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 studied the ability of immunized lymphoid cells expanded in IL-2 to mediate the cure of mice with localized and disseminated syngeneic lymphoma. Mice received 500 rad total-body irradiation before injection of tumor into the footpad. Mice were treated 5 d later when a palpable local tumor and disseminated metastases were present. Intravenous injection of in vivo immune lymphocytes cured 93% of all mice, significantly better than any control group (P less than 0.0005). Immune cells, secondarily sensitized to the FBL-3 tumor in vitro, also conferred significant survival benefit (P less than 0.005) when injected intravenously, curing 79% of the animals treated. When these in vitro sensitized cells were expanded in IL-2, 8-10-fold over 7 d, 93% of the animals thus treated were cured, (P less than 0.005). When these cells were grown for multiple generations in IL-2 they retained their ability to cure mice (56% cured, P less than 0.01). This is the first demonstration that intravenous injection of sensitized cells grown in long term culture in IL-2 is capable of curing mice of established local and disseminated syngeneic tumor.
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PMID:Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2. 698 Feb 54

Transfer of cytokine genes into tumor cells has proven a valuable approach for cancer treatment. In order to generate a more effective cancer vaccine, we transfected the human interleukin-6 (IL-6) gene into B16 melanoma cells. A B16 cell clone secreting the highest level of IL-6 was obtained by G418-resistant selection, limiting dilution and IL-6 assay. The IL-6-gene-transfected tumor cells exhibited in vitro growth inhibition, reduced tumorigenicity and decreased metastatic competence. After immunization with the inactivated IL-6-gene-transfected vaccine, the murine cytotoxic T lymphocyte activity, natural killer activity and lymphokine-activated killer activity increased markedly. After treatment with the vaccine, the tumor-bearing mice showed significant growth inhibition of subcutaneous tumor, reduction in pulmonary metastases and extension of survival time. The above therapeutic effect was better when low-dose IL-2 was administered simultaneously, although this dosage of IL-2 had no in vivo antitumor effect. These data demonstrated that IL-6-gene-transfected cancer vaccine has a potent antitumor effect via efficient induction of antitumor immunity, and a better therapeutic effect could be achieved when the vaccine is combined with low-dose IL-2 as adjuvant.
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PMID:Induction of antitumor immunity and treatment of preestablished tumor by interleukin-6-gene-transfected melanoma cells combined with low-dose interleukin-2. 749 43

We screened a panel of 8 primary and 21 metastatic melanoma cell lines for constitutive secretion of cytokines. Melanomas expressed bioactivity for TGF-beta (8/25 lines) and IFN (7/12), but not IL-2. Immunoassays detected IL-1 alpha (4/25), IL-1 beta (12/25), IL-6 (13/29), IL-8 (29/29), TGF-beta 2 (5/12) and GM-CSF (11/29), but not IL-3, IL-4, TNF-alpha, or IFN-gamma. There was no preferential association of cytokine production with cells cultured from primary versus metastatic disease, and only IL-8 was produced by all lines tested. These data demonstrate that cultured melanomas produce a variety of cytokines which are potentially capable of influencing tumor growth in vivo.
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PMID:Production of multiple cytokines by cultured human melanomas. 751 80

We have previously demonstrated that local tumor irradiation effectively enhanced the therapeutic effect of IL-2 therapy on pulmonary metastases from a murine renal adenocarcinoma, Renca. Irradiation with 300 rad to the left lung only, followed by systemic IL-2 therapy, results in increased tumor reduction in both lungs, suggesting that radiation enhances the systemic effect of immunotherapy. In this study, we show that irradiation of the tumor-bearing organ is essential for the combined effect of both modalities. This effect is radiation dose-dependent as increases in the radiation dosage result in greater tumor reduction in the irradiated field as well as systemically in nonirradiated fields when combined with immunotherapy. We find that irradiation has a direct inhibitory effect on Renca cell growth in vitro. Irradiation of Renca cells also causes an upregulation in H-2Kd class I MHC antigen detectable at 300 rad and more pronounced with 800 rad. By in vivo selective depletion of lymphocyte subsets, we demonstrate the involvement of Lyt-2+ and L3T4+ T cell subsets and AsGM1+ cells, including NK cells, in the antitumor effect mediated by tumor irradiation and IL-2 therapy. Immunohistochemistry studies, performed on lung sections, showed a significant infiltration of CD3+ T cells and macrophages in the tumor nodules following treatment with tumor irradiation and IL-2 therapy. Our studies indicate that the mechanism of interaction between tumor irradiation and immunotherapy may include radiation-induced alterations in the tumor growth and antigenicity which may enhance or trigger an anti-tumor response elicited by IL-2 and mediated by T cells, AsGM1+ cells, and macrophages.
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PMID:Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma. 755 89

The purposes of this study were to determine the maximally tolerated dose (MTD) of IL-2 when sequentially administered following TNF (at its MTD), to identify any unique toxicities, and determine the immunomodulatory effects of this combination. Patients with metastatic cancer were treated with 160 micrograms/ml rTNF by rapid i.v. infusion for 5 days, followed by rIL-2 therapy daily at doses up to 18 x 10(6) IU/m2/day for 5 days and 6 x 10(6) IU/m2/day for 7 days. Cycles were repeated at 3- or 4-week intervals until progressive disease or unacceptable toxicity developed. Fifteen patients received 46 cycles of therapy (range 1-8, median 3). Major toxicities included hypotension, weight loss, and decreased performance status comparable to that reported with rIL-2 alone. No novel toxicities were identified. Two of 14 patients who received two cycles of therapy had objective responses (1 complete, 1 partial). Both occurred in patients with malignant melanoma, lasted 30 and 75 weeks, respectively, and included a complete response in liver metastasis. Dosage reductions of IL-2 were necessary for 3 patients over 11 treatment cycles (23%), and rTNF in 1 patient for 1 cycle (2%). The MTD of 5-day infusional rIL-2 was determined at 18 x 10(6) IU/m2/day. rTNF did not augment natural killer/lymphokine-activated killer activities beyond that commonly seen with IL-2 infusions. We conclude that full doses of rTNF can be combined with escalating rIL-2 infusions in an outpatient setting without additive toxicity and with clinical activity in patients with malignant melanoma.
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PMID:Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2. 761 42

We investigated the usefullness and problems of arterial administration of lymphokine activated killer (LAK) cells in combination with systemic IL-2 in the treatment of metastatic renal cell carcinoma (RCC). Ten nephrectomized patients with extrapulmonary and/or nonresectable metastases were treated with arterial infusions of LAK cells and systemic rIL-2 (5 x 10(5) IU twice a day) for 1-12 weeks. Leukapheresis was carried out once or twice a week, and two LAK cell populations generated from two gravity subtypes of peripheral blood lymphocytes were administered separately. Five of 15 metastases treated showed appreciable regression of metastatic sites including bone, muscle and lymph nodes. Two of 15 showed a minor response. Local pain due to metastasis was relieved or disappeared in 6 patients. There was no correlation between the response of the patients and the number of LAK cells used. The 24- and 56-month survival rate was 50 and 25%, respectively. No serious side effects were experienced during treatment. We conclude that regional arterial administration of LAK cells in combination with a low dose of IL-2 is worthwhile as an alternative treatment modality to conventional therapy for a selected group of patients with advanced RCC.
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PMID:Treatment of advanced renal cell carcinoma using regional arterial administration of lymphokine-activated killer cells in combination with low doses of rIL-2. 764 36

We have achieved efficient transduction of tumour metastases in vivo by the vascular delivery of retroviral producer cells. Experimental liver metastases in mice were created by intrasplenic injection of tumour cells into the portal venous circulation. Following the establishment of micrometastases, delivery of retroviral producer cells by the same route with a vector containing the Escherichia coli beta-galactosidase (lacZ) gene demonstrated selective in vivo gene transfer to tumour deposits. By this approach, two retroviral producer cell lines encoding cytokines (IL-4 and IL-2) directed tumoricidal inflammatory responses to established metastases. Cytokine gene targeting inhibited metastasis formation and caused significant overall reduction in tumour burden. These results suggest a novel therapeutic approach for the treatment of disseminated cancer.
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PMID:Gene therapy of metastatic cancer by in vivo retroviral gene targeting. 767 Apr 93

The present study investigates the ability of recombinant interleukin 12 (rIL-12) to modulate the growth of a primary tumor as well as the outgrowth of metastatic tumor cells in an ovarian carcinoma (OV-HM) model. This aggressive tumor displayed rapid growth of the primary tumor mass, high incidence of metastases to lung and lymph nodes, and invasion from the primary s.c. site to the peritoneal cavity. Starting 12 days after s.c. tumor cell implantation, several i.p. injections of rIL-12 at 2-3 day intervals resulted in regression of growing tumors. These treated mice did not show signs of metastases or tumor recurrence at the original site. One month after tumor implantation, untreated mice did not have visible lung metastasis, but some did have palpable lymph nodes. At this stage, the primary tumors of animals without palpable lymph nodes were surgically resected. When examined 2 months later, most animals had developed lymph node and lung metastases. In contrast, rIL-12 injections after tumor resection inhibited the development of metastases in both lung and lymph nodes. This contrasted with the failure of IL-2 to prevent metastases. Even for mice already showing signs of lymph node metastases or invasion of the abdominal wall, rIL-12 administration after tumor resection prevented further invasion to the peritoneal cavity and growth of metastatic tumor cells in lung. It was somewhat surprising that the IL-12 treatment of animals after 1 month of tumor growth without resection also resulted in complete tumor regression, as well as eradication of micrometastasis that would have occurred before the treatment. Moreover, they exhibited resistance to a rechallenge with the same tumor but not with a second tumor. Thus, this tumor system provides a relevant model to clinical situations in terms of treatment of advanced tumors and metastases. These results also indicate that IL-12 can induce a curative immune response, even in the face of an aggressive micrometastasizing tumor.
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PMID:Administration of recombinant interleukin 12 prevents outgrowth of tumor cells metastasizing spontaneously to lung and lymph nodes. 767 Dec 53

To establish an efficient cell-culture system for adoptive immunotherapy, we attempted to use lipopolysaccharide(LPS)-activated B cells (LPS blasts) as costimulatory-signal-providing cells in the in vitro induction of antitumor effector cells. Both normal and tumor-draining lymph node cells were efficiently activated by both anti-CD3 monoclonal antibody (mAb) and LPS blasts, and subsequently expanded by a low dose of interleukin-2 (IL-2; anti-CD3 mAb and LPS blasts/IL-2). The expanded cells were predominantly CD8+ T cells and showed a low level of tumor-specific cytotoxic T lymphocyte (CTL) activity. The adoptive transfer of B16-melanoma-draining lymph node cells expanded by anti-CD3 mAb and LPS blasts/IL-2 showed significant antitumor effect against the established metastases of B16 in combination with intraperitoneal injections of IL-2. This treatment cured all B16-bearing mice. In addition, these mice also showed tumor-specific protective immunity against B16 at the rechallenge. Considering that activated B cells express several kinds of costimulatory molecules, these findings thus indicate an efficacy of costimulation that is derived from activated B cells for the in vitro induction of tumor-specific CTL, in co-operation with anti-CD3 mAb. The culture system presented here may thus be therapeutically useful, providing potent effectors for adoptive immunotherapy against various types of cancer.
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PMID:The antitumor effect of tumor-draining lymph node cells activated by both anti-CD3 monoclonal antibody and activated B cells as costimulatory-signal-providing cells. 772 76

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease using ex vivo activation of autologous (human) or syngeneic (murine) lymphocytes from tumor-bearing hosts (TBH) by low doses of anti-CD3 monoclonal antibody (MAb) and a mixture of previously prepared autologous cytokines (T3CS). Ex vivo activation by T3CS without tumor antigen results in expansion of CD44+ (memory) T cells. These memory T cells (ALT cells) mediate in vivo anti-tumor specificity and with cyclophosphamide (CY) are capable of curing metastatic disease in murine TBH. To determine whether CY could enhance the effectiveness of CD4+ or CD8+ subsets of ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) using CD4-depleted or CD8-depleted ALT cells and CY. ALT cells were derived from splenocytes of B16 or 3LL-TBH and activated ex vivo with T3CS. Depletion of CD4+ or CD8+ T cells was performed before or after activation with T3CS. B16-TBH or 3LL-TBH that received ACIT using CY with B16-derived or 3LL-derived CD8-depleted ALT cells, respectively, demonstrated cure of metastatic disease regardless of whether CD8+ T cells were depleted before or after T3CS activation. B16 or 3LL-TBH that received ACIT using CY with B16 or 3LL-derived CD4-depleted ALT cells also cured metastatic disease but only if CD4+ T cells were depleted after T3CS activation. Interleukin (IL)-2 added to pre-T3CS CD4-depleted ALT cells cultured with T3CS restored anti-tumor activity when combined with CY. TBH cured by ACIT using CY and ALT-cell subsets derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity in rejecting a lethal challenge of identical but not reciprocal tumor. TBH given ACIT using CY and ALT-cell subsets derived from splenocytes of syngeneic TBH with reciprocal tumors rejected lethal challenges of both tumors. Tumor specificity measured by interferon (IFN)-gamma and 51Cr-release assays was demonstrated in pre- or post-T3CS/CD8-depleted, post-T3CS/CD4-depleted and pre-T3CS + IL-2/CD4-depleted ALT-cell subsets. Our data demonstrate that ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T-cell subsets conveys long-term tumor-specific immunity.
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PMID:Adoptive transfer of ex vivo-activated memory T-cell subsets with cyclophosphamide provides effective tumor-specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma. 775 64


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