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)

We have recently reported a simple and reproducible technique for the purification and rapid expansion of homogeneous populations of large granular lymphocytes expressing a natural killer cell phenotype and high levels of broad antitumor cytotoxic activity [lymphokine-activated killer (LAK) activity]. This technique exploits the observation that, in the presence of recombinant interleukin 2 (rIL-2), large granular lymphocytes/natural killer cells become adherent to plastic surfaces, actively proliferate, and acquire high levels of LAK activity. Because of their adherent properties these cells have been termed adherent LAK or A-LAK cells. The present studies investigate the antimetastatic effects of A-LAK cells in a syngeneic rat model of experimental pulmonary and hepatic metastases. For pulmonary metastases, F344 rats received i.v. injections with a natural killer-resistant mammary adenocarcinoma, MADB106, and, for hepatic metastases, animals received an intrasplenic injection of MADB106 tumor cells followed by surgical splenectomy. Three days later, the animals were treated with A-LAK cells alone, A-LAK cells plus rIL-2, or rIL-2 alone. These treatments were compared to immunotherapy using standard cultures of LAK cells (unfractionated spleen cells) and rIL-2. The results indicate that the administration of unfractionated LAK cells plus interleukin 2 (IL-2) was effective in reducing established lung or liver metastases in this rat model. However, the results also indicate that purified populations of A-LAK cells in combination with rIL-2 demonstrate dramatic and superior antimetastatic effects when compared to LAK cells cultured under standard conditions. The antimetastatic effects of standard LAK cells or A-LAK cells plus IL-2 translated into significant survival benefits compared to animals receiving no therapy or IL-2 therapy alone. Survival after therapy with A-LAK cells plus IL-2 was significantly prolonged compared to treatment with standard LAK cells. These data suggest that purified populations of LAK cells (derived from natural killer cells) may prove superior for adoptive immunotherapy in the clinical setting.
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PMID:Enhanced antimetastatic activity of lymphokine-activated killer cells purified and expanded by their adherence to plastic. 278 50

Natural killer cell activity was assessed in 100 previously untreated pharyngeal carcinoma patients. Diminished natural killer cell function in these patients was associated with an increased risk of death from uncontrolled regional and distant metastases. During the assessment, the cell line MDA686-Ln was established from a metastatic pharyngeal carcinoma of a patient with low natural killer cell cytotoxicity. The initially cytotoxicity-resistant cell line could be lysed when natural killer cell cytotoxicity was enhanced in vitro either through enrichment of a Leu 19+ natural killer cell population by fluorescent-activated cell sorting or by interleukin-2 activation. Additionally, increased circulating immune complexes were identified in these patients, subsequently isolated, and found to block natural killer cell reactivity against MDA686-Ln. In light of this negative interaction, 38 patients were randomly evaluated for both circulating immune complex levels and natural killer cell function. Both parameters examined together were complementary in defining the risk of death with disease; four of five deaths occurred in patients with both high circulating immune complex levels and low natural killer cell function. Results support the biologic modification of natural killer cell activity for controlling metastatic pharyngeal carcinoma and point to the potential confounding influence of circulating immune complex.
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PMID:Natural killer cells and metastases from pharyngeal carcinoma. 280 42

Cryosurgery and excision were used to treat primary tumours of HSV-2-transformed hamster tumour sublines, and post-operative survival and the extent of metastatic disease were compared in the two groups. An inferior prognosis was observed following cryosurgery although the extent of metastatic disease was similar in both groups. Using this model it would appear that cryosurgery enhances the development of micrometastases rather than affecting the number of cells shed from the primary tumour during surgery. To investigate the underlying causes of the decrease in survival following cryosurgery, in vitro assays were used to monitor host immunocompetence following surgery. The results showed that whilst natural killer cell cytotoxicity was only marginally depressed, mitogen responsiveness and lymphocyte participation in a mixed lymphocyte reaction were severely reduced 3-7 days post-cryosurgery. In parallel with immunosuppression, extensive cell proliferation in the spleen of cryosurgically treated tumour-bearing animals was observed. Histological examination of the spleen demonstrated the presence of large numbers of transformed cells which correlated with the loss of mitogen responsiveness and the ability to participate in a mixed lymphocyte reaction. Further studies (manuscript submitted for publication) have demonstrated that spleen cells from animals whose tumour is treated by cryosurgery are capable of suppressing immunocompetence in vitro, implying they have a role in the uncontrolled growth of micrometastases in vivo.
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PMID:Comparison of excision versus cryosurgery of an HSV-2-induced fibrosarcoma. I. Survival, extent of metastatic disease and host immunocompetence following surgery. 283 55

In a pilot study involving 13 patients with advanced stage IV renal cell carcinoma, anti-tumor effects and toxicity of a novel form of adoptive immunotherapy were determined. The protocol utilizes infusions of autologous mononuclear leukocytes treated with the oxidizing mitogen sodium periodate (IO4-) and cultured in medium containing human recombinant interleukin-2 (IL-2), and continuous infusions of low-dose IL-2 (mean +/- SD dose = 39.5 +/- 8.6 X 10(3) U/kg/24 hours). Leukocytes (5 to 10 X 10(9] were removed by leukapheresis three times per week, mononuclear cells were separated, activated with IO4- and cultured in medium containing IL-2 (500 U/ml) for 48 to 72 hours. The cells were re-infused following the next leukapheresis procedure. IL-2 was administered five days per week. Treatment was continued for two three-week cycles. An increase in peripheral blood mononuclear cells bearing the natural killer cell (NK) surface marker, Leu 11, an increase in NK- and antibody-dependent cell-mediated cytotoxicity, and a slight increase in spontaneous cytotoxicity for non-NK targets were noted. Regressions (more than 50 percent decrease in tumor mass) of pulmonary, liver, bone, or soft tissue metastases were induced in six patients. Severe fluid retention did not develop in any patient and no patient required treatment in the intensive care unit. Five of the patients who showed a response have experienced a relapse at 5.2 +/- 1.0 (mean +/- SD) months. These observations indicate that IO4-/IL-2-activated killer cells plus continuous infusions of low-dose IL-2 can result in regression of metastatic renal cell carcinoma.
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PMID:Adoptive immunotherapy for stage IV renal cell carcinoma: a novel protocol utilizing periodate and interleukin-2-activated autologous leukocytes and continuous infusions of low-dose interleukin-2. 284 76

In this report, we describe the immunomodulatory properties and therapeutic efficacy of bestatin. Macrophage activation, but not natural killer cell augmentation, was observed both in vitro and in vivo. Immunostimulation of T-cell activity was observed in assays of allogeneic mixed lymphocyte response, but cytotoxic effector cells did not develop after an allogeneic mixed lymphocyte-tumor cell culture. Bestatin also had T-cell adjuvant activity when it was admixed with a suboptimal vaccine composed of irradiated tumor cells. We observed significant therapeutic activity against preexisting experimental and spontaneous metastases when bestatin was administered at high doses per animal for 4 weeks.
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PMID:Immunomodulatory and therapeutic properties of bestatin in mice. 294 38

Eleven patients received four consecutive weekly cycles of human recombinant interleukin 2 (IL-2) by continuous infusion for 4 days/week. Two dose levels were tested, 1 and 3 X 10(6) units/m2/day. Toxicities experienced by most patients included fever, rigors, fatigue, anemia, eosinophilia, and liver function abnormalities. All side effects from treatment reversed and no severe or life-threatening problems occurred. A marked lymphocytosis was seen following the 4 weeks of therapy. Fresh lymphocytes obtained during this lymphocytosis mediated enhanced destruction in vitro of a natural killer cell-resistant tumor cell line (Daudi). The increase in the absolute number of circulating lymphocytes and their enhanced ability to mediate direct lysis of Daudi targets resulted in a greater than 100-fold mean increase in cytotoxic potential by the end of IL-2 treatment. One patient, with renal carcinoma, who was treated at 3 X 10(6) units/m2/day experienced a sustained measurable response with greater than 50% regression of pulmonary and hepatic metastases. Five patients were retreated with a second course of IL-2, lasting 4 weeks. This therapy was well tolerated in four of these five patients, with similar immunological changes occurring. No further antitumor responses were seen in these patients. Thus, a relatively well tolerated immunotherapy regimen using IL-2 can induce dramatic increases in lymphocyte number and augment their in vitro antitumor reactivity.
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PMID:Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. 325 45

General surgical procedures are followed by a period of generalized immunosuppression that may favour the deposition of metastases seeded at operation in patients with malignant disease. In an attempt to prevent the suppression of host-antitumour immune mechanisms following surgery we have studied the immunological effects of low-dose perioperative interferon-alpha (r-HuIFN alpha). Patients were randomly allocated pre-operatively to the control (n = 15) or treatment group (n = 15). Patients in the treatment arm received a 1-week course of subcutaneous recombinant human interferon-alpha 2a (Roferon-A) at a dose of 2 megaunits daily starting on the evening before surgery. Natural killer cell, lymphokine activated killer cell cytotoxicities and endogenous interleukin 2 production were measured 1 day before surgery and on the first, third, fifth and tenth postoperative days. Treatment with r-HuIFN alpha did not prevent the postoperative impairment of interleukin 2 production or lymphokine activated killer cell cytotoxicity. However it prevented the fall in natural killer cell activity normally observed following surgery. This may have important consequences in controlling metastatic dissemination of tumour in this vulnerable period.
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PMID:Effects of low dose perioperative interferon on the surgically induced suppression of antitumour immune responses. 326 47

Tumor cell invasion of basement membranes is required at several steps in the process of metastasis. To study the genetic and biochemical events mediating invasion, a variant cell line (TK) was selected from the metastatic M2 K1735 murine melanoma cell line. A novel selection procedure was used, based on in vitro and in vivo invasion and growth upon basement membrane and stroma. Additionally, two extrapulmonary metastases of the TK cell line, TK-Eve and TK-Liver, were established as cell lines and characterized. The TK cell line demonstrates greater metastatic potential in vivo and invasive ability in vitro than the parent M2 cell line, confirming the validity of the selection procedure. In addition, the M2 and TK cell lines were examined for other cell functions involved in the metastatic process. Cellular growth rates and sensitivity to T lymphocyte and natural killer cell lysis were not determining factors in the metastatic potentials of the M2 and selected cell lines; possible macrophage contribution to metastatic behavior was noted. [35S]methionine pulse labeling of protein synthesis and karyotypic analysis confirm the close relationship of parental and selected cell lines.
Clin Exp Metastasis
PMID:A novel method for selection of invasive tumor cells: derivation and characterization of highly metastatic K1735 melanoma cell lines based on in vitro and in vivo invasive capacity. 335 13

Natural killer (NK) cells may be important in the control of circulating tumor emboli. Because of this, the suppression of natural killer cell cytotoxicity (NKCC) observed with progressive tumor burden is a concern relative to the treatment of solid tumors. Our study examines the interplay between tumor progression, elaboration of metastases, and NKCC. Mice inoculated with Lewis lung carcinoma (3LL) cells developed visible primary tumors by day 6 of tumor bearing. This tumor burden appeared to be associated with a progressive decrease in NKCC beginning after day 6 of tumor bearing. Significant splenomegaly was observed beginning by day 12. Rapidly reproducing tumor cells take up 125I-labeled 5-iodo-2'-deoxyuridine (125I-IUDR) in lieu of thymidine more readily than normal cells. Intraperitoneal injection of the labeled IUDR allowed the identification of possible pulmonary metastatic activity earlier in the tumor progression sequence than has previously been possible using standard staining procedures. A significantly increased level of lung 125I-IUDR uptake was observed in the lung beginning after day 6 of tumor bearing; this increase in 125I-IUDR uptake began at the same time as the tumor burden impairment of NKCC. Successful implantation of tumor emboli may occur very early in experimental tumor burden systems, when measurable antitumor immune effector mechanisms are not yet massively suppressed. Antitumor immunotherapy programs may therefore need to be targeted to these earlier points of tumor bearing.
Invasion Metastasis 1988
PMID:Tumor burden impairment of murine natural killer cell cytotoxicity. 336 May 92

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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