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)

The serum concentration of the new tumor marker MCA (mucinous carcinoma associated antigen) was determined by an enzyme immunoassay kit method, which is based on the use of a monoclonal antibody b12. The mean MCA values in breast cancer patients (n = 40) were significantly higher than in patients with benign breast disease (n = 55, p less than 0.001) and in control subjects (n = 37, p less than 0.001). When we used the cut-off level 11 KU/l for MCA, 6/37 (16.2%) of control subjects 7/55 (12.7%) of patients with benign breast disease, 18/40 (45.0%) of all breast cancer patients 11/19 (57.9%) of breast cancer patients with axillary node involvement, and 1/1 breast cancer patient with distant metastases were above this cut-off level. For comparison, at the cut-off level of 5 micrograms/l the CEA test was positive in 7/40 (18%) cancer cases, and in 6/19 (32%) of cancer patients with nodal involvement. Patients with axillary nodal metastasis showed higher values than patients without metastasis in both tests (p less than 0.01). The combination of MCA at 11 KU/l cut-off level and CEA at the 5.0 micrograms/l cut-off level reached the diagnostic sensitivity of 0.53, efficiency of 0.73, and specificity of 0.87. It seems that MCA is a promising tumor marker in breast cancer. Especially high values may have diagnostic significance.
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PMID:A new tumor marker MCA in breast cancer diagnosis. 317 56

We have evaluated the effects of chemotherapeutic agents on the toxicity and antitumor benefit of therapy of established murine tumors by high-dose interleukin 2 (IL-2). Cyclophosphamide (Cy), doxorubicin, and bischloroethylnitrosourea were given to normal mice prior to IL-2 administration to test the effects of these agents on IL-2-induced toxicity. Cy at doses of 100 mg/kg and 150 mg/kg completely protected mice from a 100% lethal dose of IL-2, and doses of 50 mg/kg and 150 mg/kg allowed the administration of a median of 4.5 and 10.0 more doses of IL-2, respectively, before death from IL-2 toxicity occurred. Doxorubicin at 8 mg/kg and bischloroethylnitrosourea at 20 mg/kg did not impact on toxicity in IL-2-treated mice. In mice bearing pulmonary metastases of the weakly immunogenic MCA-105 sarcoma, IL-2 increased median survival time from 33 (no IL-2) to greater than 60 days for all doses of IL-2 tested when combined with a single injection of Cy at 75 mg/kg (P less than 0.002). Increasing doses of either Cy or IL-2 produced increasing benefits on survival which were always greater than either treatment alone. These effects of Cy and IL-2 were also seen in mice bearing the nonimmunogenic MCA-101 sarcoma and a murine adenocarcinoma (MCA-38). Doxorubicin and bischloroethylnitrosourea did not consistently enhance the effects of IL-2 treatment. Cy appears to reduce the yield of in vivo generated lymphokine-activated killer cells, but these lymphokine-activated killer cells are still lytic for fresh tumor targets in vitro. Thus, the mechanism of this synergy does not appear to involve stimulation of lymphokine-activated killer cell activity, but may in part involve reduction of tumor burden by the chemotherapeutic agent, an increase in susceptibility of tumor to cellular immune lysis, and/or a decrease in suppressor cell activity mediated by the chemotherapy.
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PMID:Combined effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors. 325 59

Tumor necrosis factor and interleukin-2 each in recombinant form have antitumor activity against established tumors if used in high enough dosages. The problem associated with such high dosages is the high degree of toxicity and expense encountered. Therefore, this study was undertaken to look at the antitumor efficacy of these two lymphokines when used together at dosages well below the toxic levels. Our results using recombinant human interleukin-2 (IL-2) and recombinant human tumor necrosis factor (TNF) against established methylcholanthrene-induced fibrosarcoma (MCA sarcoma) pulmonary metastases showed that TNF and IL-2 therapy at low nontoxic dosages alone did not produce significant tumor regression, but when combined at the same dosage synergize producing significant antitumor effects in mice induced with MCA sarcoma. This was also evident from histopathological examination of the lungs where the maximum tumor reduction along with the maximum lymphocytic infiltration into tumor was seen when TNF and IL-2 were combined. In this tumor regression, inherent immunity of the treated mice was needed, since in those mice in which we induced immunosuppression by using radiation, tumor regression was not seen when TNF and IL-2 therapy was combined in the doses efficacious in immunocompetent mice. Tumor regression is also dependent on the sequence of administration of IL-2 and TNF, since when IL-2 was administered before TNF, the tumor regression was more significant than when TNF was administered before IL-2 or when both were administered simultaneously to mice with established pulmonary tumors. Therefore the synergistic effect of IL-2 and TNF could be used as an efficacious but inexpensive and nontoxic alternative to therapy with lymphokine activated killer (LAK) cells + IL-2.
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PMID:Therapy of disseminated NK-resistant tumor by the synergistic effects of recombinant interleukin-2 and tumor necrosis factor. 325 5

Lymphocytes from mice bearing the weakly immunogenic MCA 105 sarcoma contained pre-effector cells that could be sensitized and expanded in vitro to acquire anti-tumor reactivity. The in vitro sensitization (IVS) required antigenic stimulation by tumor cells and the presence of IL-2 for cellular proliferation. Recent work has also demonstrated that IVS cells could be generated in an IL-2 concentration as low as 2 U/ml. In the present study, we have evaluated therapeutic efficacy of IVS cells generated in different concentrations of IL-2 against advanced metastases established in the lung as well as in the liver. Treatment of microscopic or grossly visible pulmonary metastases established for 3 or 10 days by systemic transfer of IVS cells resulted in significant reductions of the numbers of metastases. On a per cell basis, IVS cells generated in 2 U/ml of IL-2 exhibited at least twofold greater reactivity than cells generated in 1000 U/ml of IL-2. In survival experiments, treatment of established microscopic (day 3) and visible (day 10) pulmonary metastases with 1.5 x 10(7) and 3 x 10(7) IVS cells generated in 2 U/ml of IL-2 resulted in prolongation of survival and cure of the disease in 60 and 30% of animals, respectively. The systemic anti-tumor effect of IVS cells was further investigated in mice with hepatic metastases. Treatment of day 3 microscopic hepatic metastases revealed that as little as 1.2 X 10(7) IVS cells generated in 2 U/ml of IL-2 reduced the mean number of metastases from more than 250 in various control groups to 32. Evaluation by survival demonstrated that transfer of 1.7 x 10(7) and 3.8 x 10(7) IVS cells was capable of prolonging the survival and curing 40 and 30% of mice bearing day 3 and day 9 hepatic metastases, respectively. Again, IVS cells generated in 2 U/ml of IL-2 were more effective therapeutically than cells generated in 1000 U/ml of IL-2. In all experiments, mice were also given IL-2 to enhance the in vivo reactivity of IVS cells. However, the doses of IL-2 alone had no therapeutic benefit. Taken together, our results show that adoptive immunotherapy with IVS cells generated from tumor-bearing mice was an effective means of eliminating advanced metastases in various visceral organs.
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PMID:Adoptive immunotherapy of microscopic and advanced visceral metastases with in vitro sensitized lymphoid cells from mice bearing progressive tumors. 326 61

We investigated the antitumor effects of combined immunotherapy with recombinant human interleukin-2 (rhIL-2) and the recombinant human interferon-alpha (rhIFN-alpha) A/D hybrid in the treatment of established single or multiple murine hepatic metastases. Mice bearing either weakly immunogenic MCA-106 or nonimmunogenic MCA-102 were treated with rhIL-2 alone, rhIFN-alpha alone, or the combination of lymphokines. Therapy was initiated on Day 3 or 10 and continued for 3-4 consecutive days. In the treatment of 3- and 10-day multiple MCA-106 liver metastases, significant reductions in the number of metastases, often more than 90%, were observed with the combination of rhIL-2 and rhIFN-alpha at doses of each lymphokine which had no effect when given alone. This decrease in the number of metastases resulted in a survival benefit that was seen in the combination therapy groups in a dose-dependent manner. Similarly, substantial reductions in tumor weight were seen when the combination of rhIL-2 and rhIFN-alpha was administered to mice with single large hepatic metastases. The decreases in both single and multiple metastatic tumor deposits by the combination of lymphokines were more than that predicted by the additive effect of each treatment alone. With the nonimmunogenic tumor, MCA-102, however, no benefit was derived from the addition of rhIFN-alpha to rhIL-2 therapy. Immunotherapy with recombinant murine interferon-gamma and rhIL-2 was directly compared to therapy with rhIL-2 and rhIFN-alpha. The combination of rhIL-2 and rhIFN-alpha again was found to be effective while recombinant murine interferon-gamma added toxicity but no therapeutic benefit to immunotherapy with rhIL-2 alone. The synergy between rhIL-2 and rhIFN-alpha was shown to be dependent on the host's intact immune system since mice immunosuppressed by sublethal irradiation prior to inoculation of tumor did not respond to the combined treatment. Possible mechanisms of the in vivo synergy between rhIL-2 and rhIFN-alpha are discussed.
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PMID:Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid alpha-interferon in the treatment of established murine hepatic metastases. 326 13

Production of biological response modifiers through recombinant techniques has stimulated interest in immunotherapy of cancer. One of these, interleukin-2 (IL-2), will induce in vivo as well as in vitro proliferation of noncommitted T lymphocytes into lymphokine-activated killer (LAK) cells: cells cytolytic for a broad range of tumor cells. We have demonstrated earlier that immunotherapy with IL-2 and LAK cells will reduce tumor load and prolong survival in a significant way in an intraperitoneal (ip) tumor model as well as in other models. Nevertheless, mice die of one or two metastases escaping immunotherapy. Activation of the host immune system might boost endogenous IL-2 production. Activation might also enhance immunotherapy by increasing the necessary cofactors. Loco-regional allogeneic pretreatment ip 14 days prior to syngeneic tumor challenge did not enhance, but completely abrogated, ip IL-2 and LAK cell therapy (peritoneal cancer index, 0.6 +/- 0.3 vs 2.6 +/- 0.2, P2 = 0.003). Tumor bulk is not the reason for escape of immunotherapy either. One week after intracutaneous (ic) tumor inoculation a noncurative or sham tumor resection was performed, followed by IL-2 and LAK cell therapy either ip or in and around the tumor nodule. No significant difference in tumor diameter or survival of mice was seen. Allogenic tumor cells admixed with syngeneic tumor cells will induce an inflammatory reaction locally and regionally. This inflammatory reaction in the syngeneic host will enhance the treatment with IL-2. The allogeneic (P815) and syngeneic (MCA-105) tumor cell mixture was injected ic. Growth rate was retarded and survival prolonged in a significant way when the cell mixture was treated with ip IL-2 injections; no difference was seen when the admixture was not treated or the syngeneic ic tumor alone was treated with IL-2. We conclude that host immune status and recruitment of immunocompetent cells locally to the tumor site determine the outcome of immunotherapy with IL-2 and LAK cells.
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PMID:Local conditions in the host influence immunotherapy with interleukin-2 and LAK cells. 326 2

Cell motility is an important factor in the metastatic process that can be affected by environmental conditions. A quantitative study was made of the relationship between cell motility and the colonization potential of a mouse colon adenocarcinoma cell line (MCA-38). MCA-38 cells grown in culture did not produce hepatic or pulmonary colonies following ileocolic or tail vein injection, respectively. In contrast, MCA-38 cells adapted to grow in the mouse produced colonies in both organs. The motility of the MCA-38 cells that did not produce colonies, as determined by the depth of penetration into cellulose nitrate filters (8 micron pore size), was significantly less than that of MCA-38 cells with colony-forming potential. Return to in vitro growth resulted in both a loss of colonization potential and a reduction in motility. In this system, secondary organ colonization and in vitro cell motility are positively correlated, suggesting an association between cell motility and metastatic potential.
Invasion Metastasis 1988
PMID:Relationship of in vitro cell motility and colonization potential in a mouse colon adenocarcinoma (MCA-38) cell line. 337 58

We examined the antitumor efficacy of rTNF-alpha administration on established tumor at two visceral sites, lungs and liver. Treatment of B6 mice harboring multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) 10-day pulmonary macrometastases from the MCA-106 sarcoma, with dosages of rTNF-alpha (5-10 micrograms, single dose i.v.) that caused hemorrhagic necrosis and regression of a 6 mm MCA-106 s.c. tumor, had no impact on the number (or size) of lung nodules. Similarly, rTNF-alpha failed to show an antitumor effect in B6 mice with advanced day 8 or 10 multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) hepatic metastases at single i.v. doses up to 20 micrograms, as measured by either enumeration of residual liver nodules or survival. B6 mice injected s.c. with MCA-106 sarcoma and treated with rTNF-alpha as a single i.v. dose on day 0, 3, 5, or 7 experienced marked tumor regression only after the day 7 rTNF-alpha injection, when the tumor had achieved a size of 5-6 mm in diameter. Since tumor size appeared important for rTNF-alpha susceptibility in vivo, we next induced a single hepatic tumor of the MCA-106 sarcoma by the direct injection of cells into the left lobe of the liver and treated these mice at day 10 when the nodule had achieved a size of 5-6 mm in diameter. Increasing doses of rTNF-alpha (up to 8 micrograms) given as a single i.v. injection resulted in increasingly greater reductions in hepatic tumor as well as significant survival benefit of the treated mice. Sites of regressing hepatic tumor exhibited central necrosis accompanied by polymorphonuclear leukocytes and lymphocytes. Collectively, these results show that rTNF-alpha administration can mediate a significant antitumor effect on visceral tumor and suggest that tumor size is an important factor in rTNF-alpha susceptibility not only for tumors growing at s.c. sites but also for those established at visceral sites.
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PMID:Antitumor effect of recombinant tumor necrosis factor-alpha against murine sarcomas at visceral sites: tumor size influences the response to therapy. 338 4

A murine model of experimental hepatic metastases has been developed. The cecum is exteriorized through a midline incision, and 1.5 X 10(5) MCA-38 liver-derived (LD) tumor cells in 0.1 ml was injected into the ileocolic vein (ICV). Ninety-eight percent of injected mice developed hepatic foci. The operative mortality was 6.1%. Micrometastases could first be detected on day 11. Laparotomy of 21 days revealed the presence of a mean of 18 hepatic foci. Experimental hepatic metastases could be palpated 35 days following ICV injection. Mice bearing MCA-38 LD foci survived an average of 53.3 days. This model will be of use in the development of novel approaches for the treatment of hepatic metastasis.
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PMID:Description of a murine model of experimental hepatic metastases. 346 19

The studies described in this paper showed that the combination of i.v.-transferred lymphokine-activated killer (LAK) cells and i.p. injections of recombinant interleukin-2 (RIL-2) was highly effective in vivo in reducing established pulmonary metastases of natural killer cell-resistant, MCA-105 sarcoma and B16 melanoma in mice. A 3-day in vitro incubation of normal C57BL/6 splenocytes in medium containing pure RIL-2 generated LAK cells that, when combined with RIL-2, reduced the mean number of established pulmonary micrometastases of the B16 melanoma and of the MCA-105 sarcoma from 179 and 140, respectively (in groups treated with Hanks' balanced salt solution alone), to 12 (P = 0.01) and 6 (P = 0.01), respectively. This combined immunotherapy also consistently resulted in significant prolongation of survival in mice with established, 3-day or 10-day pulmonary metastases of the MCA-105 sarcoma. Mice autopsied at time of death revealed a massive involvement of tumor in the lungs and liver in the group receiving Hanks' balanced salt solution alone compared to a small number of residual large lung or liver metastases in the group receiving LAK cells plus RIL-2. Experiments were designed to test whether variants existed in the original tumor cell inoculum that were resistant to killing by LAK cells and thus could account for the metastases that "escaped" the combined immunotherapy of LAK cells plus RIL-2 in vivo. Metastases of the MCA-105 sarcoma that escaped the combined therapy of LAK cells plus RIL-2 were dissected from the organs of mice upon autopsy and directly tested for susceptibility in vitro to lysis by LAK cells in 4-h and 18-h 51Cr release assays. Target cells derived from the metastases were lysed to an equivalent extent as those prepared from a fresh MCA-105 sarcoma that was growing s.c. In addition, successful reduction of pulmonary metastases established by the i.v. infusion of MCA-105 sarcoma cells obtained from metastases that escaped a prior round of therapy with LAK cells and RIL-2 could be achieved in vivo by the combined immunotherapy as well as by high doses of RIL-2 alone. Culture adapted, natural killer cell-resistant B16 melanoma cells surviving two successive treatments with LAK cells in vitro remained as susceptible to LAK cell lysis as untreated B16 melanoma cells in 18-h 51Cr release assays.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: survival benefit and mechanisms of tumor escape in mice undergoing immunotherapy. 348 31


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