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Biomedical subjects

H A Neumann

Publications and source records attributed to H A Neumann.

At least 109 records · Page 6Linked to original sources
PubMed1987

Phase II trial of recombinant leukocyte A interferon in advanced malignant melanoma.

A total of 21 patients with advanced metastatic malignant melanoma were treated in this efficacy study of recombinant leukocyte A interferon (interferon alpha-2a). Patients received 18 X 10(6) units interferon alpha-2a by i.m. injection daily for the first 10 weeks and then three times weekly for a further 4 months. The symptoms of toxicity observed in this study resembled those previously reported for alpha interferons and included fever, chills, fatigue, anorexia, myalgia, headache, occasional nausea and vomiting, dose-dependent reversible leukopenia, and hepatic transaminase elevations. Of the 21 patients, 12 had evidence of tumor progression, 6 had stable disease for at least 2 months, and complete remission was seen in 3 patients with stage III melanoma. We conclude that interferon alpha-2a appears to have some antiproliferative effect in metastatic malignant melanoma. While its use in stage IV patients with big tumor masses is doubtful, there seems to be therapeutic benefit in earlier stages.

Adult↗
PubMed1987

Cytotoxic activity of the thioether phospholipid analogue BM 41.440 in primary human tumor cultures.

The inhibitory effect of the new thioether alkyl lysophospholipid analogue 1-hexadecylmercapto-2-methoxy-methyl-rac-glycero-3-phosphocholine (BM 41.440, Ilmofosine) on colony formation of different spontaneous human tumors was studied in vitro using a methyl cellulose monolayer assay. The most sensitive tumors were lung (small cell, squamous cell and adenocarcinomas), gastrointestinal and ovarian cancers and hyernephromas. On the basis of the current definition of sensitivity by the National Cancer Institute, Bethesda, MD, i.e. more than 70% inhibition of colony formation at an arbitrary concentration of 10 micrograms/ml, 34 out of 64 malignancies tested were susceptible to BM 41.440.

Antineoplastic Agents↗
PubMed1987

Phase I trial of the thioether phospholipid analogue BM 41.440 in cancer patients.

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a new thioether phospholipid, which has been shown to possess antineoplastic, antimetastatic, anti-invasive and immunomodulating properties in several tumor models. The mechanism whereby this compound exerts its direct antineoplastic effect is thought to be related to specific interference with the normal phospholipid metabolism, preferentially of neoplastic cells. BM 41.440 was evaluated in a multicenter phase I study in patients (pts) with refractory cancers. In phase I A, 34 pts were orally treated with doses ranging from 0.5 to 7.0 mg/kg body weight (bw). Three different formulations were tested. The maximum-tolerated dose (MTD) was ca. 5 mg/kg bw. The limiting side effects were nausea and vomiting. There was no evidence for systemic toxicities like myelosuppression, nephro-, neuro-, hepatotoxicity or hematological side effects. The current phase I B is designed to determine the MTD of BM 41.440 administered orally on a daily schedule for at least eight weeks. So far, 19 pts have entered this trial at dose levels ranging from 1.0 to 5.0 mg/kg bw/day. Some pts receiving 1.0 and 2.5 mg/kg bw/day, respectively, have been treated, up to now, for more than nine months. Clinical progress was followed with at-least-weekly blood counts, chemistry profiles, urine analysis, liver function tests and recordings of side effects. Tumor parameters were evaluated at eight-week intervals. In parallel, pharmacokinetic investigations were performed in some pts in phase I A and IB. First results on tolerability and therapeutic efficacy of the long-term BM 41.440 treatment are reported in this intermediate evaluation.

Administration, Oral↗
PubMed1987

Inhibition of human tumor colony formation by the new alkyl lysophospholipid ilmofosine.

The cytostatic-cytotoxic effect of the new thioether alkyl lysophospholipid analogue Ilmofosine (1-hexadecylthio-2-methoxymethyl-rac-glycero-3-phosphocholine, BM 41.440) on colony formation of 30 different spontaneous human tumors was investigated in vitro with the use of a methylcellulose monolayer assay. Twenty-five neoplasms were sensitive to Ilmofosine within the concentration range tested (0-16 micrograms/ml). The most susceptible tumors were 2 colon carcinomas, 2 squamous cell carcinomas and 1 small-cell carcinoma of the lungs, 2 myosarcomas, 2 ovarian carcinomas, 1 gallbladder carcinoma, and 1 pleural mesothelioma with 50% colony formation inhibition doses ranging from 1.5 to 4.0 micrograms/ml. Due to the sensitivity criteria of the U.S. National Cancer Institute (greater than or equal to 70% inhibition of colony formation at 10 micrograms/ml), 15 of 30 tumors tested have to be considered as susceptible to Ilmofosine.

Cells, Cultured↗
PubMed1986

Cytotoxic ether phospholipids. Different affinities to lysophosphocholine acyltransferases in sensitive and resistant cells.

Alkyllysophospholipids (ALP) which are 1-O-alkyl analogs of the cell membrane component 1-acyl-sn-glycero-3-phosphocholine (1-acyl-GPC) represent a family of new antitumor drugs. Susceptibility of cells to ALP is correlated to a selective inhibition of fatty acid incorporation into 1,2-diacyl-sn-glycero-3-phosphocholine in intact cells. This report examines oleoyl-CoA-1-acyl-GPC acyl-transferase activities in cell-free systems of ALP-sensitive methylcholanthrene-induced fibrosarcoma cells (MethA cells) and ALP-resistant bone marrow-derived murine macrophages (BMM phi). The specific activities for the oleoyl-CoA-1-acyl-GPC acyltransferases were 1.05 +/- 0.06 nmol X mg-1 X min-1 and 2.98 +/- 0.27 nmol X mg-1 X min-1, respectively. The kinetic parameters for 1-palmitoyl-GPC were Km = 16.6 microM, Vmax = 4.3 nmol X mg-1 X min-1 (BMM phi) and Km = 7.6 microM, Vmax = 2.0 nmol X mg-1 X min-1 (MethA cells). In the presence of 1-O-octadecyl-2-O-methyl racemic glycero-3-phosphocholine (ET-18-OCH3), one of the most potent cytotoxic ALP, the acyltransferase was dose dependently inhibited in MethA cells with a 50% inhibition concentration at 40 micrograms/ml. The BMM phi-acyltransferase was not affected up to 80 micrograms of ET-18-OCH3/ml. The kinetic parameters (Km' = 15.4 microM, Vmax' = 2.2 nmol X mg-1 X min-1) suggest that ET-18-OCH3 is a competitive inhibitor in MethA cells. Inhibitor constants for ET-18-OCH3, calculated from Dixon plots, were found to be 423 microM (BMM phi) and 13 microM (MethA cells) indicating a 33-fold larger affinity of ET-18-OCH3 to the MethA cells than to the BMM phi acyltransferase. From these data we assume that the inhibition of oleic acid incorporation into cellular phosphocholine during the antineoplastic action of ALP may be due to different affinities of the inhibitor to the 1-acyl-GPC acyltransferases in different cell types.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1986

Comparison of bleomycin and peplomycin toxicity on clonogenic tumor cells from various human tumors.

The cytotoxic effect of bleomycin and peplomycin was compared using a methylcellulose monolayer assay for the cultivation of human tumor cells. In 3 out of 4 samples from human malignant melanomas peplomycin proved to be more cytotoxic than bleomycin. Peplomycin was more cytotoxic than bleomycin in 1 of 5 myosarcoma samples, whereas 2 samples from squamous cell carcinomas of the lung showed identical dose response curves. In 1 carcinoma of the gall bladder peplomycin was more toxic than bleomycin.

Bleomycin↗
PubMed1986

Growth patterns and hormonal sensitivity of primary tumor, abdominal metastasis and ascitic fluid from human epithelial ovarian carcinomas in the tumor colony-forming assay.

The human tumor colony forming assay was used to evaluate the response of ovarian carcinoma cells from primary tumors, ascitic fluids and metastasis to hormonal treatment. In 12/35 patients a sufficient colony formation (greater than 30 colonies/dish) was obtained in order to perform a simultaneous drug testing. The plating efficiency of the metastatic samples (0.12%) was significantly higher (P less than 0.053) than those from the primary tumor (0.076%) or those that were derived from the ascitic fluid (0.082%). Colonies from the metastatic tissues could be evaluated 2-4 days earlier than those from primary tumors. These discrepancies may be due to a heterogeneity in the clonable tumor cell compartment of primary tumor and metastasis. The antiproliferative properties of the antiestrogen tamoxifen and the progestin gestoneron were studied. In 9/12 cases a significant, dose-dependent reduction of colony formation (greater than 70-90% of the controls) was observed after continuous exposure to 1 mumole tamoxifen. No correlation between the dose response and the content of steroid receptors was found. Even estrogen receptor negative tumor samples showed a maximal antiproliferative effect of tamoxifen.

Abdominal Neoplasms↗
PubMed1985

Development of three human small cell lung cancer models in nude mice.

The transplantation of seven human small cell lung cancers (SCLC) into athymic nude mice resulted in the development of three tumor lines that are suitable for study of biology and for tests of new drugs and combinations. They were characterized and the response to known drugs was determined. An identical tumor response was observed in the nude mouse system and in the patient in all four comparisons available.

Animals↗
PubMed1985

Clonogenicity of normal and malignant hematopoietic progenitor cells after exposure to synthetic alkyl-lymphospholipids.

Alkyl-lysophospholipids (ALP) are synthetic analogues of natural lysophosphatidylcholine and represent a new class of anti-tumor agents. They are cytotoxic in vitro with a high selectivity for neoplastic cells which, in contrast to normal cells, lack an alkyl-cleavage enzyme to degrade the adsorbed ALP molecules. As ALP accumulates, it interferes with normal membrane phospholipid turnover and eventually causes disruption of membrane integrity. To evaluate the potential value of ALP in eliminating leukemic cells from remission marrows prior to autologous transplantation, we tested the effect of various ALPs on the clongenicity of normal human marrow cells and on promyelocytic leukemia HL-60. A remarkable difference in the dose response to ALP of normal marrow cells an HL-60 was observed. After an incubation period of 24 h, the same inhibition of clonogenicity in HL-60 occurred at ALP concentrations 4 times lower than in normal marrow cells. Reducing the exposure time to 6 h enhanced the selectivity further: whereas HL-60 colonies were nearly completely inhibited at 16 micrograms ALP/ml, more than 50% of normal CFU-c and BFU-E were recovered after incubation with 48 micrograms/ml. No further increase in selectivity was achieved by changing the incubation temperature. Both thioether- and alkyl-analogues were active and no difference was observed between methoxy- and acylamino-substituted ALPs. We conclude that this selective cytotoxicity makes ALP compounds worth further study as purging agents in autologous bone marrow transplantation programs.

Animals↗
PubMed1985

Cloning ovarian carcinoma cells in an agar double layer versus a methylcellulose monolayer system. A comparison of two methods.

Human ovarian cancer cells from ten patients were cultured in the agar double layer assay as described by Hamburger and Salmon and in a methylcellulose monolayer system. The assays were compared under the same experimental conditions. The rate of positives (defined as greater than 30 colonies/dish) was 75% in the methylcellulose assay and 69% in the agar double layer. Plating efficiency ranged in the methylcellulose assay between 0.021% and 0.089% and in the agar double layer from 0.015% to 0.094%. Cytological and cytochemical staining of cells obtained from colonies in both test systems and of the tumour cells prior to plating revealed the same morphology. The methylcellulose monolayer system requires less additives than necessary in the agar double layer system. Furthermore, it is easier to handle with respect to the plating procedure and less time consuming. In addition, the effect of the anti-oestrogen tamoxifen on colony formation was tested. The dose response curves for colony formation with tamoxifen proved to be identical in both systems. At a concentration of 10(-6) M an inhibition of colony formation of more than 70% of controls was observed in the agar and in the methylcellulose system.

Agar↗
PubMed1985

Cytostatic drug effects on human clonogenic tumor cells and human bone marrow progenitor cells (CFU-C) in vitro.

Human tumor cells from a squamous cell carcinoma of the lung and from a malignant melanoma and human bone marrow progenitor cells were cultured in a methylcellulose monolayer system. To obtain tumor material for repeated experiments with human tumor specimens, human xenografts grown in the nude mouse system were used. The cultures were incubated continuously with adriamycin, actinomycin-D, bleomycin, cisplatinum, and melphalan. Dose response curves for bone marrow and tumor cell colonies were established. A comparison of bone marrow and tumor cell colony dose response curves might be useful for the assessment of the drug sensitivity of tumor cells independent of in vivo pharmacologic data and duration of drug exposure.

Animals↗
PubMed1985

Effects of cytostatic drugs and 40.5 degrees C hyperthermia on human clonogenic tumor cells.

A tumor colony-forming assay was used to investigate the effect of 40.5 degrees C hyperthermia and drugs on the colony-forming ability of human clonogenic tumor cells. In order to be able to perform repeated incubations with identical tumor material, specimens were used that were augmented in the nude mouse system. Five tumor samples (two malignant melanomas, two squamous cell carcinomas of the lung and one small cell carcinoma of the lung) were incubated with seven drugs: doxorubicin, actinomycin-D, bleomycin, melphalan, vincristine, vinblastin and cisplatinum. One additional tumor specimen (chondrosarcoma) was incubated with doxorubicin immediately after resection. The incubation with drugs at 37 degrees C revealed dose response curves typical for each tumor. Incubation at 40.5 degrees C for 2 hr showed enhanced drug effects in five out of the six tumors tested. The drugs, with an enhanced effect and the pattern of enhancement were different in each individual tumor.

Animals↗
PubMed1985

Effects of cytostatic drugs and 40.5 degrees C hyperthermia on human bone marrow progenitors (CFU-C) and human clonogenic tumor cells implanted into mice.

Human spontaneous tumors after surgical resection were implanted into NMRI nude mice. Clonogenic cells from these tumors (4 malignant melanomas, 2 squamous cell carcinomas of the lung, and 1 small cell carcinoma of the lung) were cultured in a methylcellulose monolayer assay. Dose-response curves with 7 cytostatic drugs (doxorubicin, bleomycin, dactinomycin, cisplatin, vincristine, vinblastine, and melphalan) were assessed at 37 degrees C and after a 2-hour pulse at 40.5 degrees C. In addition, bone marrow cells (CFU-C) were plated in the same assay. Dose-response curves were assessed with the same drugs under the same conditions. Hyperthermic treatment without drugs did not alter the colony formation of tumor and bone marrow cells. Bone marrow samples from different donors showed homogeneous response patterns; the tumor probes revealed sensitivity patterns typical for each tumor. In 13 of 48 tumor-drug combinations a thermal enhancement of the drug effects was observed, whereas there was no significant difference between normothermic and hyperthermic cultures in the bone marrow cultures. A comparison of colony and bone marrow dose-response curves suggested that a hyperthermic enhancement can occur in single cases. However, this phenomenon seems to be due to individual properties of the tumor.

Animals↗
PubMed1984

Tumor cell colonies in bone marrow cultures from patients with small cell carcinoma of the lung.

Bone marrow specimens from 27 patients with small cell carcinoma of the lung (17 with limited and 10 with extensive disease) were plated in a culture system that supports the growth of multilineage haemopoietic progenitors CFU-GEMM. In five patients (three with extensive and two limited disease) atypical colonies could be observed that were not identifiable as haemopoietic colonies. Cytological staining and cytochemical examination as well as electronic micrographs suggest that these colonies are derived from metastatic carcinoma cells. The histological examination of marrow cells from three out of these five patients revealed no bone marrow involvement. Additional studies might provide further evidence whether bone marrow cultures are a useful probe in order to monitor bone marrow involvement in patients with small cell carcinoma of the lung.

Carcinoma, Small Cell↗
PubMed1984

Tumor colony formation from human spontaneous tumors in a methylcellulose monolayer system.

A methylcellulose monolayer system is described that facilitates the "in vitro" cultures of human spontaneous tumor cells. The tumor samples were disaggregated mechanically and cultured in 0.9% methylcellulose with 30% fetal calf serum in Iscove's modified Dulbecco's medium. Eighty-five individual tumor samples with different histological types were seeded, 45 gave rise to tumor cell colonies. The plating efficiency ranged from 0.02% to 0.22%. Cytologic and cytochemical staining from aspirated cells revealed the same morphology of cells as the cells in the suspension. A flattening of colonies, as it has been described by others using methylcellulose monolayer, was not observed.

Clone Cells↗
PubMed1984

[Significance of the colony formation test in ovarian carcinoma].

Methods and evaluation of the human tumor stem cell assay (HTSCA) are described. Advantages and disadvantages of the test system are elaborated. The in vitro/in vivo correlation in the drug screening of human ovarian carcinomas shows that the prediction of sensitivity to a cytotoxic agent is only possible in 64%. Prediction of drug resistance, however, seems to be possible in 95%. The number of patients that profit from the HTSCA seems to be only less than 10%. Our investigations describe the influence of various hormones and antiestrogens on the colony formation of human ovarian carcinoma cells. Tamoxifen and his major metabolite 4-hydroxy-tamoxifen were the most active agents. Both compounds inhibit the colony survival (70% at pharmacological concentrations) of 60% of the screened ovarian carcinomas. A significant correlation to the quantitative level of estrogen or progesterone receptors could not be proved. Colony formation of ovarian carcinoma cells was compared in the HTSCA as described by Hamburger and Salmon and in a methylcellulose-monolayer system. Our results show that the colony formation corresponds to the results of the original HTSCA: Cloning ovarian carcinoma cells in the methylcellulose-monolayer, however, seems to be technically easier and faster.

Agar↗
PubMed1984

Stimulatory activities for human multilineage hemopoietic progenitors (CFU-GEMMT) derived from patients with hemochromatosis and from normal volunteers.

A medium conditioned by leukocytes in the presence of phytohemagglutinin (PHA-LCM) promotes the growth of human multilineage hemopoietic progenitors (CFU-GEMMT) which form mixed hemopoietic colonies in culture containing granulocytes, erythroblasts, megakaryocytes, macrophages, and T-lymphocytes. PHA-LCM derived from six HLA-typed patients with idiopathic hemochromatosis and from six normal individuals were tested for growth-promoting activities for multilineage hemopoietic colony formation. Four out of six conditioned media obtained from patients with hemochromatosis supported mixed hemopoietic colony formation, as did four of six conditioned media from normal HLA-typed volunteers. Active PHA-LCM preparations from patients with hemochromatosis were similar with respect to the number and size of mixed colonies and their cellular composition when compared with conditioned media obtained from volunteers. The study indicates that no link exists between the HLA phenotype of a particular donor and the predictability of obtaining an active PHA-LCM promoting multilineage hemopoietic colony formation. PHA-LCM derived from patients with hemochromatosis had no advantage with respect to stimulatory activity for mixed colony formation when compared with conditioned media obtained from healthy volunteers.

B-Lymphocytes↗