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)

Tumor necrosis factor is a cytokine produced by activated macrophages that causes hemorrhagic necrosis in various tumours. In preliminary clinical trials, patients have developed various degrees of respiratory insufficiency following administration of rTNF. Twenty-seven patients were studied prospectively to evaluate the effect of administration of rTNF on pulmonary function. Sixteen of the 27 patients completed the eight-week course of daily IM injection of rTNF. Spirometric data and Dsb were measured at baseline and on days 8, 15, and 56 of treatment. Both patients with and without progressive pulmonary metastases demonstrated a comparable mean decline in Dsb (-10.7 +/- 9.6 percent [+/- SD] and 14.7 +/- 10.0 percent, respectively; p less than 0.01) not accounted for by either a decline in the hemoglobin content of the blood or a reduction in alveolar volume. Marked interindividual variability in the response of Dsb to rTNF therapy was noted. The reduction in Dsb reached a plateau by day 15. In contrast, alveolar volume and FVC remained essentially unchanged throughout the course of treatment. Measurements of Dsb performed two weeks after cessation of rTNF therapy in seven of the 27 patients showed only a modest trend toward recovery, which was not statistically significant. We conclude that the administration of rTNF for the treatment of malignant neoplasms in this dosage and schedule can cause significant pulmonary injury reflected by a reduction in Dsb which reaches a plateau by two weeks after initiation of therapy.
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PMID:Pulmonary toxicity of recombinant human tumor necrosis factor. 275 16

The purpose of these studies was to determine whether the production of the cytokine epidermal cell thymocyte-activating factor (ETAF) by human squamous cell carcinoma (SCC) cells correlated with their tumorigenicity and metastatic potential in athymic nude mice. Cells of the human SCC line A431 produced rapidly growing subcutaneous tumors, few experimental lung metastases, and low levels of ETAF activity in vitro. In contrast, cells of the SCC Colo-16 line produced slower growing subcutaneous tumors, high numbers of experimental lung metastases, and a high level of ETAF activity in culture supernatants. The apparent relationship between production of ETAF and experimental metastasis formation was not consistent. Clonal populations of the SCC A431 and Colo-16 were isolated in vitro. The clones of Colo-16 varied in their ability to produce experimental metastases and in production of ETAF in vitro. However, the levels of ETAF production did not correlate with the propensity of the SCC cells to produce experimental metastases. We conclude that while the growth and metastasis of human SCC in nude mice may benefit from production of the cytokine ETAF, the ETAF production per se is not invariably linked with the capability of the SCC cells to metastasize.
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PMID:Tumorigenicity and metastatic behavior in nude mice of two human squamous cell carcinoma lines that differ in production of the cytokine ETAF/IL-1. 304 10

Organ cultures of explanted V2 carcinoma specimens as well as cultured V2 carcinoma cells produced a cytokine which stimulated rabbit skin fibroblasts to synthesize increased amounts of cathepsin B. The cytokine was released by the tumor cells as a heterogeneous family of polypeptides: two inactive forms (Mr = 55,000 and 68,000) which could be activated by limited proteolysis with trypsin and three active forms with Mr values of 12,000, 16,000 and 18,000. The treatment of inactive cytokine-containing tumor-conditioned media with trypsin, followed by chromatographic separation of the products, suggested that the high-Mr inactive components may represent precursors of the active forms. Cathepsin B was immunolocalized in the tumor-host interzone in co-cultures of tumor and host tissues. Some other possible activities of the tumor cytokine which emerged from previous studies, such as the induction of host cells to produce increased levels of collagenase and extracellular matrix, as well as the stimulation of host cell proliferation, are discussed in the light of the new findings and are proposed as an important mechanism in tumor invasion.
Invasion Metastasis 1988
PMID:Tumor-host interactions in the rabbit V2 carcinoma: stimulation of cathepsin B in host fibroblasts by a tumor-derived cytokine. 328 70

The in vivo anti-tumor activity of 2 recombinant cytokines, interleukin-2 (rIL-2) and human hybrid interferon alpha (rHuIFN-alpha A/D), were tested using the murine reticulum cell sarcoma M5076. Experimental hepatic metastases, following i.v. injection of tumor cells, and tumor growth and spontaneous metastases, following s.c. injection of tumor cells, were inhibited to a greater extent in mice treated with a combination of these cytokines than in animals treated with either one alone. When used in conjunction with surgical removal of the s.c. tumor, treatment of mice with both cytokines significantly prolonged survival of tumor-bearing animals. Injection of normal mice with a combination of cytokines, but not with either cytokine alone, resulted in a marked increase in cytotoxic activity of hepatic effector cells. The effector cells in these mice appeared to be NK cells since this enhanced cytotoxicity was markedly reduced in animals treated in vivo with anti-asialo GM1 or in NK-deficient beige mice. Furthermore, no in vivo efficacy was observed in M5076-bearing beige mice treated with these cytokines. Thus, injection of mice with rIL-2 and rHuIFN-alpha A/D results in the induction of an NK-cell-like population in the liver with enhanced cytotoxic activity that correlates with the observed anti-tumor activity in vivo in this murine model. These results suggest that combinations of cytokines, in particular IFN-alpha and IL-2, can be effectively used in combination for the treatment of tumors and/or metastases.
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PMID:In vivo anti-tumor activity of combinations of interferon alpha and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. 349 83

Tumor necrosis factor is a cytokine derived from activated macrophages. This agent is cytostatic and cytolytic against transformed human cell lines in vitro and has in vivo activity against a variety of murine tumors. We report a clinical study of the pharmacokinetics, toxicity, and biological activity of i.v. and i.m. administered recombinant human tumor necrosis factor (rTNF). Twenty patients with metastatic cancer were given rTNF in doses ranging from 1 to 200 micrograms/m2 by alternating i.m. and i.v. bolus injections with a minimal intervening period of 72 h. Each patient received a maximum of eight treatments given twice weekly over a 4-week period. With i.v. bolus administration, serum concentrations of rTNF were detected by enzyme-linked immunosorbent assay at doses of 25 micrograms/m2 or greater. The clearance of rTNF in the serum was described by a monoexponential equation with a half-life calculated to be 14-18 min. After i.m. administration, serum concentrations of rTNF were consistently detected by enzyme-linked immunosorbent assay at doses of 150 micrograms/m2 or greater. Peak concentrations were observed within 2 h and rTNF was occasionally detected, at the lower limit of sensitivity of the assay, at 24 h postinjection. rTNF was well tolerated clinically in this dose range, and there was evidence of antitumor effect.
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PMID:Phase I study of recombinant tumor necrosis factor in cancer patients. 356 16

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.
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PMID:Phase I study of paclitaxel and carboplatin: implications for trials in head and neck cancer. 748 55

The successful treatment of metastases will have to include modalities that can overcome the obstacles presented by the heterogeneous nature of malignant neoplasms and the continuous evolution of variant cells. Macrophages activated to become tumoricidal by interaction with L-MTP-PE may be able to accomplish this. Osteosarcoma appears to be an ideal disease in which to employ L-MTP-PE as an additional adjuvant to present chemotherapy regimens. The lung is the most frequent site of metastases, and pulmonary micrometastases are considered to be present in the majority of patients at diagnosis. Approximately 40% of patients with osteosarcoma develop pulmonary metastases despite the administration of adjuvant chemotherapy. The 2-year disease-free interval has not improved over the past 10 years, despite multiple changes in adjuvant regimens. These data argue that there is a subpopulation of patients who harbor tumor cells that are relatively resistant to all chemotherapy. Unfortunately, this group of patients cannot be identified at the time of initial diagnosis. This necessitates the incorporation of new forms of therapy into the adjuvant chemotherapy protocols for all patients in the hope of eradicating the resistant cells harbored in the 40%. Based on the data summarized previously, L-MTP-PE may improve the clinical outcome of patients with osteosarcoma by activating pulmonary macrophages to destroy residual tumor cells that are not eliminated by chemotherapy. Monocytes from osteosarcoma patients can be rendered cytotoxic to tumor cells by in-vitro incubation with L-MTP-PE and following the intravenous administration of this agent. L-MTP-PE can be given safely to both adults and children with minimal side effects. The whole-body distribution of 99mTc-labeled liposomes containing MTP-PE confirms that the agent is taken up by the lungs. Biologic activity in osteosarcoma patients is revealed by the elevations in plasma levels of several cytokines plus stimulation of monocyte-mediated cytotoxicity following L-MTP-PE infusion and by histologic changes in the pulmonary lesions. Ifosfamide therapy given in combination with L-MTP-PE does not suppress this immune response, as judged by both plasma cytokine levels and tumor histology. Finally, L-MTP-PE has been shown to be effective as a single agent against relapsed osteosarcoma. It is unlikely that the addition of other chemotherapeutic agents to the adjuvant chemotherapy protocols will alter the 65% to 70% 2-year disease-free survival rate associated with osteosarcoma. The preceding data indicate that L-MTP-PE is an active agent against this disease and deserves further investigation. Therefore, the inclusion of L-MTP-PE with chemotherapy is a reasonable alternative to consider to improve the response rate of this disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biologic therapy for osteosarcoma using liposome-encapsulated muramyl tripeptide. 749 Feb 49

Transfer of cytokine genes into tumor cells has proven a valuable approach for cancer treatment. In order to generate a more effective cancer vaccine, we transfected the human interleukin-6 (IL-6) gene into B16 melanoma cells. A B16 cell clone secreting the highest level of IL-6 was obtained by G418-resistant selection, limiting dilution and IL-6 assay. The IL-6-gene-transfected tumor cells exhibited in vitro growth inhibition, reduced tumorigenicity and decreased metastatic competence. After immunization with the inactivated IL-6-gene-transfected vaccine, the murine cytotoxic T lymphocyte activity, natural killer activity and lymphokine-activated killer activity increased markedly. After treatment with the vaccine, the tumor-bearing mice showed significant growth inhibition of subcutaneous tumor, reduction in pulmonary metastases and extension of survival time. The above therapeutic effect was better when low-dose IL-2 was administered simultaneously, although this dosage of IL-2 had no in vivo antitumor effect. These data demonstrated that IL-6-gene-transfected cancer vaccine has a potent antitumor effect via efficient induction of antitumor immunity, and a better therapeutic effect could be achieved when the vaccine is combined with low-dose IL-2 as adjuvant.
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PMID:Induction of antitumor immunity and treatment of preestablished tumor by interleukin-6-gene-transfected melanoma cells combined with low-dose interleukin-2. 749 43

We screened a panel of 8 primary and 21 metastatic melanoma cell lines for constitutive secretion of cytokines. Melanomas expressed bioactivity for TGF-beta (8/25 lines) and IFN (7/12), but not IL-2. Immunoassays detected IL-1 alpha (4/25), IL-1 beta (12/25), IL-6 (13/29), IL-8 (29/29), TGF-beta 2 (5/12) and GM-CSF (11/29), but not IL-3, IL-4, TNF-alpha, or IFN-gamma. There was no preferential association of cytokine production with cells cultured from primary versus metastatic disease, and only IL-8 was produced by all lines tested. These data demonstrate that cultured melanomas produce a variety of cytokines which are potentially capable of influencing tumor growth in vivo.
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PMID:Production of multiple cytokines by cultured human melanomas. 751 80

Tumor metastasis is a major cause of death for cancer patients. This review proposes that the final steps in the development of a distant metastasis may be the most productive targets for clinical development. It cannot be guaranteed that, in "metastasis-free" patients, tumor cells have not invaded out of the primary lesion, intravasated and extravasated from the circulatory system, and are sitting at distant sites as occult micrometastases. The remaining processes involved in outgrowth at metastatic sites, colonization and angiogenesis, are reviewed. Colonization is thought to be accomplished by clonally dominant cell populations through progressive independence from exogenous growth factors, production of growth factors, and stimulatory proliferative responses to traditionally inhibitory cytokines. Therapeutic efforts aimed at interrupting the switch in tumor cell responsiveness to cytokines, rather than to any one specific cytokine, may be most successful at inhibiting metastatic colonization. Angiogenesis has been demonstrated to be directly or indirectly induced by a plethora of cytokines. Partial suppression of neovascularization can be achieved in tissue culture and animal models using various natural and pharmaceutical angiostatic agents. However, as with clonal dominance, such agents must be able to suppress the redundant effects of angiogenesis-promoting factors. This review discusses the current literature on colonization and angiogenesis, emphasizing its underlying mechanisms and potential therapeutic applications.
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PMID:Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. 751 89


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