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 incubation of normal murine splenocytes in recombinant interleukin 2 (RIL 2) gives rise to lymphokine-activated killer (LAK) cells that are specifically cytotoxic to fresh noncultured, autologous, syngeneic, and allogeneic primary and metastatic tumor cells, but are not toxic to normal cells. We have recently shown that the systemic injection of RIL 2 given alone or in conjunction with LAK cells can reduce the number of established pulmonary and hepatic micrometastases from a weakly immunogenic sarcoma in mice. In this report we have analyzed the response of hepatic metastases (HM) induced from both a nonimmunogenic sarcoma (MCA-102) and an adenocarcinoma (MCA-38). Treatment of mice bearing HM from the MCA-102 and MCA-38 tumors revealed that low doses of RIL 2 (5000 to 25,000 U t.i.d.) had little if any anti-tumor effect when given alone (mean percent reduction over control for the MCA-102 tumor: 14%, for the MCA-38 tumor: 10%, p, not significant). Doses of 100,000 U of RIL 2 affected a 38 and 53% reduction in the number of metastases over control for the MCA-102 and MCA-38 tumors, respectively (p less than 0.05). However, when LAK cells were added to the same doses of RIL 2, the corresponding mean percent reduction over control was 90% (p less than 0.005) and 61% (p less than 0.05) for MCA-102 and MCA-38, respectively, at RIL 2 doses of 5000 to 25,000 t.i.d. At doses of 100,000 U of RIL 2 administered with LAK cells, the corresponding percent reductions were 98 and 99%, respectively (p less than 0.005). Therapy with LAK cells plus RIL 2 can also prolong the survival of these mice. In addition, the intraportal administration of LAK cells is more effective than the i.v. administration of these cells. Thus, treatment of established HM from a nonimmunogenic sarcoma and an adenocarcinoma can be successfully mediated by the systemic infusion of LAK cells with RIL 2. These findings provide a rationale for clinical trials of infusion of LAK cells with RIL 2 in the therapy of HM in humans.
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PMID:Adoptive immunotherapy of murine hepatic metastases with lymphokine activated killer (LAK) cells and recombinant interleukin 2 (RIL 2) can mediate the regression of both immunogenic and nonimmunogenic sarcomas and an adenocarcinoma. 387 66

Incubation of resting lymphoid cells with recombinant interleukin 2 (IL-2) in vitro leads to the generation of lymphokine activated killer (LAK) cells capable of lysing fresh tumor cell suspensions in short-term chromium-release assays. Our previous studies (7) have demonstrated that the injection of LAK cells plus low doses of recombinant IL-2 were capable of inhibiting the growth of pulmonary metastases. We have now explored the ability of high doses of recombinant IL-2, administered systemically, to generate LAK cells in vivo, and to mediate antitumor effects directly. Administration of increasing doses of recombinant IL-2 intraperitoneally resulted in the generation of LAK cells in the spleens of recipient mice. Doses of 100,000 U recombinant IL-2 administered intraperitoneally approximately every 8 h for 5 d were capable of dramatically inhibiting established 3-d pulmonary metastases from the MCA-105 and MCA-106 syngeneic sarcomas and the syngeneic B16 melanoma in C57BL/6 mice. Grossly visible metastases present at 10 d after tumor injection also underwent regression following IL-2 therapy. Surprisingly, established 10 d pulmonary metastases were more susceptible to the effects of IL-2 than were the smaller 3 d pulmonary metastases. All antitumor effects of the systemic administration of recombinant IL-2 were eliminated if mice received prior treatment with 500 rad total body irradiation. The administration of high doses of recombinant IL-2 was also capable of inhibiting the growth of 3-d established subcutaneous tumors from the MCA-105 sarcoma, and of mediating the inhibition of growth and regression of established palpable subcutaneous MCA-105 sarcomas. Lymphocytes, which appeared morphologically to be activated, were present at the site of regressing tumor, and it appears that the mechanism of the antitumor effect of recombinant IL-2 administered systemically is via the generation of LAK cells in vivo, although this hypothesis remains to be proven. The ready availability of high doses of recombinant human IL-2, and the demonstration of antitumor effects seen in animal models have led us to the initiation of the clinical trials of recombinant IL-2 in humans.
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PMID:Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. 388 26

Heparin, cortisone, and combination of these two drugs were used for treatment of solitary tumors and artificial lung metastases of the fibrosarcoma NFSA and the mammary carcinoma MCA-K in C3Hf/Kam mice. Heparin reduced the number of artificial metastases of both tumors, but it did not affect the s.c. growth of these tumors. Conversely, cortisone reduced both the number of artificial metastases and the growth rate of s.c. tumors. The effect of cortisone was not further influenced by heparin. Cortisone showed a tendency for causing enhancement of spontaneous metastases. In addition, two heparin analogs, hexuronyl hexoaminoglycan sulfates were studied against MCA-K solitary tumors and their spontaneous metastases. They were ineffective when given alone, and they did not influence the effect of cortisone on the s.c. tumor growth. However, they slightly reduced the cortisone-induced enhancement of spontaneous metastases.
Clin Exp Metastasis
PMID:Treatment with cortisone plus heparin or hexuronyl hexoaminoglycan sulfates of murine tumors and their lung deposits. 407 12

A 3-Methylcholanthrene (MC)-induced fibrosarcoma and three of its clones were investigated for their metastatic potential in normal and tumor immune mice. The growth rates of the four tumors in vivo were similar. However, the mean survival times of the tumor-bearing mice were markedly different. Clone 10, the most immunogenic, showed very high metastatic potential and short survival, while clone 27, the least immunogenic, produced few metastases, resulting in much longer survival. Moderate numbers of metastases were produced by highly immunogenic 3-AM (parental tumor), and poorly immunogenic clone 34. Spleen cells from mice bearing highly immunogenic tumors lost their ability to neutralize tumors by day 28 after tumor inoculation, while those from mice bearing poorly immunogenic tumors remained cytotoxic, indicating that highly immunogenic tumors also induced immune suppression in the hosts. Immunization with specific tumors decreased the number of pulmonary metastases by 3 to 35-fold. Immunization with tumors that shared antigens provided protection against metastatic tumors as well as the local tumors. In contrast, immunization with antigenically different tumors gave no protection.
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PMID:The effect of immunity on pulmonary metastasis of a methylcholanthrene-induced fibrosarcoma and three of its clones. 648 54

Incorporation of cholesterol hemisuccinate (CHS) into the membrane of tumor cell rigidifies the lipid layer, exposes cryptic antigens, and enhances immunogenicity. The local growth and metastatic spread of the 3LL Lewis lung carcinoma were studied in conjunction with immunizations by CHS-enriched 3LL cells. C57BL/6J mice received 2 consecutive immunizations with 10(7) CHS-treated, irradiated (10,000 rad) 3LL cells. Two control groups were immunized with MCA-102 sarcoma cells or CHS-enriched syngeneic spleen cells. All groups were challenged with viable 3LL cells after immunizations. Mice pre-immunized with CHS-enriched 3LL cells showed a delayed tumor growth after subsequent challenge with 3LL. Effect of immunization on the growth of established tumors was examined in 3LL-bearing mice which were treated with 10(7) CHS-enriched tumor cells on days 1-12 after initial tumor implantation. A second identical immunotherapy was given 6 days after the first immunization. Tumor growth was significantly inhibited in mice which received the first immunization 1 day after tumor implantation, while immunization on day 3 or after inhibited the growth rate to a lesser extent. Suppression of pulmonary metastases was assessed after excision of a primary 3LL tumor growing in the foot pad which had reached 8 mm in diameter. Immunization consisted of intraperitoneal injection of 10(7) irradiated CHS-enriched tumor cells following excision and repeated after 6 days. This immunization resulted in a significant decrease in pulmonary metastasis as scored by direct counts of metastatic nodules, by [125I]iododeoxyuridine (125IUdR) incorporation, and by lung weight. Metastatic 3LL cells from nodules which survived immune elimination were isolated and implanted into mice which were pre-immunized with primary 3LL cells enriched with CHS. For comparison, a group of mice was immunized and challenged with primary 3LL cells. Inhibition of tumor growth and pulmonary metastasis formation was observed only in the mice which were challenged with the primary tumor.
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PMID:Inhibition of growth and metastases in mice by immunization with cholesterol hemisuccinate-enriched tumor cells. 650 34

Tumor-specific transplantation antigens (TSTA), which were partially purified by preparative isoelectric focusing of 3-M KCl extracts of a fibrosarcoma MCA-F induced in inbred female C3H/HeJ mice with 3-methylcholanthrene and previously shown to display immunotherapeutic activity against subcutaneous neoplasms, were effective against pulmonary metastases. Weekly sc injections of 25 micrograms fraction 15 decreased the number of pulmonary colonies after iv injection of tumor cells into syngeneic, virgin C3H/HeJ mice. The effect was immunologically specific; the immunoprotective fraction from the heterotypic, antigenically distinct MCA-D tumor did not affect the number of pulmonary MCA-F tumor colonies. Because fraction 15 treatment did not alter the number of extrapulmonary tumor colonies, the survival rates of hosts challenged iv with MCA-F cells were unaffected. The variant cell line MCA-F-4 was selected to detect prolonged host survival as a result of a therapeutic effect against pulmonary metastases. This line was selected for its proclivity for lung colonization and low propensity for growth in extrapulmonary sites. Cross-immunoprotection tests demonstrated that MCA-F-4 shares a TSTA with the parent tumor. Therapeutic administration of fraction 15 prolonged the survival of hosts in two settings: 1) after artificial iv injection of MCA-F-4 cells and 2) as treatment for hosts resected of 1-cm subcutaneous MCA-F-4 primary tumors and at high risk for spontaneous pulmonary metastases. Therefore, fraction 15 displayed therapeutic effects on both artificially induced and spontaneous pulmonary metastases.
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PMID:Immunotherapeutic effects of partially purified tumor-specific transplantation antigens on pulmonary metastases of a 3-methylcholanthrene-induced sarcoma in mice: a preliminary report. 695 56

Orthotopic transplantation of MCA-39 murine colonic tumor cells into the submucosa of the cecum results in the growth of a "primary" tumor that metastasizes to the liver. This model system parallels the sequence of events that can occur with human colon carcinoma and provides a means of evaluating the role of the immune system in hepatic metastases formation. Temporal studies of the specific antitumor response detected by a micro-leukocyte adherence inhibition (LAI) assay revealed two patterns of sensitization as the "primary" tumor grew and hepatic metastases developed. The systemic antitumor response was monophasic and disappeared prior to the formation of hepatic metastases. In contrast, the local and regional antitumor response was biphasic. The breakdown in the local and regional response may play a permissive role in the formation of hepatic metastasis.
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PMID:Murine colon adenocarcinoma: immunobiology of metastases. 735 13

The adoptive immunotherapy of cancer with sensitized T lymphocytes is well documented in several animal models. These studies indicate the existence of precursor lymphocytes, in the tumour-bearing animals, which can acquire therapeutic efficacy after in vitro manipulations. To generate immune effector cells, these precursor lymphocytes have to be antigenically stimulated in vitro by the tumour of origin. Using the weakly immunogenic MCA 205 and MCA 203 murine sarcomas, we demonstrate here that this in vitro antigenic stimulation can be achieved by sequential activation with anti-T-cell receptor (TCR) monoclonal antibody and interleukin-2 (IL-2). The culture of tumour-draining lymph node (TDLN) cells with anti-TCR/IL-2 resulted in an up to eightfold increase in cell numbers. The adoptive transfer of these activated cells mediated a significant reduction of 3-day established pulmonary metastases. Although this antibody could activate all of the TCR alpha beta-bearing T cells non-specifically, the therapeutic efficacy mediated by anti-TCR/IL-2-activated cells was tumour specific. Treatment of MCA 205 advanced pulmonary metastases resulted in prolongation of survival, and 30% of treated mice were tumour free for more than 90 days. These tumour-free mice rejected a challenge of MCA 205 but not MCA 203, indicating the development of long-lasting systemic tumour immunity. In spite of their in vivo anti-tumour efficacy, the anti-TCR/IL-2-activated TDLN cells did not exhibit detectable in vitro cytotoxicity. These results demonstrate that this activation method could be an alternative way to generating potent anti-tumour effector T cells.
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PMID:Adoptive immunotherapy mediated by anti-TCR/IL-2-activated tumour-draining lymph node cells. 782 65

We investigated factors that might contribute to the differing liver tumor colonizing potentials of MCA-38 colonic cancer cell line variants injected into the ileocolic veins of C57Bl/6J mice. Non-colonizing (MCA-38 CD) cells were sensitive to lysis by hepatic natural killer (NK) cells in vitro (51Cr-release assay) and cells with high liver-colonizing potential (MCA-38 LD) were resistant. Following abrogation of NK activity by treatment with anti-asialoGM1, liver-colonizing ability to LD cells but not CD cells was enhanced. MCA-38 CD cells were, however, capable of initial liver colonization after ileocolic vein injection. Differing patterns of membrane sialylation may have contributed to the contrasting hepatic tumorigenicities of LD and CD cells; beta-galactoside alpha 2,6-sialyltransferase mRNA levels and activity were approximately four-fold higher in LD than CD cells and qualitative and quantitative differences existed between their ganglioside profiles. In the MCA-38 model outlined, tumor cell susceptibility or resistance to NK lysis was a relatively unimportant determinant of liver-colonizing potential.
Clin Exp Metastasis 1995 Mar
PMID:Determinants of differential liver-colonizing potential of variants of the MCA-38 murine colon cancer cell line. 788 16

Previously we described the use of solid-phase anti-CD3 monoclonal antibody (mAb) to stimulate murine tumour-infiltrating lymphocytes (TIL) and their subsequent expansion in recombinant interleukin 2 (rIL-2). In a pulmonary metastases model using the methylcholanthrene-induced sarcoma MCA-105 anti-CD3 activated TIL were capable of eradicating disease similar to TIL cultured in rIL-2 only. Here we extend these observations by characterizing the biological effects of sequential solid-phase anti-CD3 activation. TIL from MCA-105 tumour activated with solid-phase anti-CD3 on day 1 were reactivated on day 14, or day 26, or both and compared to TIL grown in rIL-2 only or TIL activated with anti-CD3 once on day 1. Reactivation enhanced in vitro proliferation 1.8- to 4-fold compared to TIL activated once with anti-CD3 (P < 0.05). In addition, the total lytic capacity of the cultures was enhanced after reactivation without changing the phenotype of the TIL cultures. Reactivation resulted in a greater in vivo efficacy when the TIL were administered within 72 h of reactivation. In contrast, TIL activated with anti-CD3 on day 1 and day 14 were least effective of all TIL cultures (P < 0.05). This correlated with in vitro cytokine production. The most effective TIL cultures in vivo produced 4- to 100-fold higher amounts of cytokines, especially interferon gamma (IFN gamma) and granulocyte macrophage colony stimulating factor (GM-CSF), than the other cultures. On the other hand, the least effective in vivo TIL culture, TIL activated with anti-CD3 on day 1 and 14, produced little or no cytokines. These data suggest that in vitro production of cytokines is indicative of in vivo efficacy of anti-CD3 activated TIL.
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PMID:Reactivation of murine tumour-infiltrating lymphocytes with solid-phase anti-CD3 antibody: in vitro cytokine production is associated with in vivo efficacy. 795 95


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