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)

Approximately 24,000 cases of renal cell carcinoma are expected in the United States in 1990. Although approximately 50% of patients with local disease are cured by surgery, in patients with metastatic disease the median survival is only approximately 10 months. Neither chemotherapy nor radiation therapy has been shown to be effective against metastatic renal cell carcinoma. Immunotherapy has come to the forefront of clinical research for the treatment of metastatic renal cell carcinoma. In the past decade, the development of recombinant DNA techniques has enabled the production of large quantities of biologic response modifiers such as the interferons and interleukins. Following initial reports in 1983 by the University of California-Los Angeles (UCLA) group and the investigators at M. D. Anderson Hospital, in Houston, TX, numerous trials have demonstrated a reproducible objective response rate to interferon of 15% to 20%. These responses are independent of the interferon preparation used, and optimal dosage/schedule has not been determined. In general, responses have been correlated with the following patient factors: previous nephrectomy, good performance status, a long disease-free interval, and lung-predominant disease. Median response durations of from 8 to 10 months can be expected. The addition of vinblastine, gamma-interferon, or aspirin has not improved the therapeutic index. Interleukin-2 therapy has produced encouraging results in 10% to 15% of patients. Although high-dose therapy is associated with substantive side effects, a small cohort of patients have been in continuous remission for extended periods of time, raising the possibility of "true" complete remissions of clinical significance. Recent trials, including our trials at UCLA, have combined the interleukins and interferons in this patient population. This combination has a sound scientific basis and the results are encouraging, especially when the toxicity profile is considered. Most patients receive these combinations as outpatients and have not required hospitalization nor suffered the toxicities of the high-dosage regimens. Complete pathologic remissions have been observed using this lower dosage, outpatient schedule. Clinical trials suggest that interferon and interleukin-2 may have an expanding role in metastatic kidney cancer both as single agents and in combination outpatient biologic therapy. The future clinical trials of kidney cancer will continue to incorporate these biologic response modifiers into the therapeutic strategies of the 1990s.
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PMID:The role of interferon and interleukin-2 in the immunotherapeutic approach to renal cell carcinoma. 171 41

We investigated the efficacy of human melanoma-specific cytotoxic T-cells (CTLs) in treating experimental human melanoma metastases in a nude mouse model of adoptive immunotherapy. Hepatic metastases were generated by the intrasplenic injection of 1.5 x 10(6) human melanoma cells. Animals were then randomized to receive saline, interleukin-2 only, or CTLs and interleukin-2. CTLs were effective when administered 3 or 7 days after generation of hepatic metastases, with 96 and 88% of animals disease-free, respectively, when examined at one month. Interleukin-2 alone was not effective. In addition, CTLs were effective when as few as 2.5 x 10(6) T-cells were adoptively transferred. Only 33% of the animals were tumor-free when CTLs were administered on day 10, and CTLs were not effective when given at day 14. Human CTLs that were not cytotoxic for the tumor line used in vivo, when tested in a 51Cr assay, were also not effective in the model of immunotherapy. This suggests that the tumor-specific CTLs maintain their specificity in vivo, and eliminates a nonspecific inflammation directed against the human CTLs as a possible cause of the antitumor effect. These studies lay the foundation for clinical trials of CTLs in the adoptive immunotherapy of patients with metastatic melanoma.
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PMID:Human xenograft-nude mouse model of adoptive immunotherapy with human melanoma-specific cytotoxic T-cells. 172 11

A total of 12 patients with stage 4 renal cell carcinoma and primary renal tumors in situ was entered into a pilot study using treatment with interleukin-2 and alpha-interferon followed by radical nephrectomy. Of the patients 11 underwent nephrectomy after an initial course of immunotherapy. Ten patients were able to receive a second course of immunotherapy given after nephrectomy. One patient achieved a complete response of lung and mediastinal metastases without any change in the primary renal tumor but after nephrectomy the patient remained in complete remission for greater than 11 months. A total of 3 patients achieved a partial response at some extrarenal sites but they had progression elsewhere. Toxicity was similar to previous experience with this immunotherapy regimen. Therefore, we demonstrated that metastatic tumor regression is possible with primary renal tumors in situ and that aggressive interleukin-2-based immunotherapy can be tolerated in the presence of a large renal tumor.
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PMID:Immunotherapy with interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer with in situ primary cancers: a pilot study. 172 40

We examined the ability of bryostatin 1 (Bryo), a novel protein kinase C activator, plus ionomycin (Io), a calcium ionophore, to activate T-cells with specific antitumor activity. Lymphocytes from the draining lymph nodes (DLN) of MCA-105 tumor-bearing host mice were stimulated with Bryo/Io, either fresh or after in vitro stimulation with autologous tumor, and then were incubated in interleukin-2 at 20 units/ml. Lymphocytes sensitized with tumor cells in vitro and then stimulated with Bryo/Io exhibited significant expansion (12-fold) after a total of 3 weeks in culture and moderate cytolytic activity (40% at an effector:tumor cell ratio of (80:1) and were exclusively CD8+ T-cells. DLN cells activated immediately with Bryo/Io, without tumor antigen sensitization in vitro, displayed marked growth (130-fold expansion) over 3 weeks in culture, had weak cytolytic activity (8% at an effector:tumor ratio of 80:1), and were a mixed population of CD8+ and CD4+ cells. Despite the differences in phenotypes and in cytotoxicity, both groups of DLN cells were highly effective in vivo against MCA-105 pulmonary metastases. Bryo/Io-activated DLN cells from MCA-105 tumor-bearing hosts had no therapeutic efficacy against B16 melanoma or MCA-203 sarcoma metastases. Lymph node cells from normal mice and non-draining lymph node cells from tumor-bearing hosts could be expanded with Bryo/Io to a degree similar to that of DLN cells but had no antitumor activity. Phenotypic analyses and in vitro and in vivo depletion studies demonstrate that CD8+ cells mediated tumor regression.
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PMID:Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1. 173 41

We report the use of inhaled natural interleukin-2 in patients with metastatic disease. Six patients with metastatic renal cell carcinoma received 100,000 units natural interleukin-2, 5 times per day by inhalation in addition to a 4-day cycle of intravenous natural interleukin-2 every 2 weeks and subcutaneous interferon 5 days per week. Response was clearly correlated with metastatic site. Distinct tumor burden and the poor condition of the patient did not impair success. Pulmonary metastases responded in 5 of 5 patients. Metastases in the mediastinum, liver, abdomen and pelvis were stabilized in 4 patients. No response was noted in 3 solitary bone metastases, which were successfully removed surgically after several months of therapy, and a pleural metastasis progressed despite a clear response of the pulmonary disease in the same patient. New metastases did not develop in any of the patients during treatment (median followup 183 days of treatment, range 97 to 296 days). The over-all importance of the low toxicity of this novel route of administration (World Health Organization classification not exceeding grade 1) making long-term outpatient treatment possible must be emphasized because limitations of systemic interleukin-2 application are mainly caused by pulmonary side effects, for example pulmonary capillary leakage syndrome and edema. However, this new type of topical natural interleukin-2 application and combination with low dose intravenous interleukin-2 achieved considerable antitumor responses.
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PMID:Interleukin-2 by inhalation: local therapy for metastatic renal cell carcinoma. 173 90

A long-term-cultured cytotoxic T lymphocyte (CTL) line (E/88) was obtained from splenic lymphocytes of BALB/c (H-2d) mice bearing the weakly immunogenic colonic carcinoma C26. This line was shown to be alpha/beta TCR + V beta 6 + CD3 + CD8 + CD4- and to recognize a common tumour-associated antigen on syngeneic carcinomas and sarcomas in a major-histocompatibility--complex-restricted and T-cell-receptor(TCR)-mediated fashion. The assessment of cytotoxic activity on a panel of 30 normal and neoplastic target cells of differing etiology and histo-type showed that E/88 CTL lysed syngeneic colon carcinomas and some fibrosarcomas but not leukemias, lymphomas or mammary carcinomas. Clones derived from the E/88 line exhibited the same lytic pattern. Moreover, anti-T3, anti-Lyt2.2, anti-alpha/beta TCR and anti-V beta 6 mAbs as well as anti-H-2d antisera abolished cytotoxicity when used in blocking experiments. The therapeutic activity of E/88 CTL upon in vivo transfer was assessed in mice bearing either experimental or spontaneous metastases of C26. In both models therapy with E/88 lymphocytes in combination or not with interleukin-2 was highly effective. Adoptive immunotherapy carried out with two clones obtained from line E/88 showed comparable therapeutic effects. In addition, treatment of syngeneic mice bearing experimental metastases of in vitro E/88-lysable or E/88-resistant tumours, showed that E/88 CTL can eradicate metastases of the former but not of the latter neoplasms. These data indicate that long-term CTL lines recognizing common tumour-associated antigens can be derived from tumour-bearing animals and used in adoptive immunotherapy of tumours previously shown to be lysed in vitro by these effectors.
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PMID:Therapeutic use of a long-term cytotoxic T cell line recognizing a common tumour-associated antigen: the pattern of in vitro reactivity predicts the in vivo effect on different tumours. 176 Aug 12

Tumor infiltrating lymphocytes (TILs) are derived from solid tumors by culturing single cell suspensions of the tumors in low dose interleukin-2 (IL-2) and intermittent tumor stimulation. We have investigated the survival of TILs after intravenous injection into tumor-bearing mice. Using several murine transplantable sarcomas, we examined the in vivo survival of TILs derived from B6.PL Thy 1a/CY mice (Thy-1.1), which were used to treat established experimental metastases in C57BL/6N (Thy-1.2) mice. Donor and host lymphoid cells could be clearly distinguished by fluorescence-activated cell sorting. We found that TILs or TILs + IL-2 could extend the survival of and, in some instances, cure established experimental hepatic and pulmonary metastases. Donor TILs could be recovered from treated animals at all time points tested; in mice cured of pulmonary metastases donor TILs could be detected as late as 119 days after intravenous injection even in the absence of exogenous IL-2. The administration of a relatively low dose of IL-2 in vivo to mice receiving TILs increased the number of donor TILs recovered from the lungs of cured animals 5-10-fold at all time points but did not change the period of time during which donor TILs could be detected in vivo. Additionally, TILs could be recovered from animals cured of established metastases and such cells retained their antitumor activity in vivo. Finally, when mice cured of pulmonary metastases by TILs or TILs + IL-2 were rechallenged with tumor, donor TILs specifically accumulated at the site of tumor rechallenge up to 4 months after adoptive transfer of TILs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adoptively transferred tumor-infiltrating lymphocytes can cure established metastatic tumor in mice and persist long-term in vivo as functional memory T lymphocytes. 176 72

The prognosis of renal cell carcinoma (RCC) is related to the initial staging, assessed by nephrectomy. Metastases are present at the time of diagnosis in 30% of cases. Solitary metastases are rare. The most common metastatic sites include lungs, lymph nodes and bones. Anatomical pathways as well as local events in the secondary sites are responsible for the site specificity of the tumor spread. Patients with disseminated disease have a 5 years survival rate of less than 10%. RCC is intrinsically chemo-resistant. Vinblastine leads to a global response rate (RR) of 15%. In view of the lack of effective chemotherapeutic agents, interest has been directed towards the potential value of biological response modifiers (BRM). Response rates are about 15% with IFN alpha. Significant synergy between IFN alpha and vinblastine has not been proved. Interleukin-2 (IL-2) with or without Lymphokine Activated Killer (LAK) cells leads to a RR of 20%. Some durable complete remissions have been reported. Ideal doses and schedules remain to be determined.
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PMID:[Metastasis of renal cancer]. 179 52

Lymph nodes draining progressive tumors contain tumor-sensitized but not functional preeffector T lymphocytes. These cells can acquire antitumor reactivity after stimulation with tumor cells and interleukin-2 (IL-2). We demonstrated here that, in the absence of tumor cells, preeffector cells could be stimulated and expanded by sequential culture with anti-CD3 monoclonal antibody and IL-2. The adoptive transfer of such activated cells mediated immunologically specific reductions of established pulmonary metastases. The therapeutic effects could be enhanced by the administration of IL-2. This activation represents a secondary immune response because effector cells could be generated only from tumor-draining but not from normal or adjuvant-stimulated lymph nodes. Furthermore, treatment of advanced metastases with these cells resulted in prolongation of survival and cure of the disease. Thus, anti-CD3 may serve as a universal reagent for activating tumor-sensitized T lymphocytes for cancer therapy.
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PMID:Activation by anti-CD3 of tumor-draining lymph node cells for specific adoptive immunotherapy. 182 49

Interleukin-2 (IL-2) mediates the regression of metastatic cancer, but clinical application has been limited by the induction of dose-dependent toxicities in normal tissues. The most clinically significant toxicities occur secondary to a vascular leak syndrome and include acute respiratory failure and hemodynamic instability. Because previous studies suggested a role for pentoxifylline in attenuating the toxic effects of IL-2, we hypothesized that pentoxifylline would inhibit alterations in the microvasculature induced by IL-2 and would ultimately reduce IL-2-induced toxicity. To determine the validity of this hypothesis, we prepared four groups of rats for in vivo microvascular observation. In the first group, a bolus intravenous injection of IL-2 (1 x 10(6) units/kg) acutely induced hypotension, tachypnea, hypoxia, increased lung water, decreased microvascular blood flow, and increased leukocyte-endothelial adherence. No significant changes occurred in animals treated by pentoxifylline alone or the control IL-2 vehicle-alone group. However, pentoxifylline inhibited many of the IL-2-induced systemic and microvascular effects, such as hypotension, tachypnea, increased lung water, hypoxia, and increased leukocyte-endothelial adherence, but not tachycardia or increased microvascular protein leakage. These data support our hypothesis that systemic toxicities induced by IL-2 are associated with alterations in the microcirculation, which may be ameliorated by pentoxifylline.
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PMID:Pentoxifylline inhibits interleukin-2-induced leukocyte-endothelial adherence and reduces systemic toxicity. 185 30


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