initial phase of tumor growth. Stereological point counting from light microscopy (LM) of standard histological sections has been used to yield data regarding blood content. Tumor-bearing mice were perfused through the aorta with a fixation solution and were infused with a low-viscosity radiopaque gel (Microfil) or resin (Mercox). Soft x-rays of the whole animal were used for identifying the feeding vessels to the tumor. Tumors with Microfil were sliced and used for microangiography and light-microscopic observation while those with resin were used to make corrosion casts for scanning electron microscopy (SEM). The different characteristics of the tumor blood vessels in different aged mice were most obvious through SEM of vascular corrosion casts. In comparison with tumors in young mice those of similar size in old hosts had more necrosis, reduced presence of angiogenic features, decreased vessel density, reduced penetration into the tumor, and enhanced tortuosity of the vessel lumen. Transmission electron microscopy (TEM) revealed incompletely developed wall structure of the vessels regardless of host. The above results are consistent with the hypothesis that retarded angiogenesis may be responsible in part for the limited growth of tumors in old hosts.

Animals↗
PubMed1986

Regional fibrosis after intraperitoneal administration of mafosfamide.

Mafosfamide is a cyclophosphamide analog which, unlike cyclophosphamide, does not require enzymatic activation and does not cause urinary tract toxicity. Administration of mafosfamide intraperitoneally, but not intravenously, causes a delayed, dose-dependent fibrotic peritoneal reaction associated with an increased incidence of delayed mortality. This phenomenon might complicate interpretation of in vivo laboratory studies of activity and toxicity in which the intraperitoneal route of administration is utilized. Further, this toxic effect presents a problem for the clinical development of this agent for regional therapies such as intraperitoneal installation.

Abdominal Muscles↗
PubMed1986

The effect of disulfiram on cyclophosphamide-mediated myeloid toxicity.

We have previously shown that disulfiram (DSF) blocks the urotoxicity of cyclophosphamide (CYT) in mice and increases the oncolytic effect of CYT in the L1210 murine leukemia. However, mice treated with CYT and DSF appeared to have longer-lasting neutropenia than animals treated with CYT alone. To determine whether DSF uroprotection of CYT-treated mice was associated with increased myeloid toxicity, we examined the effects of DSF plus CYT treatment on the bone marrow granulocyte/macrophage progenitor cell (GM-CFC). Marrow cellularity and GM-CFC numbers were analyzed at 1, 2 and 3 days after injection of CYT (62.5 or 125 mg/kg) or CYT plus DSF (200 mg/kg). CYT alone caused a decrease in total marrow cellularity varying from 20% to 50% of control. Animals given CYT plus DSF had a somewhat greater decrease in total marrow cellularity than those treated with CYT alone. However, in mice treated with CYT plus DSF, the GM-CFC were relatively well preserved and the recovery of the GM-CFC was not prolonged by DSF. It appears from these studies that the acute toxic effect of CYT on the granulocyte/macrophage progenitor cells is not enhanced by DSF.

Animals↗