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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the safety, tolerance, and clinical effects of the combined administration of subcutaneous recombinant human interleukin-2 and interferon alfa-2b in 54 patients with advanced cancer, for whom no effective standard therapy was available. Treatment courses consisted of a 2-day interleukin-2 pulse (14.4-18 million units (MU) m2/day), followed by 3.6 up to 4.8 MU/m2/day, 5 days per week, over 6 consecutive weeks and interferon alfa-2b at 3 up to 6 MU/m2, administered two-three times weekly for 6 weeks. Overall, patients received more than 90% of the projected dose of interleukin-2 and interferon alfa-2b, respectively. Of 54 evaluable patients (32 renal cell cancer, 12 melanoma, eight colorectal cancer, one B-cell lymphoma, one Hodgkin's disease), four complete responses occurred in patients with renal cell carcinoma, and a greater than 50% reduction in tumour size (partial response) in six renal cell carcinoma patients and one melanoma patient. Moreover, 21 patients (13 renal carcinoma) had stable disease. The median duration of response was 19 months (range 16-22 months) in complete responders. Clinical responses were associated with a mean peripheral blood eosinophil count of more than 1,000/microL (P less than 0.05 versus non-responders). Systemic toxicities included fever, chills, nausea, anorexia, and hypotension limited to WHO grades I and II in more than 80% of patients treated. No treatment-related deaths occurred. This combination of subcutaneously administered recombinant interleukin-2 and interferon alfa-2b has significantly diminished the side effects normally observed with high-dose intravenous recombinant interleukin-2, which requires admission to hospital. It has been shown to induce objective tumour regression in out-patients with progressive metastatic renal cell carcinoma and malignant melanoma.
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PMID:The out-patient use of recombinant human interleukin-2 and interferon alfa-2b in advanced malignancies. 179 91

Multiple administration of sublethal doses of recombinant murine tumor necrosis factor (TNF), e.g., 2 micrograms i.p. twice daily for 4 to 6 consecutive days, produces tachyphylaxis to the anorectic effects of TNF and tolerance towards a lethal challenge with recombinant murine TNF. The objective of this study was to examine whether the antitumor efficacy of TNF was retained in mice made tolerant. We treated tolerant and nontolerant C57BL/6 mice bearing a syngeneic B16BL6 melanoma tumor with repeated administrations of recombinant murine TNF (5 to 12.5 micrograms/injection) alone or in combination with recombinant murine gamma-interferon (5,000 to 50,000 units/injection). When the paralesional administration route was used, the tolerance-inducing pretreatment protected mice against the lethal outcome of both the single and the combination treatments (100% versus 40% survival in the former case; 80% versus 0% survival in the latter case) and still allowed complete regression of the tumor. When the i.p. route of administration was used, the final outcome was less positive; nevertheless, a significant protection against the lethal effects of the treatment was achieved without reduction of the antitumor efficacy. It is concluded that the toxic and antitumor activities of TNF are not inevitably linked and that their separation is an achievable research and perhaps a clinical goal.
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PMID:Induction of tolerance allows separation of lethal and antitumor activities of tumor necrosis factor in mice. 182 31

The effect of recombinant human interferon-gamma (rHuIFN-gamma) and interferon-alpha (rHuIFN-alpha) as in vivo stimuli for the activation of human monocytes was investigated on the basis of the bactericidal activity of peripheral blood monocytes in 11 patients with metastatic melanoma before and during treatment with interferons. Patients received increasing doses of rHuIFN-gamma and a fixed dose of rHuIFN-alpha, both administered subcutaneously three times a week. The rates of intracellular killing of Listeria monocytogenes and Salmonella typhimurium after in vitro phagocytosis by monocytes collected from melanoma patients before interferon treatment were increased (P less than 0.01) by a factor of 1.7 and 1.4, respectively, relative to the rate constants in blood monocytes of healthy donors. During treatment with the interferons, the rates of intracellular killing of the bacteria by patients' monocytes did not further increase. The findings underscore the immunogenicity of malignant melanoma and put into question the macrophage activating activity of IFN-gamma with respect to the bactericidal activity of monocytes.
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PMID:Increased intracellular killing of bacteria in vitro by monocytes of patients with metastatic melanoma before and during treatment with interferon-gamma and interferon-alpha. 182 24

An HLA-A2-specific cytotoxic T lymphocyte (CTL) clone (CTL49), capable of killing the HLA-A2-negative autologous melanoma (Me665/2) in a T cell receptor and MHC-independent fashion, lysed six of 16 Me665/2 tumour clones in short-term (4 and 18 hour) 51Cr-release assays. In long-term (96 hour) lytic assays, CTL49 could lyse all the 16 tumour clones. The lysis observed in the 96 hour assay could be enhanced by stimulating CTL49 with anti-CD3 monoclonal antibodies (MAb) and interleukin-2 (IL-2). Supernatants of anti-CD3- or antigen-stimulated CTL49, known to contain tumour necrosis factor (TNF) alpha and interferon (IFN)gamma, were also able to lyse all but one (665/2/51) of the tumour clones in 96 hour assays. Absence of lysis of tumour clone 2/51 by supernatants correlated with resistance of the same tumour clone to lysis by recombinant IFN-gamma plus TNF-alpha. Antibodies to TNF-alpha and, to a lesser extent, to IFN-gamma, reduced significantly the 96 hour lysis of Me2/9 and Me2/10, two of the tumour clones killed in long term but not in short term assays. Winn assays in nude mice revealed that CTL49, stimulated with anti-CD3-MAb plus IL-2, could abolish tumour cell growth when injected together with clones 2/9 or 2/10. These results indicate that intra-tumour heterogeneity for susceptibility to lysis can be overcome even by a single CTL clone providing that appropriate signals (i.e. anti-CD3-MAb and IL-2) are supplied to an effector able to mediate tumour cell lysis by multiple mechanisms.
Melanoma Res
PMID:An autologous T cell clone overcomes intra-melanoma heterogeneity for susceptibility to cell-mediated lysis by using multiple lytic mechanisms: in vitro and in vivo analysis. 184 13

We assessed the ototoxicity associated with oral alpha-difluoromethylornithine (DFMO) administration in 58 patients with metastatic malignant melanoma. One hundred seventy-nine sequential audiograms obtained from patients treated with DFMO alone (16 patients) or in combination with alpha 2b-interferon (42 patients) were evaluated. DFMO doses ranged from 2 to 12 g/m2/d and were given over periods of 2 to 50 weeks. Total doses ranging from 60 g/m2 to 1390 g/m2 were correlated with clinical effects and pure tone audiometric changes. By regression analysis cumulative DFMO dose showed a consistent and statistically significant positive relationship to hearing loss at multiple frequencies (500, 1000, 2000, 4000, and 8000 Hz). Patients with normal (threshold less than 30 db) baseline audiograms demonstrated more hearing loss than those with abnormal (threshold greater than or equal to 30 db) baseline audiograms at the higher frequency levels. Of the patients with normal prestudy hearing thresholds 10% or less developed a demonstrable hearing deficit at cumulative DFMO doses below 150 g/m2. Conversely, up to 75% of the patients who received more than 250 g/m2 developed a clinically demonstrable hearing loss. Other factors which adversely affected hearing included age, male gender, and the concomitant use of alpha 2b-interferon. In summary, the risk of clinically significant hearing loss in patients treated with DFMO was primarily related to dose and the presence of a pre-existing hearing deficit.
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PMID:Dose-related alpha-difluoromethylornithine ototoxicity. 186 65

Immune cytokines have been shown to play important roles in regulating immune cell functions. Interleukin-4 (IL4), originally described as a B-cell growth factor, is known to activate and differentiate other immune cells. IL4 has been given as an immunotherapeutic to tumor-bearing hosts. In this report, we set out to determine whether IL4 can directly modulate growth and expression of surface antigens on human melanoma cells. The effect of recombinant IL4 alone and in combination with recombinant gamma-interferon (IFN) or recombinant alpha-tumor necrosis factor (TNF) on melanoma cell lines was examined. IL4 significantly inhibited cell growth of all cell lines examined at 100-500 units/ml; but a dose-dependent differential response to individual cell lines occurred. The effect of IL4 was augmented by combination with IFN or TNF. Melanoma-associated ganglioside antigens (GM3, GD3, GM2, GD2) and human leukocyte antigen class I and DR on the cell surface of melanoma cells were assessed by flow cytometry and/or a radiometric binding assay. IL4, IFN, or TNF alone enhanced human leukocyte antigen class I, DR, and beta 2-microglobulin antigen expression. IL4 alone and in combination with IFN or TNF increased the GM3/GD3 ratio expression. GD2 was enhanced significantly by IL4, IFN, and TNF. Pretreatment of melanoma with IL4 or with other cytokines prior to stimulation with peripheral blood lymphocytes significantly enhanced mixed lymphocyte tumor reaction activity as compared with non-treated melanoma used as stimulators. These studies demonstrate that IL4 alone or in combination with IFN and TNF can modulate melanoma growth activity and surface antigen expression to a more differentiated and immunogenic phenotype.
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PMID:Modulation of human melanoma cells by interleukin-4 and in combination with gamma-interferon or alpha-tumor necrosis factor. 190 Dec 39

In vivo stimulation of pulmonary alveolar macrophages (PAMs) may enhance tumor cell cytotoxicity. A model using aerosolized gamma-interferon (gamma-IFN) and lipopolysaccharide (LPS) was developed to induce enhanced PAM activation in vivo in C57BL/6 mice. Mice received four doses of aerosol (2 doses/day) consisting of gamma-IFN (10(4) microU/mouse) and LPS (100 micrograms/mouse). Other groups received either gamma-IFN alone, LPS alone, or saline (control). Cells were harvested by bronchoalveolar lavage. Macrophage cell count demonstrated an increase in macrophage recruitment in the gamma-IFN and LPS group. PAMs were evaluated for in vitro cytotoxicity against B16-F10 melanoma cells. Treatment groups demonstrated enhanced cytotoxicity over controls, and the combination (gamma-IFN plus LPS) was significantly better in cell killing than either treatment modality alone (p less than or equal to 0.02). Activated PAMs selectively killed tumor cells, but did not kill the 3T3 fibroblast cell line. Peritoneal macrophages from mice treated by inhalational gamma-IFN + LPS were enhanced (indicating a systemic effect), but not to the same extent as PAMs. These studies suggest that inhalation of gamma-IFN + LPS can selectively enhance in vivo cytotoxicity of murine PAMs. This may potentially be applicable to human tumor management.
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PMID:Aerosolized gamma-interferon and lipopolysaccharide enhances cytotoxicity of murine pulmonary alveolar macrophages. 190 97

In an adjuvant clinical trial, 34 high-risk malignant melanoma patients were treated with natural interferon (IFN)-beta and recombinant IFN-gamma. Patients with tumor location on head, neck, and trunk received 3 million IU IFN-beta intravenously (IV) three times weekly for 24 weeks. Patients with tumor location on the extremities received subcutaneous (SC) injection of 2 million IU of IFN-beta distal the locoregional lymph nodes instead. All patients were given 50 micrograms IFN-gamma SC on 3 consecutive days every 4 weeks. Antibody formation was detected by coincubation of IFN and patients' serum and assessment of the inhibition of the cytopathic effect by a virus suspension. Soluble interleukin-2 receptors (sIL-2R) were determined by enzyme-linked immunosorbent assay (ELISA) technique. No antibodies against IFN-gamma were observed. The overall incidence of antibody formation to IFN-beta was 55.8% (19/34). Ninety-two percent of the SC-treated patients (13/14) and 30% (six of 20) of the IV-treated patients developed antibodies. Soluble interleukin-2 receptors were found to be significantly lower in antibody-positive patients than in antibody-negative patients. The authors conclude that IFN-beta antibody formation is frequent and might influence IFN induced sIL-2R elevation in vivo.
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PMID:Formation of neutralizing antibodies against natural interferon-beta, but not against recombinant interferon-gamma during adjuvant therapy for high-risk malignant melanoma patients. 190 14

Previous studies have suggested that, in human melanoma, expression of HLA-A2 antigen is important for tumor cell recognition by autologous T-lymphocytes. Because of the recent demonstration that expression of HLA Class I antigens may be selectively lost in several human tumors, including melanoma, we derived pairs of tumor infiltrating lymphocytes (TIL) and melanoma cell lines from 4 human lymphocytic antigen (HLA)-A2+ patients with metastatic melanoma. We observed that, although all 4 TIL cultures expressed HLA-A2 antigen, only 2 melanoma cell lines did so. Melanoma cells derived from the other 2 patients showed neither surface expression of the HLA-A2 antigen nor presence of the corresponding mRNA. We also observed some correlation between loss of HLA-A2 expression and level of c-myc transcription. TIL derived from patients whose melanoma cell lines had normal expression of HLA-A2 had a CD8 phenotype and were capable of lysing autologous melanoma cells. Melanoma cell killing was CD3 and major histocompatibility complex Class I restricted in both cases, but HLA-A2 restricted in only one case. On the other hand, TIL derived from the 2 patients whose melanoma cell lines had lost expression of HLA-A2 had a predominant CD4 phenotype and virtually no cytotoxic activity. Preincubation of the HLA-A2 negative melanoma cell lines with alpha- or gamma-interferon did not induce the re-expression of the HLA-A2 antigen. In an attempt to restore HLA-A2 antigen expression in one of the melanoma cell lines that were HLA-A2 negative, we transfected these cells with the HLA-A2 gene subcloned in the pSV2-neo vector. Four transfected clones, with high levels of HLA-A2 antigen expression, were expanded and characterized. Proliferative and cytotoxic activities of TIL against the autologous transfected clones as well as the untransfected parental melanoma cell line were measured and compared. CD4+ TIL showed no difference in the proliferative response to autologous parental and HLA-A2 transfected clones. However, we observed selective recognition of the HLA-A2 expressing clones by autologous cultured peripheral blood lymphocytes (which contained CD8 cells) as well as allogeneic CD8+ TIL with a HLA-A2 restricted pattern of recognition. In contrast, virtually no cytotoxic activity was detected against either parental or HLA-A2 transfected clones. Overall, our data suggest that selective down-regulation of HLA-A2 antigen expression in melanoma cells may represent one of the mechanisms by which tumor cells escape immunological recognition.
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PMID:Expression of HLA-A2 antigen in human melanoma cell lines and its role in T-cell recognition. 190 4

Induction of HLA class I antigens on cultured melanoma cells FO-1 after transfection with a human or a mouse B2m gene was associated with a statistically significant reduction in their susceptibility to natural killer (NK) cell-mediated lysis. These results indicate that the structural differences between human and mouse beta 2-mu do not abolish the ability of the HLA class I molecular complex to modulate NK cell-mediated lysis of melanoma cells FO-1. The role of HLA class I antigens in the phenomenon is corroborated by the ability of anti-HLA class I MAb to enhance, although to a different extent, the susceptibility of transfected FO-1 cells to NK cell-mediated lysis. Gamma interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) significantly reduced the susceptibility to NK cell-mediated lysis of transfected FO-1 cells. Surprisingly, TNF-alpha reduced the extent of lysis more than IFN-gamma, although the latter cytokine enhanced HLA class I antigen expression more than the former one. This finding, in conjunction with a reduction in the susceptibility to NK cell-mediated lysis of untransfected FO-1 cells incubated with IFN-gamma or TNF-alpha, suggests that the two cytokines reduce NK cell-mediated lysis of transfected cells by modulating not only the expression of HLA class I antigens, but also that of other structures. Induction of HLA class I antigens and their modulation with IFN-gamma did not affect the susceptibility to lymphokine-activated killer (LAK) cell-mediated lysis of transfected FO-1 cells. Characterization of the molecular mechanism(s) underlying abnormalities in HLA class I antigen expression by melanoma cells and of the role of these molecules in the interactions of melanoma cells with various types of effector cells may suggest novel immunotherapeutic approaches to melanoma.
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PMID:Reduction in susceptibility to natural killer cell-mediated lysis of human FO-1 melanoma cells after induction of HLA class I antigen expression by transfection with B2m gene. 190 28


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