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PubMed1989

Potential usefulness of a cultured glioma cell line induced by Rous sarcoma virus in B10.A mouse as an immunotherapy model.

A cultured glioma cell line, SR-B10.A, which was derived from a brain tumor induced in an adult female B10.A mouse by Rous sarcoma virus (RSV), has been established. The morphological appearance of the tumor produced by s.c. inoculating SR-B10.A cells was analogous to an astrocytoma of human glioma. Glial fibrillary acidic protein as well as S-100 protein was positive in these SR-B10.A tumor cells. A population doubling time of the cultured cells was 18.5 hours. Chromosomal analysis revealed a defect in one of the sex chromosomes. Integration of RSV genome was proven to be positive in SR-B10.A cells. It was possible to generate cytotoxic effector cells in the syngeneic B10.A mouse against SR-B10.A. The tumor-bearing syngeneic hosts harbored a suppressor activity in the splenocytes. Although recombinant human tumor necrosis factor (rH-TNF) had no growth inhibitory effect on the SR-B10.A cells in vitro, the s.c. implanted and growing tumor regressed when rH-TNF was administered intratumorally several times. In addition, this anti-tumor effect was completely abrogated when the host mice were treated with wholebody x-ray irradiation prior to the tumor cells inoculation. In contrast, neither rH-TNF (i.v.) nor cyclophosphamide (i.p.) induced the regression of SR-B10.A, indicating that efficacy of the locally administered rH-TNF is dependent on the host immune mechanism. These results suggest that SR-B10.A is a potentially useful tumor model in evaluating efficacy of immunomodulators.

Animals↗
PubMed1989

Enhancement of cytotoxicity of cisplatin in vitro by recombinant human tumor necrosis factor and/or recombinant human interferon-alpha, -beta and -gamma.

This study was conducted to investigate the modulatory effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon (rH-IFN)-alpha, -beta and -gamma, either alone or in combination, on the cytotoxicity of cisplatin, using MTT assay, against MKN-45 (human stomach adenocarcinoma). MKN-45 was resistant to rH-TNF even at doses up to 10(3) U/ml. rH-IFN-gamma inhibited the survival of MKN-45 dose-dependently, while rH-IFN-alpha and -beta did not inhibit the survival of MKN-45 even at the highest concentrations tested (10(4) U/ml). Combination of rH-TNF with rH-IFN-alpha, -beta or -gamma did not significantly inhibit the survival of MKN-45, except for a combination of 10 U/ml of rH-TNF and 10(3) U/ml of rH-IFN-gamma (P less than 0.05). Cisplatin inhibited the survival of MKN-45 dose-dependently. By the simultaneous combination of cisplatin with rH-TNF and/or rH-IFN-alpha, -beta or -gamma, cytotoxicity of cisplatin was enhanced and the combination effects were additive. The effects of rH-TNF and rH-IFN-alpha, -beta and -gamma on the modification of cytotoxicity of cisplatin were evaluated in terms of modification index (MI), demonstrating that rH-TNF, rH-IFN-alpha, -beta and -gamma all augmented the cytotoxicity of cisplatin: MI values at 10(3) U/ml of rH-IFN-alpha, -beta and -gamma were 1.4, 1.4 and 2.3, respectively; those at the same concentrations of rH-IFN-alpha, -beta and -gamma in the presence of 10 U/ml of rH-TNF were 3.6, 2.5 and 5.1, respectively. These results demonstrating that the cytotoxicity of cisplatin was enhanced by rH-TNF and/or rH-IFN-alpha, -beta or -gamma suggest that cancer may be more effectively treated with the combination of cisplatin with these biological response modifiers than with cisplatin alone.

Adenocarcinoma↗
PubMed2001

Development of a three-dimensional transmigration assay for testing cell--polymer interactions for tissue engineering applications.

The ability of synthetic or natural scaffolds to support invasion of cells from surrounding tissue is a key parameter for tissue engineering (TE). In this study, the migration of fibroblasts, chondrocytes, and osteoblasts into biodegradable polymer scaffolds was evaluated using a novel, three-dimensional (3-D) transmigration assay. This assay is based on a cell-populated contracted collagen lattice with a biodegradable polymer scaffold implanted at the center of the collagen gel. Cell migration into the scaffolds was assessed both quantitatively and qualitatively following various time lengths in culture using image analysis. Chondrocytes, incorporated within the collagen lattice, migrated into polymer scaffolds, when cultured both statically or in a rotating bioreactor. However, the bioreactor cultures resulted in a significantly greater cell invasion as compared to static cultures. There was a cell density-dependent osteoblast migration from collagen lattice into polymer scaffold, when tested in the transmigration assay. In addition, polymer scaffolds, treated with or without recombinant human platelet-derived growth factor (rh-PDGF-BB) were evaluated for fibroblast migration. The presence of rh-PDGF-BB resulted in significantly greater fibroblast invasion as compared to untreated scaffolds. Our studies suggest that the transmigration model provides a rapid system for testing cell invasion of potential scaffolds for tissue engineering applications.

Becaplermin↗
PubMed1992

Secondary structure of human granulocyte colony-stimulating factor derived from NMR spectroscopy.

Recombinant 15N-, 13C-labeled human granulocyte colony-stimulating factor (rh-metG-CSF) has been studied by 2D and 3D NMR using uniformly labeled protein as well as residue-specific 15N-labeled samples. Assignment of the 1H, 15N backbone, and 60% 1H sidechain resonances has enabled the determination of the secondary structure of the protein. The secondary structure is dominated by alpha-helical regions with four stretches of helices between residues 11-41, 71-95, 102-124 and 144-170.

Amino Acid Sequence↗
PubMed1987

Phase I study of recombinant human tumor necrosis factor.

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.

Adult↗
PubMed2003

Clinical and physiological findings, and possible aetiological factors of rectal hyposensitivity.

BACKGROUND: Rectal hyposensitivity (RH) relates to insensitivity of the rectum on anorectal physiological investigation and appears common in functional bowel disorders. The clinical significance of this physiological abnormality is unclear. METHOD: RH was defined as one or more sensory threshold volumes raised beyond the normal range (mean plus two standard deviations) on rectal balloon distension. Clinical information and results of other anorectal physiological investigations were evaluated in 261 patients with RH. RESULTS: Patients with RH most commonly presented with constipation (48 per cent), constipation and incontinence in combination (27 per cent), or faecal incontinence (20 per cent). Thirty-eight per cent of patients had a history of previous pelvic surgery, 22 per cent a history of anal surgery and 13 per cent a history of spinal trauma. In patients with RH presenting with symptoms of constipation or incontinence, impaired rectal sensation was the only abnormality on physiological investigation in 48 per cent and 31 per cent respectively. CONCLUSION: Patients with RH display marked heterogeneity in terms of presenting symptoms. The exact causes of RH are unknown, but there is evidence to suggest that pelvic nerve injury and spinal trauma are possible aetiological factors. RH appears important in the aetiology of both constipation and faecal incontinence, and may be useful as a predictor of surgical outcome.

Adolescent↗
PubMed1984

High affinity epidermal growth factor receptors on the surface of A431 cells have restricted lateral diffusion.

Rhodamine-labelled epidermal growth factor (Rh-EGF) was shown to bind to A431 cells grown at low density both to a small number of high affinity receptors (KD = 2.8 X 10(-10) M; fraction of total binding sites approximately 0.12) and also to a large number of low affinity receptors (KD = 4 X 10(-9) M; fraction of total binding sites approximately 0.88). Measurements of the lateral diffusion of EGF receptors on the cell surface were made using Rh-EGF and the technique of fluorescence photobleaching recovery. The high affinity receptors (labelled with 1.6 X 10(-10) M Rh-EGF, 5% of EGF binding sites occupied) did not show lateral mobility over the temperature range 3 degrees-37 degrees C. The low affinity receptors (labelled with 2.4 X 10(-7) M Rh-EGF, 90% of EGF sites occupied) showed at least 75% fluorescence recovery after photobleaching, and lateral diffusion coefficients of approximately 2 X 10(-10) cm2/s. These results show that the two populations of EGF receptors defined by binding studies differ in their freedom to diffuse laterally. The observation that the high affinity receptors are immobile indicates that lateral diffusion of receptors, at least over a distance of a few hundred nanometres or more, may not be required for the action of low concentrations of EGF.

Carcinoma, Squamous Cell↗
PubMed2002

Cell-surface expression of RhD blood group polypeptide is posttranscriptionally regulated by the RhAG glycoprotein.

In most cases, the lack of Rh in Rh(null) red cells is associated with RHAG gene mutations. We explored the role of RhAG in the surface expression of Rh. Nonerythroid HEK293 cells, which lack Rh and RhAG, or erythroid K562 cells, which endogenously express RhAG but not Rh, were transfected with RhD and/or RhAG cDNAs using cytomegalovirus (CMV) promoter-based expression vectors. In HEK293 cells, a low but significant expression of RhD was obtained only when RhAG was expressed at a high level. In K562 cells, as expected from the opposite effects of the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) on erythroid and CMV promoters, the levels of endogenous RhAG and recombinant RhD transcripts were substantially decreased and enhanced upon TPA treatment of RhD-transfected cells (K562/RhD), respectively. However, flow cytometry and fluorescence microscopy analysis revealed a decreased cell-surface expression of both RhAG and RhD proteins. Conversely, TPA treatment of RhAG-transfected cells increased both the transcript and surface expression levels of RhAG. When K562/RhD cells were cotransfected by the RhAG cDNA, the TPA-mediated induction of recombinant RhAG and RhD transcription was associated with an increased membrane expression of both RhAG and RhD proteins. These results demonstrate the role of RhAG as a strictly required posttranscriptional factor regulating Rh membrane expression. In addition, because the postulated 2:2 stoichiometry between Rh and RhAG observed in the native red cell membrane could not be obtained in cotransfected K562 cells, our study also suggests that as yet unidentified protein(s) might be involved for optimal membrane expression of Rh.

Antigens, Surface↗
PubMed1989

Phase II clinical trial of high-dose recombinant human tumor necrosis factor.

Based on a phase I study in 1986, 22 patients have been entered in a phase II study of high-dose human tumor necrosis factor (rH-TNF) since May 1987. Of these patients, 18 are evaluable at present, 2 are still under investigation, and 2 have dropped out. All had advanced stages of cancer (9 soft-tissue sarcomas, 3 melanomas, 5 hypernephromas) and inclusion in the study was ethically acceptable (informed consent). The daily dose of rH-TNF was 15 x 10(5) units/m2, escalated to 21 x 10(5) units/m2 (683-956 micrograms/m2 every week; range 1-6 cycles). Additional prophylactic ketoprofen administration was carried out. Of the 18 evaluable patients, 4 responded with no change (2/4, clinical improvement) and 14 showed progressive disease. The main toxicities observed were hypotension (decrease in systolic blood pressure, 21-60 Torr), leukocytosis, increases in ALAT/ASAT (WHO grade 0-4), fever (WHO grade 1-2), chills (mild to moderate), neurotoxicity (WHO grade 0-2), and nausea/vomiting (WHO grade 0-3).

Adult↗
PubMed1987

Effect of recombinant human tumor necrosis factor on the induction of murine macrophage tumoricidal activity.

The ability of recombinant human tumor necrosis factor (rH-TNF) alone or in combination with lymphokines (LK) to induce the in vitro activation of murine macrophages was evaluated. The treatment of C57BL/6 mouse resident peritoneal exudate cells (PEC) with rH-TNF and LK was found to induce the activation of macrophages to a tumoricidal state against P815 mastocytoma cells. Neither rH-TNF nor LK alone induced macrophage cytotoxic activity. Furthermore, the macrophage activation seen was not due to small amounts of contaminating lipopolysaccharide. The TNF plus LK-mediated macrophage activation could be totally ablated by rabbit antiserum to murine gamma-interferon, thus suggesting a role for gamma-interferon in this system. Since adherent cells (greater than or equal to 95% macrophages) only marginally responded to stimulation with rH-TNF plus LK and the addition of nonadherent PEC caused a marked augmentation of rH-TNF plus LK-mediated macrophage activation, the involvement of nonadherent PEC was suggested. In addition, using antibodies and complement to deplete subsets of cells from the nonadherent PEC, the requirement for cells bearing Thy 1.2 and asialo GM1 surface markers was demonstrated. These results suggest that TNF may play an autocrine regulatory role in concert with lymphokines in macrophage-mediated host defense against malignant neoplasia.

Animals↗
PubMed1991

Granulocyte-macrophage colony stimulating factor does not improve neutrophil oxidative metabolism in a patient with variant X-linked chronic granulomatous disease.

Variant X-linked chronic granulomatous disease (CGD) is characterised by a decreased but still measurable respiratory burst and cytochrome b content of phagocytes resulting in a clinically milder form of the disease. We examined the in vivo effect of recombinant human granulocyte-macrophage colony stimulating factor (rh-GM-CSF) on the neutrophil functions of a patient treated for liver abscess. The number of white blood cells was markedly increased at the highest dose of GM-CSF injected (30 micrograms/kg per day). This was mainly due to a large increase in eosinophils and to a lesser extent in neutrophils. No change in the deficient neutrophil respiratory burst nitroblue tetrazolium (NBT)-reduction, superoxide (O2-)-production and cytochrome b content was observed during 6 weeks of therapy with increasing doses of GM-CSF. No significant clinical improvement of the liver abscess was observed during treatment with GM-CSF.

Adolescent↗
PubMed1996

Cachectic effect of ciliary neurotrophic factor on innervated skeletal muscle.

Recombinant human ciliary neurotrophic factor (rh-CNTF) was reported to attenuate skeletal muscle wasting in rats after unilateral transection of the sciatic nerve (M. E. Helgren, S. P. Squinto, H. L. Davis, D. J. Parry, T. G. Bolton, C. S. Heck, Y. Zhu, G. D. Yancopoulos, R. M. Lindsay, and P. S. DiStefano. Cell 76: 493-504, 1994). Under the experimental conditions reported herein, the absolute masses of the denervated gastrocnemius and soleus muscles were not increased in mature or immature rats of either sex by treatment with rhCNTF. At the highest doses of rhCNTF (1 and 0.1 mg/kg), increases in the ratio of the masses of the denervated to the contralateral innervated gastrocnemius and soleus muscles could be attributed entirely to a muscle-wasting effect on the contralateral innervated muscle rather than any muscle-sparing effect on the denervated muscle. The muscle-wasting effects of rhCNTF were associated with reductions in body weight gain and reduced food intake. Pair-fed rats lost less body weight and skeletal muscle mass than rhCNTF-injected freely fed rats but experienced significantly greater loss of visceral mass. Male rats displayed greater loss of body weight and skeletal muscle mass than female rats. Recombinant inhibitors of the cachectic cytokines, tumor necrosis factor and interleukin-1, did not significantly alter the wasting effects of rhCNTF. These findings demonstrate that, in contrast to its well-characterized trophic effects on cells of the nervous system, rhCNTF causes atrophy of skeletal muscle by mechanisms involving both anorexia and cachexia based on the results of pair-feeding experiments.

Animals↗
PubMed2003

BALB/C mice injected with LSTRA leukemic cell line are cured by in vivo treatment with IL-2 + GM-CSF.

We studied the effects of the in vivo administration of interleukin-2 (IL-2) (at low doses) + GM-CSF in BALB/C mice injected intraperitoneally with LSTRA murine leukemic cell line in order to test the possible role of this immunotherapeutic approach in the eradication of leukemia. Mice were injected intraperitoneally on day -1 with different concentrations of LSTRA cells. On day 0, mice received a lethal dose of TBI of 700 cGy from a Cs(137) source, followed by a single high dose of recombinant human-granulocyte-colony stimulating factor (rh-G-CSF) (1 microg/g) intraperitoneally 2h after TBI. This procedure rescued 80% of mice but only mice injected with the lower concentration of LSTRA cells (10(3)) could be cured. The lethal dose (LD 100/60) of LSTRA in normal mice was 10(4). The subcutaneous administration of rh-IL-2 (4.000 IU/mouse per day, from day +1 to +28) + rm-GM-CSF (1 microg/kg per day) from day +7 to +28 cured mice injected with 10(4) LSTRA cells and 40% of mice injected with 10(5) cells. Mice injected with 10(6) cells died from leukemia. We observed an increase in LAK activity on days +21 and +28 without an increase in NK activity. We show that BALB/C mice injected with LSTRA cell line can be cured by in vivo activation with IL-2 + GM-CSF depending on the cell dose injected. The curability of leukemia was confirmed at the molecular level with a PCR method.

Animals↗
PubMed1996

Preventive effect of hepatocyte growth factor on acute side effects of cyclosporin A in mice.

Cyclosporin A (CsA) is a potent, widely-prescribed immunosuppressant which has serious side effects. When recombinant human hepatocyte growth factor (rh-HGF) was co-administrated with CsA to mice, the severe digestive and/or neurological symptoms and degenerative changes in renal tubular cells and hepatocytes seen with cases of CsA administration were remarkably attenuated and mortality linked to CsA-administration was prevented by rh-HGF. HGF-administration stimulated the DNA synthesis of hepatocytes and renal tubular cells and facilitated reconstruction of hepato-renal tissue structure in vivo. Induction of HGF mRNA expression in the liver and kidney in CsA-administered mice was suppressed in the early stage of organ injury, while HGF mRNA levels increased in the lung three days after CsA-treatment. These observations suggest that the biological action of endogenous HGF is partly impaired after CsA-induced organ injury. Importantly, HGF had no apparent effect on the CsA-induced suppression of interleukin-2 mRNA expression in vitro, thereby indicating that the immunosuppressive potential of CsA was not affected by HGF. Whether or not HGF will prove to have such positive effects in patients requiring CsA-treatment is the subject of ongoing study.

Animals↗
PubMed2000

Commercial recombinant human beta-nerve growth factor and adult rat dorsal root ganglia contain an identical molecular species of nerve growth factor prohormone.

Examination of commercial recombinant human beta-nerve growth factor (rh-beta-NGF) preparations with polyclonal antibodies specific to 13-kDa NGF and pro-NGF-specific domains revealed the presence of high-molecular-mass immunoreactive proteins, including a 60-kDa NGF prohormone. On incubation with a mixture of N- and O-specific glycosidases, the 60-kDa NGF pro-hormone generated a 32-kDa protein corresponding to the molecular size of NGF precursor predicted by the cloned human NGF cDNA. Highly sensitive chemiluminescence immunoblot analysis of adult rat dorsal root ganglia, spinal cord, and colon tissues with NGF- and pro-NGF domain-specific antibodies also revealed the presence of high-molecular-mass proteins, including the 60-kDa NGF prohormone. Based on the presence of the 60-kDa NGF prohormone in dorsal root ganglia and its efferent tissues, we suggest that proteolytically unprocessed, glycosylated NGF prohormone may mediate interactions between neurons and the tissues they innervate.

Animals↗
PubMed1988

Effect of recombinant human tumor necrosis factor on tumor and spleen in mice.

The ability of recombinant human tumor necrosis factor (rH-TNF-alpha) to induce regression of sarcoma 180 in vivo was evaluated. The tumor was cured by TNF in the course of 4 weeks. TNF inhibited proliferation of sarcoma 180 cells in vitro, which suggests a direct effect of TNF on tumor cells in vivo. In parallel to the TNF effect on tumor growth, some cell parameters in spleen were investigated. Activation of splenic macrophages was enhanced in vitro. This result suggests that macrophages may participate in the host defense against the tumor. In the first phase of therapy, TNF did not affect the proliferation of splenocytes but increased the transition of G0 into G1 cells. Furthermore, TNF normalized the tumor-induced increase of null cells in tumor-bearing mice. All parameters investigated in spleen reached normal values at the time of tumor regression. Our results suggest that various mechanisms may be involved in TNF-induced regression of sarcoma 180.

Animals↗
PubMed1987

Phase I clinical trial of recombinant human tumor necrosis factor.

A phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48 X 10(4) units/m2. Drug was given as 1-h i.v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearance and a short plasma half-life, generally less than 0.5 h.

Adult↗