Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human interferon-induced intracellular protein homologous to the murine Mx-protein has recently been identified by means of a specific monoclonal antibody. Three of six melanoma cell lines elicited this intracellular human Mx-homolog upon incubation with IFN-alpha or IFN-gamma, yet all six melanoma cell lines tested were susceptible to the antiproliferative effect of IFN-alpha and IFN-gamma. Compared per antiviral unit, IFN-gamma had weaker Mx-inducing but stronger antiproliferative activity than IFN-alpha. These data suggest that the IFN-induced Mx-homologous protein is not involved in the antiproliferative action of IFN on malignant melanoma cell lines. Furthermore, 51 patients with advanced malignant melanoma were treated thrice weekly with 10 x 10(6) IU rIFN-alpha-2b and 6 x 10(6) nIFN-alpha, respectively. Nine of the 51 patients experienced systemic objective tumor responses (3 complete response, 6 partial response), but had Mx concentrations in their mononuclear cells equal to the Mx levels of non-responders during IFN-alpha therapy. Therefore, the level of Mx-homologous protein induced during IFN therapy is not a predictive marker for an antitumor response in malignant melanoma.
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PMID:Correlation of the antiproliferative effect and the Mx-homologous protein induction by IFN in patients with malignant melanoma. 170 9

We have previously demonstrated that interferon (IFN) treatment of mice bearing the spontaneously metastasizing B16F10L murine melanoma on days -5 to -1 prior to surgical removal (day 0) of the primary tumor resulted in survival of greater than 50% of treated mice. The antitumor effect was correlated with an early increase of natural killer (NK) cell cytotoxicity followed by a later developing specific cytolytic T-cell response. The purpose of this study was to establish definitively the roles of NK, CD4, and CD8 cells as mediators of the antitumor/antimetastatic effects of IFN treatment by administration of anti-asialo-GM1, anti-L3T4, and/or anti-Lyt-2 antisera. Depletion of NK cells, alone or in combination with T-cells, eliminated the protective effect of IFN treatment. Depletion of both CD4 and CD8 cells, however, did not significantly alter the therapeutic effect of IFN therapy. Collectively, these data conclusively demonstrated the importance of NK cells as mediators of the IFN induced antitumor state. However, in mice depleted of CD4 cells alone, the protective effect of IFN was eliminated, in spite of the presence of intact NK cells. In vitro analysis of NK cytotoxicity on day 1 after surgery demonstrated (a) a lack of IFN induced stimulation of NK activity in CD4 depleted mice and (b) a significant increase in both baseline and IFN induced NK cytotoxicity in CD8 depleted mice. These data suggested a CD8 cell mediated inhibition of NK activity/stimulation in CD4 depleted mice, possibly responsible for the lack of response to IFN therapy in that group. These results demonstrate the importance of not only individual components of the immune system but also the interaction of these components in both the natural and IFN induced control of spontaneous B16F10L metastases.
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PMID:Role of natural killer and T-cells in interferon induced inhibition of spontaneous metastases of the B16F10L murine melanoma. 170 66

Several new investigational agents have shown some promise in the treatment of patients with disseminated melanoma. While earlier studies of combination chemotherapy led to increased toxicity without improved anti-tumor effect, more recent combination regimens have produced responses up to 50%. One of these is a dose-intensification regimen using high-dose cisplatin and the chemoprotective drug WR-2721. Other treatments under study include autologous bone marrow transplantation plus thiotepa, a combination regimen of chemotherapy and interferon, and newer agents such as taxol, tauromustine, and detrorubicin.
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PMID:New approaches to the chemotherapy of melanoma. 171 35

The possibility for new interferon therapy was investigated using the effect of endogenous human interferon-beta (HuIFN-beta) on various culture cell lines. Cell lines were exposed to superinduction agents (poly I: poly C, cycloheximide, and actinomycin D) and the production of endogenous interferon analyzed. Quantitative determination of HuIFN-beta and messenger ribonucleic acid (mRNA) showed HuIFN-beta was induced in all of five glioma cell lines, one of two melanoma cell lines, and all of three lung carcinoma cell lines as well as fibroblasts. Northern blot analysis showed HuIFN-beta mRNA induced in glioma cells was identical to that from fibroblasts. Endogenous HuIFN-beta induced from glioma cells had a cytostatic or cytocidal effect against various human glioma cell lines, even those resistant to fibroblast-derived HuIFN-beta. These results show it may be possible to use the induction of excess endogenous cytotoxic HuIFN-beta in human glioma tissue itself.
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PMID:Superinduction of cytotoxic interferon-beta in glioma cells. 172 75

Interleukin-2 (IL-2) and gamma interferon (gamma-IFN) may be synergistic in inducing cell-mediated antitumor cytotoxicity. In order to determine the dose-limiting toxicities and define a maximum tolerated dose of these two agents in combination, we performed a Phase I clinical trial of intravenous IL-2 plus intramuscular gamma-IFN. Patients received both agents on a thrice-weekly schedule consisting of 4 weeks of treatment followed by 2 weeks of rest. Twenty-five patients were treated and received gamma-IFN doses between 0.05-0.25 mg/m2 (1-4 x 10(6) U/m2) with IL-2 doses from 0.33 mg/m2 to 2.33 mg/m2 (6-42 x 10(6) IU/m2). Two patients had partial responses of melanoma and adenocarcinoma of the lung lasting greater than 11 and 8 months, respectively. The toxicities of the combination were those expected from each agent, with no unusual effects, no irreversible organ toxicities, and no patient deaths. The doses recommended for outpatient administration on this schedule are IL-2, 2.0 mg/m2 plus gamma-IFN, 0.25 mg/m2, a dose combination that is unassociated with significant organ toxicity.
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PMID:Phase I trial of interleukin-2 plus gamma-interferon. 173 48

The role of cell adhesion molecules (CAM) LFA1, ICAM-1, LFA3, VLA1, VLA4, CD29, CD44, and CD56 in tumor-infiltrating lymphocyte (TIL) and natural killer cell (NK)-mediated killing of target cells was studied. Melanoma cell lines and autologous TIL were derived from seven patients with metastatic melanoma, and cytotoxicity assays were done in the presence and absence of monoclonal antibodies (MoAb) to CAM expressed on melanoma cells or TIL. The melanoma cell lines analyzed were all positive for CD29 and LFA3 expression, negative for LFA1 expression, but showed variable expression of ICAM-1, VLA1, VLA4, CD44, and CD56. The effects of anti-CAM antibodies on TIL-mediated melanoma killing fell into three categories: (1) consistent inhibition of TIL-mediated killing was observed when melanoma cells were pretreated with anti-ICAM1 and anti-LFA-3 MoAb or when TIL were pretreated with anti-LFA1; (2) no effect was observed when melanoma cells were pretreated with anti-CD56; or (3) a discreet, but significant, inhibition was observed when target cells were pretreated with anti-CD29, anti-VLA1, anti-VLA4, and anti-CD44. Cytotoxicity was significantly enhanced by pretreatment of target cells with gamma-interferon (gamma-IFN), although gamma-IFN did not augment surface expression of the CAM studied. The NK-mediated killing of K562 cells was blocked by anti-LFA1, anti-CD18, and anti-ICAM, and partially inhibited by anti-CD44 MoAb. Together, these results suggest that several accessory CAM may play a role in regulating cellular cytotoxicity. Because cytotoxicity generally correlated with the level of expression of CAM in melanoma cells, weak CAM surface expression may provide a means for melanomas to escape immune surveillance.
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PMID:Expression of cell adhesion molecules in human melanoma cell lines and their role in cytotoxicity mediated by tumor-infiltrating lymphocytes. 173 16

The toxicity and/or the stimulation of natural killer cell activity that resulted from exposure to alpha-interferon varied according to circadian dosing time, both in mice and in human beings. Ten patients with advanced renal cell carcinoma or melanoma were treated with recombinant alpha-interferon-2b using a continuous 21-day intravenous schedule at circadian modulated rate. Patients received 15-20 MU/m2/day in an ambulatory care program. The drug was delivered via an external programmable-in-time pump. Thirty-nine courses of therapy were given (2-12 courses per patient). Severe side effects included World Health Organization grade III somnolence (one patient, 1 course) and grade III-IV neutropenia (five patients, 10 courses). Karnofsky performance status decreased by 40% in 3 patients (five courses). Two of these patients were withdrawn from the study because of toxicity. Disease was stabilized in four of the seven patients evaluable for response. Seven of the 10 patients are alive at 15 months' median follow-up. Two have continued with chronotherapy for 9+ and 13+ months, respectively. A large interpatient variability characterized the maximally tolerated dose. Two patients led their usual activities while receiving 20 MU/m2/day for three courses or more. Conversely, two patients exhibited severe side effects with 10 MU/m2/day. As compared with schedules of standard administration or continuous flat infusion, this circadian schedule of infusion allowed a large increment in total daily dose and dose intensity. A starting dose of 15 MU/m2/day was well tolerated by 8 of 10 patients and can be recommended using this circadian modulated schedule.
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PMID:A phase I trial of 21-day continuous venous infusion of alpha-interferon at circadian rhythm modulated rate in cancer patients. 176 78

We treated 14 patients (4 malignant melanoma/10 renal carcinoma) with a combination of continuous infusion interleukin-2 (IL-2) and subcutaneous alpha-interferon. Variable concentrations of albumin were added to the infusion of IL-2. The toxicity of this regimen seems to be related to the percentage of albumin added to the IL-2 infusion. Partial responses were observed in 3 cases. Interestingly, 1 patient's response appeared dependent on the addition of human serum albumin. The mechanism of these effects is unknown, but the use of albumin with IL-2 should be carefully investigated in future studies.
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PMID:The importance of added albumin during continuous intravenous infusion of interleukin-2 with alpha-interferon. 178 73

We investigated the immunological properties of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TIL), which were used for adoptive therapy of renal cell carcinoma (RCC) (seven patients) by focusing on natural killer (NK) cells, and metastatic melanoma (six patients) by focusing on cytotoxic T lymphocytes. TIL from five of seven cases proliferated well in culture with AIM-V serum-free medium and 1000 U/ml rIL-2 in 3-L gas permeable bags, whereas TIL from two RCCs exhibited delayed proliferation. Proliferation of CD3-CD56+ NK cells with major histocompatibility complex-nonrestricted cytotoxicity in RCC-TIL (n = 6, mean = 651-fold, ranging from 39- to 3450-fold) for the first 2-4 weeks was 63 times higher than that of noncytotoxic CD3+ T cells (n = 6, 10.3-fold ranging from 0.8 to 35-fold). Thereafter, CD3+ T cells predominantly proliferated, and proliferation of CD3+ T cells (n = 5, 743-fold) for 5-6 weeks were 24 times higher than that of CD3-CD56+ NK cells (n = 5, 31-fold). Significant numbers of RCC-TIL became adherent to the surfaces of the bags several weeks after initiation of culture. These adherent TIL consisted of more CD3-CD56+ NK cells and exhibited higher cytotoxicity than did nonadherent TIL. Adherent RCC-TIL produced interferon (IFN)-gamma, while nonadherent TIL did not. These results suggest that initially cytotoxic CD3-CD56+ NK cells and, later, noncytotoxic CD3+ T cells proliferated in culture of RCC-TIL for adoptive therapy. These noncytotoxic TIL were primarily transferred to RCC patients, who also received cyclophosphamide, IL-2, and IFN-alpha. In contrast to RCC-TIL, IL-2-activated melanoma TIL consisting of all CD3+ T cells displayed modest levels of cytotoxicity, primarily restricted to autologous melanoma cells in all cases tested. The cytotoxic melanoma TIL were adoptively transferred to melanoma patients. Three of seven RCC patients responded to the adoptive therapy.
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PMID:Study of tumor-infiltrating lymphocytes for adoptive therapy of renal cell carcinoma (RCC) and metastatic melanoma: sequential proliferation of cytotoxic natural killer and noncytotoxic T cells in RCC. 179 Jan 39

This paper aims to summarize current experience with alpha interferon and provide direction for future study. There are four areas in which alpha interferon has proven or potential activity: antiviral, premalignant, adjuvant and advanced disease settings. The three main viral diseases in which interferon alfa-2b has been shown to have activity are chronic viral hepatitis, acquired immunodeficiency syndrome, and human papilloma virus infections. In vitro studies suggest that alpha interferon may inhibit transformation of some premalignant conditions into malignant disease; e.g., vaginal intraepithelial neoplasia. In the adjuvant setting, it is possible that a biological response modifier, such as alpha interferon, may have a role in helping the immune system to destroy residual tumour cells following tumour bulk reduction with radiation or chemotherapy. A higher response rate has been seen in patients with small tumour bulk compared to those with large tumour bulk (e.g., malignant melanoma, ovarian carcinoma), and in patients with early, rather than late, disease (e.g., chronic myelogenous leukaemia, hairy cell leukaemia, multiple myeloma, non-Hodgkin's lymphoma). This may be due to efficacy in a small tumour bulk setting or due to an immunoadjuvant role. In advanced disease, the question is how best to exploit the possible synergistic effects between alpha interferon and other therapeutic modalities. The optimum dose, schedule and patient populations for combined treatment have yet to be determined. The major objective of this paper is to determine how best to capitalize upon the current state of knowledge to build for future trials of alpha interferon, and to determine whether the existing data suggest an adjuvant role for interferon after initial tumour regression.
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PMID:alpha Interferon: the potential drug of adjuvant therapy: past achievements and future challenges. 179 68


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