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)

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

The effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells and human recombinant interleukin 2 (IL2), on palpable intradermal (i.d.) bladder tumor were studied. The murine transitional cell carcinoma MBT-2 was used in C3H mice. IL2 was given intraperitoneally at 5,000 U/injection three times a day for 5 consecutive days beginning on day 10. LAK cells were generated in vitro from normal splenocytes: 10(7)-10(8) LAK cells were transferred intravenously on day 10 and, in some experiments, also on day 13. IL2 alone, LAK cells alone (total 8 x 10(7], and both in combination showed little or no influence on intradermally growing MBT-2 tumors. Cyclophosphamide was also combined with adoptive immunotherapy (IL2 and LAK). CY (100 mg/kg, i.p. on day 9 or 10) alone was able to suppress i.d. MBT-2 growth significantly. The combination treatment of IL2 and LAK cells with CY caused additional tumor growth suppression in a manner dependent on the total number of LAK cells transferred. The amount of the additional tumor growth suppression was, however, relatively small when compared with CY plus IL2-treated groups. In comparison, experimentally induced 3-day and 10-day pulmonary metastases of MBT-2 cells were treated by the same protocol of IL2 and LAK cells but without CY. IL2 alone reduced the number of gross metastatic nodules in the lung. The addition of LAK cells to the IL2 almost entirely eradicated the 3-day metastatic nodules but was less effective against the 10-day metastases. The data suggest that adoptive immunotherapy with IL2 and LAK cells mediates tumor regression of micrometastases at a selected organ (lung), but is ineffective against the same tumor growing in the skin or in gross metastatic nodules. Host immune suppression by CY was not beneficial in this model in creating a successful therapeutic effect of LAK cells and IL2.
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PMID:Ineffectiveness of adoptive chemoimmunotherapy with lymphokine-activated killer cells, interleukin-2, and cyclophosphamide on palpable intradermal murine bladder cancer. 325 20

Adoptive transfer of autologous lymphokine-activated killer cells (LAK) in conjunction with recombinant interleukin-2 (rIL-2) has been reported to produce significant regression in metastatic disease in patients with advanced cancer. In an effort to confirm the results reported by the Surgery Branch of the National Cancer Institute, the same IL-2/LAK regimen was used in cancer patients at six extramural cancer centers. In this report we will review our experience with mononuclear cell removal from the blood of cancer patients using apheresis technology and extracorporeal handling of these cells to generate a selective, highly cytotoxic cell population.
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PMID:Apheresis techniques in lymphokine-activated killer cell production. 326 Aug 97

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

The systemic administration of recombinant interleukin-2 (IL-2) either alone or in combination with lymphokine activated killer cells is a new approach to the immunotherapy of metastatic cancer in man. Renal toxicity is often a dose-limiting side effect of IL-2 administration. This prospective study of 17 consecutive patients receiving parenteral high dose IL-2 documents a reversible syndrome of hypotension, oliguria, fluid retention, azotemia and very low urinary excretion of sodium (median FeNa of 0.04%). The median nadir urinary uric acid to urinary creatinine ratio during IL-2 therapy was 0.2. This IL-2 regimen induces a reversible renal hypoperfusion syndrome (pre-renal azotemia) without evidence of acute uric acid nephropathy. Hypophosphatemia [median serum phosphorus of 1.9 mg/dl (0.61 mmol/l)] prompted further study of tubular function. Urinary excretions of phosphorus, calcium and magnesium were very low. Arterial blood gases revealed hyperventilation without alkalemia. The hypophosphatemia probably reflects increased utilization of inorganic phosphorus by rapidly proliferating lymphoid cells.
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PMID:Metabolic and renal effects of interleukin-2 immunotherapy for metastatic cancer. 326 37

Immunotherapy with interleukin 2 and lymphokine-activated killer cells can result in regression of metastatic cancer. Dermatologic complications associated with this therapy include erythema, pruritus, and a mild desquamation. Three patients with a history of psoriasis received high-dose interleukin 2 alone or in conjunction with lymphokine-activated killer cells for treatment of metastatic renal cell carcinoma. Two patients developed an erythrodermic exacerbation during therapy while the third patient experienced a localized flare. Topical treatment was effective in inducing remission in all three patients. Histologic analysis of serial skin biopsy specimens revealed psoriasiform changes in involved skin as well as epidermal spongiosis and a perivascular mononuclear cell infiltrate. The psoriatic exacerbation from interleukin 2 did not affect antitumor response to the therapy and should not be considered a contraindication to treatment.
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PMID:Interleukin 2 and psoriasis. 326 40

Adoptive immunotherapy with high-dose interleukin 2 and lymphokine-activated killer (LAK) cells has proved to be successful in the treatment of some patients with metastatic cancer, but not without a significant degree of associated toxic effects. The primary goal of this study was to substantially reduce the toxicity of this complex and expensive treatment, while maintaining or improving efficacy. To this end, 29 patients were treated with LAK cells in conjunction with a low-dose regimen of interleukin 2 and a prolonged period of administration following LAK cell infusion. This protocol resulted in a considerable reduction in toxicity, as compared with that described in previous studies, without compromising the efficacy. This study offers further confirmation that adoptive immunotherapy of metastatic cancer can be clinically beneficial to patients for whom no other effective therapy is presently available.
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PMID:A new regimen of interleukin 2 and lymphokine-activated killer cells. Efficacy without significant toxicity. 326 42

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

In vivo patterns of lymphocytes sensitized against autologous tumor (in vitro) were studied in seven patients with metastatic cancer as a potential candidate for an alternative method of radioimmunodetection and adoptive immunocytotherapy. Peripheral blood lymphocytes (PBL) were either activated in Interleukin-2 (IL-2) [lymphokine activated killer (LAK) cells] or sensitized against autologous tumor cells by in vitro co-culture (IVC) and expanded in IL-2 (educated cells); both were then labelled with 111In. Labelled autologous cells (1 x 10(7)-5 x 10(8)) were administered to patients and biodistribution studied by imaging under a gamma camera at various time intervals. In 4/7 cases, imaging with the educated cells showed concentrations of radioactivity at sites that correlated positively with clinically detectable metastatic tumor. By contrast, only one instance of positive uptake was seen with the LAK cells. Other than slight fever in three cases, infusions of labelled PBL were well tolerated. Educated lymphocytes were cytotoxic against autologous tumor cells and the cytotoxic reactivities of the educated cells were maintained in continuous culture in IL-2 for 4-6 weeks. Evidence of accumulation of radiolabelled educated autologous cells at a significantly higher frequency than that of the LAK cells suggests that in vitro expanded educated PBL might be better candidates for radioimmunodetection of human cancer, and continuous cultures of such educated autologous PBL might be sources for repeated administration of these effector cells.
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PMID:Imaging pattern of previously in vitro sensitized and interleukin-2 expanded autologous lymphocytes in human cancer. 326 47


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