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

Sensitized T lymphocytes can mediate potent antitumor effects when transferred to tumor-bearing animals. Employing the MCA 105 and MCA 106 sarcomas, we were able to generate antitumor effector cells by immunization of syngeneic mice with tumor cells admixed with Corynebacterium parvum. These immune splenocytes could be further sensitized and expanded in culture by the in vitro sensitization (IVS) method utilizing tumor stimulator cells and IL-2. Adoptive immunotherapy of pulmonary metastases mediated by noncultured splenocytes from immunized mice or immune IVS cells showed exquisite specificity between the two sarcomas. These results demonstrate the presence of tumor-specific antigens on MCA 105 and MCA 106 tumor cells which can serve as target molecules for immunotherapy. Recently, we have generated therapeutic T lymphocytes from mice bearing progressively growing tumors by the IVS method. However, IVS cells from tumor-bearing mice showed cross-reactivity between the MCA 105 and 106 sarcomas in adoptive immunotherapy experiments. Since these IVS cells did not affect other control tumors, the limited cross-reactivity suggests the presence of common tumor-associated antigens on MCA 105 and MCA 106 tumor cells which can also serve as the target for tumor rejection. Therefore, immune responses to progressive tumor growth and to immunization are distinct with respect to antigen recognition by T lymphocytes.
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PMID:Distinct immunologic specificity of tumor regression mediated by effector cells isolated from immunized and tumor-bearing mice. 278 60

In a murine pulmonary metastases model, interleukin-2 (IL-2), a lymphokine capable of expanding all classes of T lymphocytes, synergizes with interferon-alpha (IFN-alpha) to reduce established metastases and prolong survival. We tested whether indomethacin (INDO), which inhibits synthesis of prostaglandin E2 (a potent immunosuppressor), could further augment the antitumor efficacy of these lymphokines. Age-matched C57BL/6 mice bearing pulmonary micrometastases of a weakly immunogenic fibrosarcoma MCA-106 were treated intraperitoneally for 6 consecutive days, starting on day 3 with (1) saline solution, (2) IL-2 (50,000 units twice a day), (3) IFN-alpha A/D (50,000 units per day), and (4) IL-2 and IFN-alpha A/D. Half of each treatment group was given plain water and the rest INDO-treated (14 micrograms/cc) drinking water throughout the duration of the experiment. Pulmonary metastases were enumerated on day 21. IFN or INDO alone had little effect, whereas IL-2 reduced metastases and prolonged survival. All combination treatments, including INDO/IFN, decreased metastases and prolonged survival except INDO/IL-2/IFN in which several early deaths negated any significant survival prolongation. Early mortality (less than 21 days) was seen with IFN/INDO (8.3%), IL-2/IFN (7.7%), and IL-2/IFN/INDO (8.3%) indicating toxicity of these treatments. Spontaneous proliferation of splenocytes from non-tumor-bearing mice treated for 5 days showed that INDO combined with IL-2 or IFN enhanced proliferation measured 3 days after cessation or treatments. A striking reduction in T-cell marker (Thy 1.2+) in groups treated with IL-2/IFN, INDO/IL-2, INDO/IFN, and INDO/IL-2/IFN 3 days after cessation of IL-2 and IFN suggests that a non-T-cell is amplified when INDO is combined with IL-2 or IFN. These results show that INDO can enhance efficacy of IL-2 or IL-2/IFN. Furthermore, INDO/IFN offers an equi-efficacious, albeit similarly toxic, alternative to IL-2 treatment of tumors and may be useful clinically.
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PMID:Indomethacin-enhanced immunotherapy of pulmonary metastases using IL-2 and IFN-alpha. 278 16

Resection of hepatic metastases from colorectal cancer has been shown to prolong survival in some patients. Whether this results from a reduction of tumor burden or is an indirect effect mediated by hepatectomy is questionable. Male C57BL/6Ros 8-week-old mice underwent ileocolic vein injection of a suspension of 0.3 mL of 2 x 10(5) viable liver-derived murine (MCA-38) colonic adenocarcinoma cells. This model produces hepatic metastases in all lobes of the liver. At 7, 14, or 21 days after tumor injection, mice were randomized to receive either 42% resection of the liver or laparotomy alone. Survival in the animals with hepatectomy was significantly prolonged when the hepatectomy was performed 14 or 21 days after tumor injection.
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PMID:Hepatectomy prolongs survival of mice with induced liver metastases. 291 37

A syngeneic transplantable sarcoma induced in C57BL/6 mice, MCA 105, was used in studies to examine host suppression on the adoptive immunotherapy of established intradermal and experimentally induced pulmonary and hepatic metastases. Fresh immune splenocytes were generated from mice immunized to the MCA 105 tumor by a mixture of viable tumor cells and Corynebacterium parvum. The adoptive immunotherapy of intradermal MCA 105 tumor with immune cells required prior immunosuppression of the recipient by sublethal irradiation with 500 R or T-cell depletion. The effect of whole-body sublethal irradiation appeared to eliminate a systemic host suppression mechanism, since partialbody irradiation involving the tumor-bearing area did not permit successful immunotherapy. Host irradiation was not required to achieve successful immunotherapy of experimentally induced pulmonary or hepatic metastases. In nonirradiated recipients bearing both intradermal and pulmonary tumors, host suppression did not affect the function of transferred immune cells to induce regression of pulmonary metastases. Thus, suppression of adoptive immunotherapy appears to be relevant to tumors confined to the skin and subcutaneous tissue but not to tumor in visceral sites, such as the lung and liver.
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PMID:Differences in the effects of host suppression on the adoptive immunotherapy of subcutaneous and visceral tumors. 293 46

Systemic transfer of sensitized lymphocytes can effectively mediate the regression of established tumors. However, virtually all prior experimental applications of this approach have utilized lymphocytes from animals that have been immunized to reject tumor challenge. A similar source of cells is not available in the human. With the use of a weakly immunogenic murine tumor, MCA 105, we demonstrate here that following in vitro sensitization (IVS) with viable tumor cells and interleukin 2, the nontherapeutic lymphoid cells from mice bearing a progressively growing tumor acquired antitumor reactivity capable of mediating the regression of established pulmonary metastases. Although the IVS system induced nonspecific lymphokine-activated killer-like cytotoxic activity from lymphoid cells of normal as well as tumor-bearing mice, therapeutically active cells could only be generated from cultures initiated with lymphoid cells from tumor-bearing animals, indicating that the IVS was a secondary in vitro immune response. Without other treatment, the IVS cells could mediate antitumor effects. However, low doses of exogenous interleukin 2 administration could enhance their therapeutic efficacy. By in vivo T cell subset depletion with monoclonal antibodies, the primary effector cells were identified as belonging to cytotoxic/suppressor T cell lineage expressing the Lyt-2 phenotype. In addition, these therapeutic effector cells could be further expanded in numbers in vitro with continuous stimulation by tumor cells in the presence of interleukin 2. Compared to the number of cells initiating the culture, as many as 126 times the number of cells were obtained after 9 days of IVS followed by in vitro expansion for an additional 5 days. Studies on the kinetics of the occurrence of the pre-effector lymphocytes during tumor growth revealed that they were readily obtained from draining lymph nodes of mice with a broad range of tumor burdens as well as durations of tumor growth. The ability to generate and expand, in vitro, therapeutically active lymphocytes from tumor-bearing hosts has important implications for cellular therapy of human cancers.
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PMID:Generation from tumor-bearing mice of lymphocytes with in vivo therapeutic efficacy. 295 16

We have previously demonstrated that following the adoptive transfer of immune cells, the regression of established pulmonary metastases from a weakly immunogenic sarcoma, MCA 105, required the collaboration of two T cell subsets. In this study, we found that the critical role played by L3T4+ immune cells was to provide a helper function since tumor regression proceeded in the absence of L3T4+ immune cells if exogenous interleukin 2 (IL-2) was administered. To extend these observations, we analyzed the events leading to the induction and generation of L3T4+ and Lyt-2+ immune T cells after immunization of mice with viable tumor cells admixed with Corynebacterium parvum. The basic protocol involved immunization, surgical excision of the immunization site on day 7, and challenge with viable tumor cells on day 21. The ability of mice to reject tumor challenge provided a means to evaluate the occurrence of a systemic antitumor immunity. With the use of this experimental protocol, we have found that depletion of T cell subsets in vivo with either L3T4 or Lyt-2 monoclonal antibodies after active immunization abrogated the development of antitumor immunity. Mice immunized and depleted of L3T4+ but not Lyt-2+ T cells were able to reject tumor challenge if exogenous IL-2 was given for 7 days. However, the rejection of tumor challenge required 3 days of additional exogenous IL-2 administration. These results indicate that the induction of Lyt-2+ immune T cells depended on the helper function of L3T4+ T cells via the secretion of IL-2. In the absence of L3T4+ immune lymphocytes, the expression of antitumor immunity by Lyt-2+ immune cells could be facilitated by in vivo administration of exogenous IL-2. The induction of L3T4+ immune T cells, on the other hand, occurred independently of the Lyt-2+ T cell response because the transfer of spleen cells from Lyt-2+ cell-depleted, immunized animals was able to restore antitumor reactivity in L3T4+ cell-depleted, immunized mice. These results demonstrate the intricate cellular interactions leading to the induction as well as the expression of antitumor immunity.
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PMID:Cellular interactions and the role of interleukin 2 in the expression and induction of immunity against a syngeneic murine sarcoma. 295 48

The effect of treatment with the hypoxic cell radiosensitizer misonidazole (MISO) and the radioprotector diethyldithiocarbamate (DDC) on the formation of spontaneous lung metastases of four different spontaneously metastasizing murine tumors was investigated. The tumors were mammary carcinoma MCA-K, hepatocarcinoma HCA-1, and sarcomas SA-4020 and SA-NH. Multiple daily treatments with MISO significantly enhanced the incidence of metastases only in MCA-K. Because only MCA-K, but not the three remaining tumors, is immunogenic, the treatment with MISO may be associated with the promotion of metastasis primarily in the immunogenic tumors. Treatment of mice with DDC had no influence on metastatic spread. However, when given prior to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), DDC reduced BCNU-induced enhancement of HCA-1 metastases.
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PMID:Effect of the radiosensitizer misonidazole and the radioprotector diethyldithiocarbamate on spontaneous metastasis formation of murine tumors. 301 3

Previous studies have shown that successful adoptive immunotherapy of a newly induced, weakly immunogenic murine sarcoma, MCA 105, can be achieved either with fresh noncultured immune spleen cells or with immune cells after in vitro stimulation and expansion. In this study, we utilized in vivo and in vitro depletions with monoclonal antibodies (mAb) of T-cell subpopulations expressing the L3T4 or Lyt-2 antigens to investigate the phenotype of the T-cells that mediate in vivo tumor regression. The efficiency of depletion was assessed by flow microfluorometric analysis and by the ability of specifically treated spleen cell populations to generate allogeneic cytotoxic T-lymphocytes. The therapeutic efficacy of adoptively transferred fresh noncultured MCA 105 immune cells was abrogated by in vivo administration of either L3T4 or Lyt-2 mAb to mice bearing 3-day established pulmonary metastases. In vitro treatment of fresh noncultured MCA 105 immune cells with either L3T4 or Lyt-2 mAb and complement also abrogated their antitumor efficacy confirming the initial findings. However, mixing L3T4 and Lyt-2 mAb and complement-treated MCA 105 immune cells reconstituted the antitumor efficacy indicating that cellular cooperation between these two lymphoid subpopulations was essential for the regression of established tumors. Unlike fresh noncultured immune cells, the antitumor efficacy of in vitro sensitized and expanded immune cells was abrogated by in vivo treatment with Lyt-2 but not with L3T4 mAb indicating Lyt-2+ cells alone played a major role in mediating the regression of tumors. These findings provide evidence for an in vitro-induced differentiation of therapeutic T-lymphocytes. Our results thus suggest that the antitumor activities expressed by the two types of cells may represent T-cells at different stages of immunological differentiation.
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PMID:In vitro differentiation of T-cells capable of mediating the regression of established syngeneic tumors in mice. 310 46

The capacity of different cytokines to upregulate major histocompatibility complex (MHC) expression on murine tumor cells in vitro, and on s.c. tumors or pulmonary metastases in vivo has been examined. Interleukins-1, -2, and -4 (IL-1, -2, -4), tumor necrosis factor-alpha (TNF-alpha), alpha-interferon (IFN-alpha), and gamma-interferon (IFN-gamma), were incubated with tissue culture lines of murine tumor cells displaying low (MCA-101), intermediate (MCA-102, -106), or high (MCA-105) Class I expression. IFN-alpha and IFN-gamma significantly increased Class I but not Class II antigens on all lines. TNF-alpha, IL-1, -2, and -4 had no significant effect on Class I or II expression in vitro. Mice bearing pulmonary metastases or s.c. lesions generated by MCA-101 and -102 were treated with IFN-alpha or IFN-gamma i.p. or i.v., or with a single dose of TNF-alpha i.v. Immunoperoxidase staining of lung metastases or subcutaneous tumors showed an increase in Class I but not Class II expression on MCA-102 tumors treated with IFN-alpha or IFN-gamma. IL-1, -2, or TNF-alpha had no effect on MHC Class I or II expression in vivo. None of the cytokines tested could upregulate MHC Class I or II expression on MCA-101 tumors in vivo. Flow cytometry analysis demonstrated an increase in Class I but not Class II expression on MCA-102 and MCA-106 tumor cells from s.c. tumor treated with IFN-alpha or IFN-gamma. A kinetic analysis of the flow cytometry data revealed that augmented MCA-102 Class I levels persisted for several days after cessation of in vivo therapy with IFN-alpha. Our data suggest one possible mechanism for the synergistic antitumor effects of IL-2 and IFN-alpha.
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PMID:Modulation of murine tumor major histocompatibility antigens by cytokines in vivo and in vitro. 313 84

In a methylcholanthrene-induced tumor (MCA-F) model in C3H/HeJ mice, curative resection of a progressive tumor promotes artificial lung metastases following intravenous injection of a highly metastatic cell variant designated clone 9-4. The number of metastatic lung colonies depends upon the status of host immunity at the tumor resection: mice resected 7 or 14 days, but not 28 days after tumor inoculation display significantly retarded postoperative, experimentally induced lung metastases. The number of lung colonies in mice that had tumors resected at 14 days was three times greater than in mice that had 28-day neoplasms resected. Neither therapy with weekly injection of 50 micrograms tumor-specific transplantation antigen, which had been extracted using a single phase of 2.5% 1-butanol (CBE), nor 20 mg/kg cyclophosphamide (CY) alone prevented lung colonization. Assessment of helper-suppressor ratios in the spleen from mice after tumor surgery showed that CBE administration decreased the ratio in mice after resection of 14-day tumors, but not after resection of 28-day tumors. Combined therapy with specific tumor antigen and an antisuppressor cell agent reduced metastases, regardless of the tumor size.
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PMID:Antigen-specific therapy of experimental metastases. 315 89


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