Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this investigation, systemic administration of interleukin-1 (IL-1) and local adjuvant therapy were shown to modify immunological parameters associated with the lymphatics draining the site of experimental tumor inoculation. These immunological parameters were shown to be modified early (within 7 days) following tumor inoculation and within the time period of IL-1 administration. IL-1 induced a marked increase in the number of lymphocytes within the brachial and axillary lymph nodes associated with the tumor inoculation site. This increase was characterized by an overall augmentation in the number of CD8+ and CD4+ lymphocytes. In vitro, these lymph node cells showed enhanced proliferation in response to interleukin-2 (IL-2) when compared to non-IL-1 treated animals, and were capable of mounting a potentially greater cytotoxic response for both NK sensitive and NK resistant tumor targets. Without IL-1 administration, temporal and sequential lymph node cellular changes were observed, but were diminished and delayed when compared to the IL-1 treated animals. By adoptive transfer of tumor resistance, lymph node cells from IL-1 treated animals were demonstrated to be tumor-protective in vivo. These results demonstrate that systemic IL-1 induces regional changes in the lymphatics of mice undergoing primary tumor challenge with adjuvant therapy and that these changes result in tumor protection for the host.
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PMID:Systemic IL-1 and adjuvant treatment of an experimental tumor. II. Immune status during primary tumor challenge. 129 Jul 22

The treatment of metastatic renal cell carcinoma with immunotherapy has resulted in objective anti-tumor responses in 15-30% of patients. To enhance the therapeutic effects of immunotherapy, it is becoming evident that this approach should be combined with other treatment modalities. In this study, a spontaneously metastasizing murine renal adenocarcinoma (Renca), transplanted under the renal capsule, was treated with either radiation therapy, immunotherapy or a combination of both. In order to distinguish between the local and systemic effects of radiation therapy, total body irradiation was compared to irradiation of the tumor-bearing kidney only, or irradiation of the whole mouse with the tumor-bearing kidney shielded. Immunotherapy was administered with interleukin-2 (IL-2) alone or with IL-2 and lymphokine activated killer (LAK) cells. Combined radiation and immunotherapy induced a better anti-tumor response than either modality alone. The best response was obtained by local tumor irradiation and IL-2 therapy and resulted in a significant reduction in primary tumor size, elimination of lung metastases and a significant increase in survival.
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PMID:Synergy of radiation therapy and immunotherapy in murine renal cell carcinoma. 140 69

Polyethylene glycol-modified recombinant human interleukin-2 (PEG-IL-2) represents a cytokine with prolonged circulatory half-life and increased antitumor activity as compared to recombinant interleukin-2 (rIL-2) after systemic administration. We studied whether PEG-IL-2 would also be advantageous in locoregional immunotherapy using a syngeneic tumor model. Intradermal inoculation of line-10 tumor cells into the flanks of strain-2 guinea-pigs results in a fast-growing tumor and regional lymph-node metastases. Treatment schedules were started on day 7 after inoculation in animals with established tumors. First, groups of 5-6 animals were treated with repeated intratumoral and perilymphatic rIL-2 or PEG-IL-2 injections. PEG-IL-2 caused significant growth inhibition of both the primary tumor and the regional lymph-node metastases at lower doses and with less frequent administration than rIL-2. The best schedule for PEG-IL-2 was 3 injections a week for 5 weeks, resulting in cure of 4/17 and 5/5 (p less than 0.01) animals at the 2 most efficient dose levels tested. Subsequent experiments indicated that the intratumoral and not the perilymphatic injection route was essential for the obtained antitumor effect. Furthermore, 12/12 animals cured after PEG-IL-2 treatment rejected a rechallenge with line-10 tumor cells, whereas no cures were seen after rIL-2 injections. PEG-IL-2 therefore appears to be a valuable substance for intratumoral immunotherapy.
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PMID:Polyethylene-glycol-modified interleukin-2 is superior to interleukin-2 in locoregional immunotherapy of established guinea-pig tumors. 161 87

Patients with head and neck squamous cell carcinomas (HNSCCs) manifest defects in cell-mediated immune function. Previous studies in this laboratory have demonstrated regional alterations in the immunocompetence of draining lymph nodes (LNs) in HNSCC patients. In this investigation, we studied functional activity of lymphocytes from lymph nodes in different locations in the radical neck dissections (RNDs) from patients undergoing operations for HNSCC. Lymphocytes from nodes close to the primary tumor ("near" lymph nodes or NLN) exhibited a significant decrease in interleukin-2 (IL-2)-activated cytotoxicity when compared to lymphocyts from distant nodes ("far" lymph nodes or FLN). In addition, co-culture experiments suggested the existence of a soluble regulatory factor, produced by lymph nodes, that inhibited the development of lymphokine-activated killer (LAK) cells in vitro. Further experiments with conditioned supernatants from the lymph node cells confirmed the presence of this soluble inhibitory factor. The inhibitory effect is significantly greater in NLNs than in FLNS. This hierarchical phenomenon suggests a regional network of immunosuppression in HNSCC patients. It is likely that tumor- and lymph node-induced suppression plays a role in limiting the efficacy of current immunotherapy protocols in human beings. A greater understanding of mechanisms of local inhibition of immune function will aid in improving adoptive immunotherapy for treatment of cancers in human beings.
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PMID:Hierarchical immunosuppression of regional lymph nodes in patients with head and neck squamous cell carcinoma. 176 90

Peripheral blood mononuclear cells (PBM) from normal donors and patients with recurrent glioma were activated initially for 48-72 h with phytohemagglutinin-P (PHA) and recombinant human interleukin-2 (IL-2), and then proliferated in vitro for up to 5 months with IL-2. These cells are termed mitogen-stimulated lymphokine-activated T killer (T-LAK) cells. We measured patterns of T-LAK cell growth, in vitro cytolytic activity on a panel of continuous and primary tumor cells, and the phenotypes of the cells in these cultures. Lymphocyte viability declined dramatically over the first 3-5 days; and then the remaining cells in these cultures began to divide and maintained a constant 30-36 h doubling time for long periods in vitro. Phenotyping revealed that cells in the initial few days of culture were heterogeneous, but became almost totally CD3 T cells after 7-10 days in culture. The T-LAK cells from individual normal donors and cancer patients demonstrated a non-genetically restricted cytolytic ability against a panel of both continuous cell lines and primary autologous and allogeneic glioblastoma cells in vitro. This technique provides a method of generating large numbers of autologous cytolytic T cells with non-restricted anti-tumor activity that can be derived from peripheral blood mononuclear cells.
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PMID:Generation of stimulated, lymphokine activated T killer (T-LAK) cells from the peripheral blood of normal donors and adult patients with recurrent glioblastoma. 201 99

Lymphokine-activated killer (LAK) cells were generated from splenocytes of rats bearing a weakly immunogenic Dunning prostate tumor (R-3227 AT-3) and activated with recombinant interleukin-2 (rIL-2). The maximal LAK activity was obtained from splenocytes of rats bearing tumors for 10 to 14 days after incubation with 1000 U/ml./day of rIL-2 for five to eight days. The majority of these LAK cells expressed high levels of asialo GM1 (89%), laminin (83%), OX-19 (80%) and OX-8 (88%) surface markers. LAK cells exhibited higher cytotoxicity to rat prostate tumor cells and mouse lymphoma in vitro than to other non-prostate tumor cells or normal rat splenocytes and thymocytes. Splenocytes of rats bearing prostate tumors have higher LAK activity than normal splenocytes. The Winn type assay showed that Dunning prostate tumor growth was inhibited effectively by LAK cells at a tumor cell:LAK cell ratio of 1:50. The therapeutic efficacy of LAK cells in the treatment of primary solid prostate tumors and pulmonary metastases of Dunning rats was evaluated. LAK cells in combination with rIL-2 showed a greater therapeutic benefit in 1) prevention of prostate tumor metastases to lung, 2) retardation of the primary tumor growth, 3) regression of spontaneously established pulmonary metastases, and 4) prolongation of survival as compared to untreated controls or those groups treated with LAK cells or rIL-2 alone. The results of this study indicate that the conjunctive therapeutic approach of using surgical therapy to remove primary solid tumors followed by adoptive immunotherapy with LAK cells plus in vivo administration of IL-2 may be potentially valuable in the treatment of prostate tumors, particularly for the spontaneous pulmonary metastases.
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PMID:Adoptive immunotherapy using lymphokine-activated killer cells and recombinant interleukin-2 in preventing and treating spontaneous pulmonary metastases of syngeneic Dunning rat prostate tumor. 205 87

Natural interleukin-2 is a lymphokine with an immunoregulatory function. The recombinant interleukin-2 (rIL-2) is cloned from a human lymphoblastoid T-cell line for this trial. The gene is expressed in E-coli, allowing production of large quantities of rIL-2. This study is an open label phase I-II trial designed to evaluate the toxicity and efficacy of a rIL-2 in disseminated renal cell carcinoma. After surgical resection of the primary tumor, 3 X 10(6) units/m2 day rIL-2 is administered by 2-hr IV infusions daily for 5 days every other week for a total of eight cycles. At the conclusion of eight cycles of therapy, the patients were re-evaluated for response. Patients with complete and partial responses were eligible to receive an additional eight cycles every other week. Patients demonstrating progressive disease during this study were withdrawn. The toxicities of the high-dose rIL-2 included transient hypotension, pyrexia, malaise, and skin rashes. The transient hypotension responded to fluid replacement, and the other toxicities also responded to symptomatic treatment. The early results in ten patients indicate two partial and one complete response. We have concluded that administration of high-dose interleukin-2 has acceptable toxicities with encouraging response and deserves a phase III study.
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PMID:A phase I-II study of high-dose recombinant human interleukin-2 in disseminated renal-cell carcinoma. 326 82

Previous studies have indicated the efficacy of adoptive immunotherapy utilizing recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells in the treatment of advanced neoplastic disease. However, this therapeutic approach is associated with considerable toxicity, primarily due to the systemic administration of rIL-2. The present study was undertaken to determine the efficacy of a newly developed water-soluble glucan, when administered in combination with LAK cells, in the therapy of experimental hepatic metastases. Mice were challenged subcutaneously (1 X 10(4) cells) with reticulum cell sarcoma M5076 on day 0. Therapy was initiated on day 15, when a palpable primary tumor mass and hepatic micrometastases were evident, and continued at 3-day intervals up to day 54. Sarcoma-bearing mice received glucan (250 mg/kg) intravenously, either alone or in combination with LAK cells (1 X 10(7)/mouse). Control mice received 5% (wt/vol) dextrose in water. Glucan-LAK cell therapy significantly suppressed primary tumor growth, inhibited the progression of hepatic metastases and prolonged survival in sarcoma-bearing mice. Splenocytes, incubated with rIL-2 for 72 h, exhibited significant natural killer (NK) cell activity and were cytotoxic to sarcoma cells in vitro. Glucan-LAK cell administration resulted in significant increases in splenic NK cell activity and Kupffer cell-mediated tumoricidal activity. In addition, bone marrow proliferation was enhanced following the co-administration of glucan and LAK cells. Due to its nontoxic nature and immunostimulating properties, soluble glucan may prove to be an attractive biological response modifying agent for utilization in adoptive immunotherapy of advanced neoplastic disease.
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PMID:Soluble glucan and lymphokine-activated killer (LAK) cells in the therapy of experimental hepatic metastases. 328 99

A methylcholanthrene-induced fibrosarcoma model in C3H/HeJ mice demonstrated that combined chemoimmunotherapy, including partially purified, 1-butanol-extracted, tumor-specific transplantation antigen (1 microgram), cyclophosphamide (20 mg/kg), and continuous intrasplenic (IS) or intravenous (IV) infusion of purified human interleukin-2 (IL-2) (120 U/d) reduced the outgrowth of 4-mm established tumors, while IL-2 alone only modestly decreased tumor growth. For tumors larger than 1 cm, only the triple regimen with IS IL-2 significantly inhibited tumor growth, whereas IL-2 alone or the triple regimen with IV IL-2 failed to retard tumor growth. Furthermore, the first regimen significantly decreased pulmonary metastases after primary tumor resection. The Lyt-2+ phenotype predominated in the effector population of animals treated with this regimen, while L3T4+ cells predominated in those treated with the triple regimen that included IV IL-2. Thus, continuous IS IL-2 administration potentiates the efficacy of antigen-specific chemoimmunotherapy.
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PMID:Continuous intrasplenic interleukin-2 combined with antigen-specific chemoimmunotherapy. 349 96

Antigenic differences between primary tumors and their cervical lymph node metastases of 12 patients with head and neck cancers were examined by measuring their sensitivity to cytotoxic lymphocytes (CL). Cytotoxicity was induced by autologous mixed lymphocyte (CL). Cytotoxicity was induced by autologous mixed lymphocyte tumor cell culture (MLTC), and further cultivation with recombinant interleukin-2 (rIL-2). The effector cells which were used in this study consisted of OKT3+8+ and OKT3+4+ subpopulations. Their cytotoxic nature was different from lymphokine activated killer cell (LAK cell) activity. Cytotoxicity of CLs stimulated by autologous primary tumor cells (CLP) was observed in 7 out of 12 patients (58.3%). In contrast, cytotoxicity of CLs stimulated by metastatic tumor cells (CLM) was observed in 4 out of 12 patients (33.3%). In the cases in which both CLP and CLM were successfully induced, cross-reactivity tests and cold target inhibition tests were performed. These results suggested that a reduction in immunogenicity had occurred at the metastatic site, and sensitivity against autologous CL was different between primary and metastatic tumor cells.
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PMID:Differences of sensitivity to autologous cytotoxic lymphocytes between primary tumor and its cervical lymph node metastases. 350 23


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