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At least 883 records · Page 49Linked to original sources
PubMed1991

Augmentation of antiproliferative activity of CPT-11, a new derivative of camptothecin, by tumor necrosis factor against proliferation of gynecologic tumor cell lines.

The co-operative effects of recombinant human tumor necrosis factor (rH-TNF) and CPT-11, a new derivative of camptothecin, against the proliferation of human gynecologic tumor cell lines were examined in vitro. The ishikawa cells were responsive to rH-TNF, the HHUA cells exhibited a minimal degree of responsiveness to rH-TNF, and the HeLa S3 and Caov-3 cells were unresponsive to rH-TNF. The HHUA, Ishikawa and Caov-3 cells were responsive to CPT-11, and the HeLa S3 cells were relatively sensitive to CPT-11 cytotoxicity. In all four cell lines, rH-TNF at clinically achievable concentrations exhibited synergy with CPT-11. The combination therapy of rH-TNF and CPT-11 will be a new approach against gynecologic cancers.

Antineoplastic Agents, Phytogenic↗
PubMed1988

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.

Chemical and Drug Induced Liver Injury↗
PubMedDate not supplied

Recombinant human tumor necrosis factor causes regression in patients with advanced malignancies.

Fifteen patients with advanced solid tumors of various types were treated by the intratumoral administration of recombinant human tumor necrosis factor (rH-TNF). The treatment appeared to benefit the 4 cases of superficial tumors: there were 1 complete response, 1 partial response and 2 minor responses. In all 11 patients with deep-seated tumors, including 6 cases of pancreatic cancer, 4 of liver cell cancer and 1 of metastatic liver tumor, no tumor regression was observed, but progression stopped in all these tumors. Seven of the 11 with deep-seated tumors showed a decrease in tumor markers and/or the development of tumor necrosis. Fever, hypotension and fatigue were the main clinical side effects. No significant changes were found in hematologic, renal or liver parameters. These results suggest that administration of rH-TNF to the tumor site has the potential for controlling local tumor growth.

Adult↗
PubMed1996

Enhancement of leishmanicidal activity of human macrophages against Leishmania major and Leishmania donovani infection using recombinant human granulocyte macrophage colony stimulating factor.

The in vitro effect of recombinant human Granulocyte Macrophage Colony Stimulating Factor (rh-GMCSF) on the leishmanicidal activity and superoxide anion productivity of macrophages derived from human blood monocytes (MOs) were investigated. MOs treated with 25, 125, or 250 U/mL of rh-GMCSF for 72 h prior to infection with leishmania parasites, manifested significant dose-dependent increase in its leishmanicidal activities against Leishmania major and Leishmania donovani parasites. The percentage of increase in leishmanicidal activity of L. major-infected MOs were 22.71, 64.34 and 81.34, respectively while in L. donovani-infected MOs, it reached 3.01, 32.28 and 74.38, respectively. Treatment of leishmania-infected MOs with rh-GMCSF (250 U/mL) for different periods of time up to 96 hours, induced a significant time-dependent reduction in the percentage of infected cells and the parasitic load (No. of amastigotes/100 MOs). After 96 h of treatment with rh-GMCSF, the percentages of reduction in the infection rates were 82.45 in L.major-infected MOs (p < 0.001) and 39.65 in L. donovani-infected cells (p < 0.01). The percentage of reduction in the parasitic load reached 90.82 (p < 0.001) and 36.6 (p < 0.05) in MOs infected with L. major and L. donovani, respectively. The priming effect of rh-GMCSF on superoxide anion production by human MOs stimulated with phorbol myristate acetate (PMA) was both dose-dependent and time-dependent. In 72 hour-old human MOs, the maximum superoxide anion release was generated by MOs primed for 45 min with 500 U/mL of rh-GMCSF. These cells produced 8.960 +/- 2.075 nmol/5 x 10(4) MOs/ 180 min as compared to 4.563 +/- 1.773 nmol/5 x 10(4) unprimed cell control/180 min (p < 0.001).

Animals↗
PubMed1994

Risk factors for fetal death in white, black, and Hispanic women. Collaborative Group on Preterm Birth Prevention.

OBJECTIVE: To document the relation between stillbirth and various demographic, obstetric, and medical risk factors. METHODS: We analyzed the risk factors and medical origins of 403 stillbirths. The population studied included 34,350 births occurring during the March of Dimes Preterm Birth Prevention Trial. All births occurring in five perinatal centers from 1982-1986 were included in the analysis. Stillbirth was defined as those infants born at 20 weeks' gestation or later whose Apgar score was 0 at 1 and 5 minutes. RESULTS: Stillbirth occurred in 1.2% of all births. Fifty-one percent occurred before 28 weeks and only 18% were at term. Blacks had a greater risk of stillbirth when compared to other women. Prior preterm delivery yielded nearly a two-fold increase in the risk of stillbirth. Preeclampsia, chronic hypertension, and class A or class B-R diabetes were not associated with an increased risk of stillbirth. Other medical factors (hemoglobinopathies, Rh sensitization) resulted in a greater than sixfold increase in the rate of stillbirth, and congenital anomalies resulted in a fivefold increase. Abruption was associated with a 12-fold increase in the risk of stillbirth; nearly 14% of all stillbirths were associated with abruption. CONCLUSION: Eighty-two percent of all stillbirths occurred before term, and more than 50% occurred before 28 weeks. The majority of stillbirths were not explained by medical complications, but instead were often associated with other risk factors related to preterm birth. Further investigations are needed to understand the complex etiology of stillbirth.

Adolescent↗
PubMedDate not supplied

Combined effect of 5-fluorouracil and recombinant tumor necrosis factor against human gastric carcinoma cell lines.

This study was performed to investigate the direct effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interleukin-2 (rH-IL-2), either alone or in combination, on the cytotoxicity of 5-FU measured by MTT assay against human gastric adenocarcinoma cell lines (MKN-28 and MKN-45), and also to determine the optimal schedule for their combination. The antitumor activity of rH-TNF was enhanced more than 42% by 10(2) U/ml of rH-IL-2. The enhancing effects of rH-TNF and rH-IL-2 on the cytotoxicity of 5-FU were evaluated in terms of Modification Index(MI), the MI value at 10 U/ml rH-TNF was 1.6; the MI at the same concentration of rH-TNF in the presence of 10(2) U/ml of rH-IL-2 was 2.1. These results demonstrated that the antitumor effect of 5-FU was enhanced 1.6 times by 10 U/ml of rH-TNF and further enhanced by the combined use of rH-TNF and rH-IL-2. The combined effect of equal concentrations of 5-FU and rH-TNF was superior or equivalent to that of 5-FU or rH-TNF alone. The sequence of 5-FU followed by rH-TNF and rH-IL-2 showed a higher inhibitory effect than the reverse sequence. This sequence combination seems worthy of further consideration for the treatment of gastric cancer.

Adenocarcinoma↗
PubMed1987

In vitro antitumor effect of recombinant human tumor necrotizing factor on cultured human cancer cell lines and freshly isolated lung cancer cells by the human tumor clonogenic assay.

In vitro antitumor effects of human recombinant tumor necrotizing factor (rH-TNF) were examined against nine lung cancer cell lines including six non small and three small cell lung cancer, four stomach cancer cell lines and 30 freshly isolated lung cancer cell samples by the human tumor clonogenic assay. rH-TNF did not show any inhibitory effect on the colony formations of lung and stomach cancer cell lines, except for PC10 established from squamous cell carcinoma even at the high concentration. The overall response rate of fresh material was 11.5%. The colony formations of only two materials from 20 patients without prior chemotherapy were significantly suppressed by rH-TNF in vitro. Three specimens of adenocarcinoma exhibited more than 70% decrease in colony number by treating with 100 and 1000 u/ml of rH-TNF resulting in the response rate of 15.8% (3/19). From these results, it can be concluded that rH-TNF has modest direct cytotoxic effect on lung cancer, and additional study against adenocarcinoma of the lung might be warranted.

Antineoplastic Agents↗
PubMed1987

In vitro growth inhibition of cisplatin-resistant human lung cancer cell lines by recombinant human tumor necrosis factor and/or recombinant human interferon-gamma by virtue of collateral sensitivity.

The colony-inhibitory effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon-gamma (rH-IFN-gamma) were evaluated in four human lung cancer cell lines and their cisplatin-resistant sublines. The cell lines tested were PC-7 and PC-9 (adenocarcinoma), H69 and N231 (small cell lung cancer) and four cisplatin-resistant sublines, PC-7/1.0, PC-9/0.5, H69/0.2 and N231/0.2, which were 20.0, 7.1, 4.8 and 8.4 fold resistant to cisplatin, respectively, compared to the respective parental cell line in terms of IC50 in a soft agar colony assay. All parental cell lines were resistant to rH-TNF and rH-IFN-gamma, alone or in combination. However, two resistant sublines showed sensitivity to rH-TNF and rH-IFN-gamma. Colony formation by PC-9/0.5 was significantly inhibited, in the absence or presence of cisplatin, by 10(2) U/ml of rH-TNF (less than 50% of control) and the inhibition was synergistic with that produced by 10(3) or 10(4) U/ml of rH-IFN-gamma. RH-IFN-gamma inhibited the colony formation of H69/0.2 only at the highest concentration tested (10(4) U/ml) (less than 50% of control) and the combined effect with rH-TNF was additive. These results suggest that rH-TNF and rH-IFN-gamma may have some potential in overcoming cisplatin resistance by virtue of collateral sensitivity.

Cisplatin↗
PubMed1988

Synergistic cytotoxicity of recombinant human TNF and various anti-cancer drugs.

A synergistic increase in the cytotoxic effects of recombinant human tumor necrosis factor (rH-TNF) and anti-cancer drugs was demonstrated in vitro. The cytotoxicity of rH-TNF against L-M cells in combination with Mitomycin C (MMC), Adriamycin (ADM), Cytosine arabinoside (Ara-C), Actinomycin D (ACD), Daunomycin (DM), Cisplatin (CDDP), Vincristine (VCR), and 5-Fluorouracil (5FU), based on the concentration necessary for 50% inhibition of cell growth (IC50), was 4 to 347 times as high as that of rH-TNF alone. The results suggest that combination therapy including rH-TNF and anti-cancer drugs may be of value in the treatment of malignancy in human patients.

Antineoplastic Agents↗
PubMed1987

Antitumor effects of recombinant human tumor necrosis factor against human tumor xenografts transplanted into nude mice.

Antitumor activities of recombinant human tumor necrosis factor (rH-TNF) against human tumor xenografts in nude mice were studied. Thirteen human tumor xenografts serially transplanted into nude mice were used for experiments; five gastric, two breast, two gallbladder, one colon and one esophageal carcinoma, one liposarcoma and one squamous carcinoma of the neck. They were inoculated into the subcutaneous tissue of BALB/c nu/nu nude mice and the treatment was started when the estimated tumor weight reached 100-300 mg. rH-TNF was administered intratumorally at schedule of qd X 5 or q3d X 5. rH-TNF showed a marked antitumor activity against various human tumors. The hemorrhagic necrosis was observed in all types of the human tumor xenografts (100 per cent), and the complete regression of the tumor was noted in 4 of 11 tumors (36.4 per cent). On the contrary, intraperitoneal rH-TNF exhibited little antitumor effect. The additive effect in the combination of TNF and Mitomycin C was observed against two Mitomycin C resistant gastric tumors.

Animals↗
PubMed1998

Cytotoxicity induced by recombinant human tumor necrosis factor-alpha dependent on the types of its receptors on canine cells.

Based on the recent findings that show how recombinant human tumor necrosis factor (rh-TNF)-alpha has potent antitumor activity on human cancer patients when it locally administrated, we have tested the cytotoxicity of rh-TNF-alpha on 3 canine cultured cells: (1) canine kidney carcinoma (CKCa-1), (2) mastocytoma and (3) Mardin Darby canine kidney cells (MDCK). The cell surface expression of TNF-alpha receptors on these canine cells was also determined with anti-human TNF RI and RII polyclonal antibodies. Our data shows that on CKCa-1 which has TNF RI receptors rh-TNF-alpha induced cytotoxicity. By contrast, it exhibited no toxicity on canine mastocytoma which has mainly RII receptors. The data also suggest actinomycin D (ACT-D), an anticancer antibiotic, enhanced the cytotoxicity of rh-TNF-alpha. Combined with ACT-D, rh-TNF-alpha showed the cytotoxicity on MDCK which possessed both TNF RI and RII receptors. The results indicate that the cytotoxicity of rh-TNF-alpha depends on the presence of TNF RI receptors on canine tumor cells.

Animals↗
PubMed2001

Effect of recombinant human basic fibroblast growth factor on acute inflammation in mice and rats.

AIM: To investigate the anti-inflammatory effects of recombinant human basic fibroblast growth factor (rh-bFGF). METHODS: Several inflammation models such as croton oil-induced ear swelling, carrageenan-induced hind paw edema, and acute peritonitis in rats or mice were prepared. Superoxide dismutase (SOD) activity was measured by hydroxyamine method, nitric oxide (NO) concentration by Griess reaction assay, nitric oxide synthase (NOS) activity by NADPH-diaphoras stain assay, N-acetyl-beta- D-glucosaminidase (NAG) activity by colorimetry, prostaglandin E2 (PGE2) production by radioimmunoassay (RIA), malondialdehyde (MDA) content by thiobarbituric acid (TBA) fluorescence technique, and protein content by Coomassie brilliant blue method in peritoneal exudate in rats. RESULTS: Recombinant human bFGF 2, 4 kU/kg im inhibited croton oil-induced ear swelling and carrageenan-induced paw edema in mice. In addition, rh-bFGF 2, 4 kU/kg im reduced neutrophil counts in the rat peritoneal exudate, and lessened protein content in peritoneal exudate in rats and mice. In the rat peritonitis induced by carrageenan, rh-bFGF 4 kU/kg decreased the MDA and NO levels, inhibited the NOS activity, augmented the SOD activity, and lowered the production of PGE(2) in exudate. However, rh-bFGF had no effect on NAG content. CONCLUSION: Recombinant human bFGF has an anti-inflammatory effect and its mechanisms are related to the inhibition of NOS activity, reduction of NO, MDA, and PGE(2) content, and increase of SOD activity.

Animals↗
PubMed1992

Effects on tumour microcirculation in mice of misonidazole and tumour necrosis factor plus hyperthermia.

We examined the effects of misonidazole (MISO) and recombinant human tumour necrosis factor (rh-TNF) on tumour blood flow in mice given hyperthermic treatments. MISO (500 mg kg-1) or rh-TNF (6 x 10(4) unit kg-1) was administered intraperitoneally (i.p.) prior to hyperthermia to nude mice bearing a xenoplanted human gastric cancer and tumour blood flow was measured by a hydrogen diffusion method based on polarographic determinations. MISO plus hyperthermia produced a temperature-dependent decrease in blood flow and, at 43.5 degrees C, the flow decreased to 15-30% of control and remained low for up to 24 h. Blood flow following rh-TNF plus hyperthermia was less than that at the same temperatures following MISO plus hyperthermia, and, at 43.5 degrees C, the flow decreased to 10-20% of control and remained low for up to 48 h. Tumour growth delay was closely related to the duration of the decrease in blood flow. Thus, the profound decrease in tumour blood flow following hyperthermia plus MISO or rh-TNF and the consequential tumour regression may well be of potential clinical significance.

Adenocarcinoma↗
PubMed2000

Preparative two-step purification of recombinant human basic fibroblast growth factor from high-cell-density cultivation of Escherichia coli.

Aggregation and precipitation are major pitfalls during bioprocessing and purification of recombinant human basic fibroblast growth factor (rh-bFGF). In order to gain high yields of the soluble protein monomer with high biological activity, an efficient downstream process was developed, focussing on the combination of expanded bed adsorption (EBA) and heparin chromatography. After expression in E. coli TG1:plambdaFGFB, cells were harvested and washed; then the rh-bFGF was released via high pressure homogenization. The high viscosity of the feedstock of about 40 mPa s, showing non-newtonian behaviour, was reduced to 2 mPa s by the addition of DNase. The homogenate (5.6 l) was loaded directly on an expanded bed column (C-50) packed with the strong cation-exchanger Streamline SP. In the eluates, histone-like (HU) protein was identified as the main protein contaminant by sequence analysis. The thermodynamics and kinetics of rh-bFGF adsorption from the whole broth protein mixture were determined in view of competition and displacement effects with host-derived proteins. Optimal binding and elution conditions were developed with knowledge of the dependence of rh-bFGF adsorption isotherms on the salt concentration to allow direct application of eluates onto Heparin HyperD. This affinity support maintained selectivity and efficiency under CIP and over a wide range of flow-rates; both is advantageous for the flexibility of the purification protocol in view of a scalable process. Remaining DNA and HU protein were separated by Heparin HyperD. The endotoxin level decreased from approximately 1,000,000 EU/ml in the whole broth to 10 EU in 3 mg bFGF per ml. The final purification protocol yields >99% pure rh-bFGF as judged from SDS-PAGE and MALDI-TOF mass spectrometry with high mitogenic activity (ED50=1-1.5 ng/ml) of the lyophilized sample. In comparison to the conventional process, the overall protein recovery rose by 15% to 65% with saving time and costs.

Chromatography, Affinity↗
PubMed1991

[Ureteral cancer resembling pulmonary edema induced by recombinant human tumor necrosis factor].

A 73-year-old woman with ureteral cancer and multiple systemic metastasis was admitted complaining of dyspnea on exertion after administration of recombinant human tumor necrosis factor (rH-TNF). On chest examination, coarse crackles were heard during inspiration throughout the lungs. Chest roentgenogram revealed a ground glass infiltration, an air bronchogram in the right lung field and an ill-defined right pulmonary artery. Her symptom and chest roentgenological finding improved and coarse crackles were not heard after discontinuation of rH-TNF. Neutrophils and lymphocytes of bronchoalveolar lavage fluid increased and transbronchial lung biopsy specimens showed slight thickening of alveolar septa with infiltration of inflammatory cells. The pulmonary edema was thought to be caused by rH-TNF which induces adherence of neutrophils to endothelium and stimulates them to increase lysosomal enzyme release and oxygen radical production. As a results, it is thought pulmonary permeability might be increased.

Aged↗
PubMed1994

TNF receptor number-dependent cytotoxicity to TNF-resistant human esophageal cancer cell lines by combination with recombinant human necrosis factor and hyperthermia.

The synergistic effect of recombinant human tumor necrosis factor (rh-TNF) and hyperthermia on five established cell lines of human esophageal cancer (SGF series) was analyzed by in vitro assays. The SGF cell lines were either resistant or slightly sensitive to rh-TNF. However, they became highly sensitive to rh-TNF even at as low a concentration as 10 U/ml and dose-dependently when combined with hyperthermia (43.5 degrees C, 60 min). This result was due to synergistic effects of rh-TNF and hyperthermia, and the degree of the effect increased with the hyperthermic temperature and TNF concentration. The number of TNF receptors per cell varied widely from cell line to cell line, from 4,400 to 23,100, which did not correlate to the extent of cytotoxicity by rh-TNF alone. The degree of synergistic effect of rh-TNF and hyperthermia was evaluated quantitatively in terms of a Synergistic Index (S. I. = Predicted cell viability/Experimental cell viability): A significant correlation was found between the logarithmic S. I. and the number of TNF receptors. These findings indicated that the combination of rh-TNF and hyperthermia produced a significant antitumor effect even on the cell lines poorly sensitive to TNF in a receptor-dependent manner, although the cellular sensitivity to TNF alone was not directly correlated to the number of TNF receptors.

Drug Screening Assays, Antitumor↗
PubMed1989

Exacerbation of toxic effects by endotoxin contamination of recombinant human tumor necrosis factor.

The toxic effects of endotoxin-free human recombinant tumor necrosis factor (rH-TNF), shown to contain less than 50 pg endotoxin/mg rH-TNF, were investigated and compared with those of rH-TNF and endotoxin coadministered at 4-400 ng endotoxin/mg rH-TNF in female Sprague-Dawley rats. The mean lethal dose of 5.9 mg/kg rH-TNF found for the endotoxin-free rH-TNF was far higher than that attributed to rH-TNF by other investigators. Coadministration with endotoxin derived from E. Coli. Salmonella abortus equi, or Serratia marcescens reduced the apparent mean lethal dose of rH-TNF in correspondence to the endotoxin concentration, with a value of 0.7 mg/kg rH-TNF observed at 1600 ng, 757 ng, and 5260 ng endotoxin/mg rH-TNF, respectively. Coadministration also resulted in more severe histopathologic and physicochemical effects than rH-TNF alone. Histopathologic abnormalities observed only in coadministration included interlobular edema and hemorrhage of the pancreas and, most remarkably, splenomegaly, which was not observed with rH-TNF alone even at lethal doses. The results indicate that particular care in determining endotoxin contamination is essential in any consideration of TNF toxicity.

Animals↗
PubMed1997

Stabilization of rat heart mitochondria by alpha-tocopherol in rats.

alpha-Tocopherol (alpha-T) acts by different mechanisms: scavenging free oxygen radicals (FOR) and stabilizing membranes; both may contribute to the prevention of the pathogenesis of diseases like cardiovascular events. The present work shows that alpha-T breaks the vicious cycle generated by damaged mitochondria. The latter stimulate the immune system increasing FOR formation that leads to more damaged mitochondria. alpha-T inhibits lipid peroxidation induced by recombinant human tumor necrosis factor (rh-TNF). Polymorphonuclear neutrophils (PMN) are activated by TNF to produce FOR causing lipid peroxidation of cardiomyocyte membranes. Since TNF is used as a therapeutic agent against certain tumors, treating patients with alpha-T could protect them against systemic side effects of TNF.

Animals↗