Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Passive immunization against TNF allowed non-tumor-bearing C3H/HEN mice and tumor-bearing C57BL/6 mice to tolerate significantly more doses of IL-2 before death (p less than 0.005 and p less than 0.001, respectively). The antitumor effect of IL-2 against both 3-d and 10-d pulmonary metastases was maintained in mice treated concurrently with neutralizing antibodies to TNF. In one experiment with 10-d pulmonary metastases, increased administration of IL-2 made possible by passive immunization against TNF significantly improved the antitumor response compared to equitoxic doses of IL-2 and control antibody. The results indicate that TNF is a mediator of IL-2 toxicity but contributes minimally to the antitumor effects of IL-2. Strategies to inhibit TNF may improve the therapeutic index of IL-2 as a neoplastic agent.
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PMID:Passive immunization against tumor necrosis factor partially abrogates interleukin 2 toxicity. 278 1

These studies were designed to examine the immunodulatory and immunotherapeutic properties of recombinant murine interferon gamma (rM IFN-gamma) and recombinant human tumor necrosis factor (rH TNF). We report that rM IFN-gamma activated murine natural killer cells and macrophages in a dose-dependent manner in vivo. The rM IFN-gamma, which demonstrated a bell-shaped therapeutic response curve, must be administered at specific doses and schedules to produce optimal therapeutic activity. Optimal activity was observed after i.v. administration of 50,000 U/animal rM IFN-gamma three times per week. In contrast, rH TNF produced its major therapeutic activity in the treatment of metastatic disease after i.v. but not i.p. administration. The therapeutic effects of rH TNF were as great in these in vivo systems as those of rM IFN-gamma. Furthermore, rH TNF had additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unlike rM IFN-gamma, rH TNF did not activate natural killer cells in vivo or in vitro but did augment in vivo and in vitro macrophage tumoricidal activity. It also had synergistic cytostatic properties with rM IFN-gamma for some murine tumor cell lines in vitro. High levels of rH TNF were readily detected in the serum with a half-life of approximately 30 min after i.v. administration. In contrast, only minimal serum TNF activity occurred after i.p. administration, suggesting that i.v. administration may more efficiently facilitate systemic therapeutic activity. In summary, rH TNF and rM IFN-gamma have therapeutic activity for metastatic disease as individual agents and additive therapeutic activity when used in combination. Furthermore, it appears that in addition to therapeutic potential as cytostatic agents, the immunomodulatory properties of rH TNF have a role in its therapeutic properties.
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PMID:Immunomodulatory and immunotherapeutic properties of recombinant gamma-interferon and recombinant tumor necrosis factor in mice. 310 65

In recent studies, we have demonstrated that recombinant human tumor necrosis factor (rH TNF), as a single agent, has only minimal therapeutic activity for the treatment of metastatic disease, but when combined with recombinant murine gamma-interferon (rM gamma-IFN), we observed significantly more therapeutic activity than when either agent was administered alone. However, this combination also resulted in increased toxicity. Thus, we undertook a systematic toxicologic study of rH TNF alone or in combination with rM gamma-IFN. Briefly, the toxicity was similar to the generalized Shwartzman's reaction seen during endotoxin shock, with multifocal microthrombi and ischemic necrosis as sequelae. Lesions were observed in the lungs, liver, gastrointestinal tract (preferentially in the duodenum and cecum), testes or uterus, and bone marrow. Our results suggest that TNF (either directly administered or induced in situ) and its induction of arachidonic acid metabolites form one element of toxicity in this model. This conclusion is supported by studies revealing that the toxicity of rH TNF in combination with rM gamma-IFN can be reduced by inhibitors of the cyclooxygenase/lipoxygenase pathway.
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PMID:Toxicity of tumor necrosis factor is synergistic with gamma-interferon and can be reduced with cyclooxygenase inhibitors. 311 9

The present studies were undertaken to examine the immunotherapeutic properties of recombinant murine interferon-gamma (rM IFN-gamma), recombinant human tumour necrosis factor (rH TNF), and recombinant human interleukin-2 (rH IL-2) in preclinical metastasis models. It was observed that these cytokines have disparate mechanisms of therapeutic activity as well as different optimal therapeutic protocols. Thus, not only is the dose important to the therapeutic activity of each of the agents; so also is the route of administration, schedule of administration, duration of administration, and sequence of administration. The rM IFN-gamma has a narrow window of activity, with a bell-shaped therapeutic response with a dosage optimum at 50,000 U/animal of rM IFN-gamma administered 3 times per week. In contrast, rH IL-2 has optimal therapeutic activity for the treatment of metastatic disease after i.p. as compared to i.v. administration. This appears to be associated with the serum pharmacokinetics, since longer serum concentrations are achieved following i.p. administration although lower serum levels are also achieved. RH IL-2 has a biphasic dose-response curve for therapeutic activity with optima from 100 to 1000 U/animal and at doses greater than 100,000 U/animal. The lower doses appear to be associated with T cell augmentation whereas the higher doses are associated with NK cell or LAK cell augmentation. RH TNF has therapeutic activity for the treatment of metastatic disease after i.v. but not i.p. administration. High levels of rH TNF are readily detected in the serum following i.v. administration, with a serum half-life of approximately 30 min. In contrast, only minimal serum TNF activity is observed after i.p. administration, suggesting that this may be the origin of the increased therapeutic activity following i.v. administration. Furthermore, rH TNF has additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unfortunately, the additive therapeutic activity of rM IFN-gamma and rH TNF is also associated with increased toxicity. However, in preliminary experiments it was found that the b.i.d. administration of aspirin at 25 mg/kg resulted in decreased toxicity. In summary, the recombinant cytokines provide a challenge both preclinically and clinically to the development of optimal therapeutic protocols, and suggest that close attention must be paid to the dose, route, schedule, duration, and sequence of their administration.
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PMID:Preclinical approaches to the treatment of metastatic disease: therapeutic properties of rH TNF, rM IFN-gamma, and rH IL-2. 311 44

The antitumor effect of recombinant human tumor necrosis factor (rH-TNF) on two clones of rat fibrosarcoma with different metastatic potential to lymph nodes was examined. The colony formation of clone A, which has high metastatic potential, was completely inhibited by continuous exposure to rH-TNF at 50 U/ml. In contrast, colony formation of clone G, which has low metastatic potential, was not inhibited by high concentrations of rH-TNF (10,000 U/ml). The inhibitory effect of rH-TNF on colony formation by clone A was also observed with a 1-h exposure to rH-TNF. This effect was time and concentration dependent, as determined by the colony assay, 3H-thymidine uptake assay, and 51Cr-release assay. 3H-thymidine and 3H-uridine uptake per cell of clone A exposed to rH-TNF was not decreased. This suggests that the mechanisms of the antitumor effect of rH-TNF were not due to inhibition of DNA and RNA synthesis of tumor cells. In vivo growth and lymph node metastases of clone A inoculated i.p. to Donryu strain rats were completely suppressed by 14 consecutive i.p. injections of 10(5) or 10(6) U/kg per day of rH-TNF. On the other hand the growth of clone G was not influenced by rH-TNF administration.
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PMID:The different effects of recombinant human tumor necrosis factor on rat fibrosarcoma sublines. 359 81

The interaction of tumor cells with endothelial cells is a key event in tumor metastasis. We established an in vitro invasion assay system, in which the invasion of tumor cells after interaction with endothelial cells can be examined. Two chamber culture wells separated by porous membrane were used. Human umbilical vein endothelial cells (HUVEC) were placed on porous membranes coated with matrix components. The invasion by HT1080 fibrosarcoma cells was determined in this system by counting the number of cells that moved through the membranes from upper to lower chambers. HUVEC cells did not migrate through the membranes as judged by the staining with UEA-I. Observation by scanning electron microscopy revealed that HT1080 cells bound to HUVEC surfaces and migrated underneath the HUVEC monolayer. Effects of antibodies specific for cell surface adhesion molecules on the migration of HT1080 cells were examined. Invasion of uncoated membranes and membranes coated with HUVEC cells was compared. Antibody against E-selectin significantly suppressed an increase of HT1080 cell invasion of HUVEC monolayers stimulated by IL-1 beta or TNF alpha. Antibody against integrin alpha 3 subunit remarkably inhibited the invasion of HUVEC cell-coated membranes, suggesting that integrins with the alpha 3 subunit may play an important role in the transendothelial invasion by HT1080 cells.
Clin Exp Metastasis 1994 Jul
PMID:A novel in vitro assay system for transendothelial tumor cell invasion: significance of E-selectin and alpha 3 integrin in the transendothelial invasion by HT1080 fibrosarcoma cells. 751 60

We have reported that patients with metastatic melanoma treated with an autologous, dinitrophenol-modified vaccine develop inflammatory responses at tumor sites. Histologically, these inflamed lesions are characterized by T cell infiltration, which is sometimes associated with tumor cell destruction. We tested biopsy specimens of eight subcutaneous metastases that had developed inflammation following vaccine treatment for expression of mRNA for interferon gamma (IFN gamma), interleukin-4 (IL-4), tumor necrosis factor alpha (TNF alpha), and IL-10. Post-vaccine, inflamed biopsies contained mRNA for IFN gamma (5/8), IL-4 (4/8) or both (3/8), and for TNF alpha (4/7). In contrast, IFN gamma mRNA was detected in only 1/17 and TNF alpha mRNA in 2/16 control specimens (pre-treatment lymph node metastases or non-inflamed subcutaneous metastases). mRNA for IL-10, a cytokine with anti-inflammatory properties, was detected in 24/25 melanoma metastases and was independent of lymphoid content; in situ the reverse transcriptase/polymerase chain reaction confirmed that melanoma cells were the major source. These findings may provide a new parameter by which to measure the effects of cancer immunotherapy.
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PMID:Expression of cytokine mRNA in human melanoma tissues. 755 83

Interleukin 1 alpha (IL1 alpha) and tumor necrosis factor alpha (TNF alpha) have been successfully incorporated into specific phosphatidylcholine (PC) and phosphatidylserine (PS) multilamellar vesicle (MLV) liposomes by modifying the concentration of calcium ion and pH of the encapsulation buffer. Under these conditions, some of the cytokines may attach to the exterior surface of the MLV and therefore be readily accessible to target cells for receptor binding and signal transduction. These cytokine-associated liposomes are stable for up to 2 weeks in serum-free buffer, and leakage of cytokines into medium containing 10% fetal bovine serum was about 50% at the end of a 3-day incubation period at 37 degrees C. The biological activities mediated by liposomal IL1 alpha and TNF alpha were specific: the stimulation of thymidine uptake in T-helper D10 lymphocytes and the cytolysis of TNF alpha-sensitive L929 target cells could be blocked by specific neutralizing antibodies in a dose-dependent fashion. When administered intravenously into C57BL/6 mice bearing the syngeneic B16F10 murine melanoma cells, dual entrapment of liposomal IL1 alpha and TNF alpha significantly reduced the number of metastatic tumor nodules in the lungs and prolonged the life span of the animals. Thus, liposomal IL1 alpha and TNF alpha displayed significant in vivo antitumor activity against the IL1 alpha- and TNF alpha-resistant B16F10 metastatic murine melanoma.
Clin Exp Metastasis 1995 Jul
PMID:Antitumor effects of liposomal IL1 alpha and TNF alpha against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice. 760 87

The purposes of this study were to determine the maximally tolerated dose (MTD) of IL-2 when sequentially administered following TNF (at its MTD), to identify any unique toxicities, and determine the immunomodulatory effects of this combination. Patients with metastatic cancer were treated with 160 micrograms/ml rTNF by rapid i.v. infusion for 5 days, followed by rIL-2 therapy daily at doses up to 18 x 10(6) IU/m2/day for 5 days and 6 x 10(6) IU/m2/day for 7 days. Cycles were repeated at 3- or 4-week intervals until progressive disease or unacceptable toxicity developed. Fifteen patients received 46 cycles of therapy (range 1-8, median 3). Major toxicities included hypotension, weight loss, and decreased performance status comparable to that reported with rIL-2 alone. No novel toxicities were identified. Two of 14 patients who received two cycles of therapy had objective responses (1 complete, 1 partial). Both occurred in patients with malignant melanoma, lasted 30 and 75 weeks, respectively, and included a complete response in liver metastasis. Dosage reductions of IL-2 were necessary for 3 patients over 11 treatment cycles (23%), and rTNF in 1 patient for 1 cycle (2%). The MTD of 5-day infusional rIL-2 was determined at 18 x 10(6) IU/m2/day. rTNF did not augment natural killer/lymphokine-activated killer activities beyond that commonly seen with IL-2 infusions. We conclude that full doses of rTNF can be combined with escalating rIL-2 infusions in an outpatient setting without additive toxicity and with clinical activity in patients with malignant melanoma.
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PMID:Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2. 761 42

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. 761 44


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