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

This investigation was conducted to provide preclinical in vivo tumor response data collected under standardized conditions with a range of clinically useful drugs combined with type I (alpha/beta) or type II (gamma) interferon. Murine tumor models used were P388 leukemia, Meth A sarcoma, and B16 melanoma. Eleven cytotoxic drugs were studied. Interferon combinations with cytosine arabinoside provided consistent indications of activity greater than that of the respective single agents. Doxorubicin and cisplatin each prolonged the time to treatment failure, relative to single-agent results, when they were combined with gamma-interferon in the Meth A and B16 models. Interferon combinations with methotrexate, 6-mercaptopurine, 6-thioguanine, ampligen, suramin, 5-fluorouracil, cyclophosphamide, and vinblastine yielded no evidence of any positive therapeutic interactions under the conditions of this study.
 ...
PMID:Evaluation of combinations of interferons and cytotoxic drugs in murine tumor models in vivo. 211 61

Interferon (IFN) and tumor necrosis factor (TNF) suppress the development of experimental metastasis and when used together, TNF and IFN show synergistic activity. However, the use of TNF is limited by its ability to initiate inappropriate hemostasis. Hemostatic effects are exaggerated by the procoagulant activity of certain tumor cell lines. Therapy with anticoagulants are indicated to block the effects of tumor cell products as well as chemotherapeutic side effects. Heparin is a glycosaminoglycan with diverse biological activity, including the ability to rapidly accelerate the inactivation of active clotting factors. The present studies have explored the therapeutic effects of combining heparin with TNF or interferon on experimental metastasis in mice using a melanoma cell line (B16BL6). Our data indicate that continued heparinization augments the antitumor activity of both interferon and TNF. Alterations of the hemostatic and immune systems play a role in the producing the observed effect.
 ...
PMID:Augmentation of antimetastatic activity of interferon and tumor necrosis factor by heparin. 212 17

We have performed seven phase II trials with recombinant interferons (IFN) involving 191 patients with biopsy-proved, measurable disseminated malignant melanoma. The regimens and numbers of patients have included IFN-alpha 2A, 50 X 10(6) U/m2 subcutaneous (SQ) TIW (regimen A, 31 patients); IFN-alpha 2A, 12 X 10(6) U/m2 SQ TIW (regimen B, 30 patients); IFN-alpha 2A with cimetidine as an immunorestorative agent (regimen C, 35 patients); IFN-gamma (regimen E, 29 patients); IFN-alpha 2A with IFN gamma (Regimen E, 20 patients); IFN-alpha 2A with bis-chloroethylnitrosourea (BCNU) (regimen F, 30 patients); and IFN-alpha 2A with the biochemical modulator, difluoromethylornithine (DFMO) (regimen G, 16 patients). The objective regression rates were as follows: A, 23%; B, 20%; C, 23%; D, 10%; E, 5%; F, 7%; G, 0%. Despite the higher response rate from regimen A, there appeared to be no survival advantage from any of these programs. The median time to progression was 1 month with a median survival time of 6 months. Most regressions involved soft tissue disease, were partial, and occurred within 2-3 months of treatment. Four patients received IFN for approximately 6 months and have manifested extraordinarily durable regressions of greater than 4+ years. The alpha-regimens produced a flu-type illness and anorexia which were dose-related. Leukopenia was most noteworthy with regimens containing gamma-interferon. Ongoing trials involving alternative and improved immune-related modalities are awaited with keen interest.
 ...
PMID:Disseminated malignant melanoma and recombinant interferon: analysis of seven consecutive phase II investigations. 212 46

The antitumor activities of human interferon (IFN) alpha, beta, and gamma alone or in combination were studied on four human melanoma cell lines (StML-11, StML-12, StML-14, and SKMel-28) in various concentrations (1-50,000 IU/ml IFN alpha, 0.1-1000 IU/ml IFN beta, 1-10,000 IU/ml IFN gamma) in vitro. In all experiments IFN beta exhibited the most potent antiproliferative effect of all IFN tested. After 3 d of incubation a 50% growth inhibition was achieved with 20-40 IU/ml for natural IFN beta and with 600-1200 U/ml for recombinant IFN gamma. Substantially higher doses (7,000 to more than 50,000 IU/ml) of recombinant IFN alpha 2a were required to achieve a 50% growth inhibition. A strong synergistic antiproliferative activity resulted from the combination of IFN alpha with IFN gamma and IFN beta with IFN gamma. None of the IFN tested induced terminal differentiation of melanoma cells in vitro. The formation of dendrites was inhibited, and the portion of differentiated cells in vitro was reduced after treatment with IFN in comparison to the untreated controls (untreated controls: 100%; portion of differentiated cells after treatment with IFN alpha: 58%-74%, IFN beta: 48%-96%, IFN gamma: 10%-33%). The melanin synthesis was slightly elevated after treatment with IFN alpha (untreated controls: 100%; after treatment with IFN alpha: 103%-157%, ns.) and decreased significantly after treatment with IFN beta (49%-71%, p less than 0.05) as well as with IFN gamma (80%-88%, ns.). Cell surface markers were modulated varyingly by the IFN: HLA-I antigens were enhanced by all IFN, with IFN beta emerging as the most potent inducer. Only IFN gamma, however, induced a de novo expression of HLA-DR and -DQ antigens and increased the expression of the ICAM-1 molecule and of the melanoma progression marker A.1.43. Possibly, these findings indicate a biologically more aggressive phenotype of melanoma cells.
 ...
PMID:Antitumor activities of interferon alpha, beta, and gamma and their combinations on human melanoma cells in vitro: changes of proliferation, melanin synthesis, and immunophenotype. 212 47

Eighteen patients with advanced metastatic malignant melanoma (stage IVUICC 1987) were entered into a prospective trial with a combination of systemic fibroblast interferon-beta and recombinant interferon-gamma. Treatment was performed over a 6-week period with 3 x 5 x 10(6) U i.v. interferon-beta and 5 X 100 micrograms s.c. interferon-gamma every week. Under this therapy 16 patients showed a progressive disease, and 2 patients had a stable disease. The median time of survival was 7.5 months. Successive immunological examinations showed no significant immunomodulating effect after the 6 weeks of interferon treatment. We conclude that the combination of interferon-beta and -gamma is insufficient in the treatment of advanced metastatic malignant melanoma when administered by this dose, route and schedule.
 ...
PMID:Systemic therapy of advanced metastatic malignant melanoma with a combination of fibroblast interferon-beta and recombinant interferon-gamma. 212 2

The authors present their experience of the malignant, mucosal melanomas involving the nasal cavity and paranasal sinuses through a retrospective study of 7 cases, observed in Rouen from 1977 to 1988. The results are compared to a review of world literature. The mucosal melanoma of the nose and sinus is a rare entity, representing approximatively 40 per cent of all sinonasal neoplasias. The signs and symptoms of sinonasal melanomas are non-specific. Therefore, the diagnosis is often delayed. The histological diagnosis is difficult given the substantial polymorphism of these tumors and the experience of achromatous forms. Electron microscope study and immuno-histo-chemical techniques using various monoclonal antibodies make it possible to eliminate the other major, differential diagnoses. Surgery is the primary method of treatment, sometimes combined with adjunctive postoperative radiotherapy. More recently, combined treatment with interferon and cimetidine appears to be interesting. The prognosis is very poor, if compared to skin melanomas, with a five year survival rate of 5 to 30 per cent. Local recurrence at the primary site and distant metastases are the most common caused of treatment failure.
 ...
PMID:[Melanoma of the nasal fossae and sinuses, apropos of a series of 7 cases]. 213 Apr 2

Between October 1987 and October 1989 we have treated 110 patients with advanced solid tumors with recombinant interleukin-2 (rIL2) based immunotherapy. In renal cell cancer we have studied rIL2 alone, rIL2 combined with rIL2 activated lymphocytes (LAK), and in an ongoing study rIL2 and LAK and alpha-interferon (alpha IFN). There is suggestive evidence of increasingly good results in these consecutive studies. In melanoma the combination of rIL2 and chemotherapy was investigated, followed by an ongoing study of rIL2 and alpha IFN. In these studies rIL2 has been administered as a continuous intravenous infusion of 18 x 10(6) International Units/m2/day for 5 days (18 x 10(6) IU = 3 x 10(6) Cetus Units = 6.9 Biological Response Modifiers Program (BRMP) Units). Patients with non-small cell lung cancer are entered in a phase I-II study of rIL2 and alpha IFN. The rIL2 administration differs from the above mentioned schedule in that rIL2 is given at a maximum dose of 6 x 10(6) IU/m2/day for 28 days on an outpatient basis. In a phase I study we have searched for the maximum tolerated dose of a daily time 4 schedule of rIL2. In the second part of this study a daily time 4 schedule, every week for 4 weeks is being investigated. Finally, we are investigating the safety and efficacy of local regional administration of rIL2 in patients with head and neck cancer, mesothelioma, and liver metastasis of colorectal cancer.
 ...
PMID:Interleukin-2. The experience of the Rotterdam Cancer Institute; Daniel den Hoed Kliniek. 214 93

Type I interferon and difluoromethylornithine have been shown to exert an antiproliferative effect, both alone and in combination, in several tumor cell lines. Using B16 melanoma cells, we have shown that these two drugs inhibit growth over 72 hr in vitro. The estimated ED50 values for difluoromethylornithine and type I interferon were 31.1 +/- 1.1 microM and 22.3 +/- 2.7 IU/ml, respectively. When used in combination, a marked synergism was observed, as detected by isobologram analysis. Type I interferon, at concentrations that exhibited synergistic activity with difluoromethylornithine, did not affect ornithine decarboxylase activity or intracellular polyamine concentrations. These data suggest that the synergistic antiproliferative effect of murine type I interferon in combination with difluoromethylornithine is not mediated via polyamine depletion. When we examined the type I interferon receptor numbers on the B16 cells exposed to 5 IU/ml murine type I interferon for 72 hr, a 40% decrease was observed, compared with that seen in control cells. Difluoromethylornithine, at 10 microM, did not affect type I interferon receptor numbers. However, when added to the cells in the presence of murine type I interferon, difluoromethylornithine completely inhibited down-regulation, suggesting that down-regulation of the type I interferon receptor is a polyamine-dependent process. These observations may provide a basis for enhancing the therapeutic efficacy of interferon treatment through control of interferon receptor down-regulation.
 ...
PMID:Difluoromethylornithine prevents the down-regulation of type I interferon receptors: a possible mechanism for a synergistic antiproliferative effect. 214 87

The specificity analysis of a CD3+, WT31+, CD8+ cytotoxic T lymphocyte (CTL) clone (CTL 49), isolated from peripheral blood lymphocytes of a melanoma patient (no. 665) after mixed lymphocyte culture with an HLA-A2+ allogeneic lymphoblastoid cell line (VSKB-LCL), revealed that CTL 49 could lyse, in addition to HLA-A2+ lines, autologous HLA-A2- melanoma (Me665/2) and K562 targets. Killing of VSKB-LCL, but not of Me665/2, could be inhibited by anti-CD3 and by anti-HLA-A2 antibodies or by modulation of the CD3 complex. Cold-target competition studies showed that K562, but not VSKB-LCL, could compete with Me665/2 for lysis by CTL 49. However, unlike K562, Me665/2 could be lysed by CTL 49 in a Ca2(+)-independent fashion in 4 h and 18 h assays. CTL 49 expressed mRNA specific for tumor necrosis factor (TNF alpha) and, to a lesser extent, for lymphotoxin (TNF beta). Exposure of the clone to anti-CD3 antibodies induced the expression of interferon(IFN)-gamma-specific mRNA. Antibodies to TNF alpha, TNF beta and IFN reduced the lysis of Me665/2, but not of K562, by CTL 49 in 18-h cytotoxic assays. Antibodies to TNF alpha and to IFN gamma almost completely inhibited the lysis seen on Me665/2 (but not on K562), in 96-h assays, by supernatants isolated from VSKB-LCL- or anti-CD3-stimulated CTL 49 cells. Taken together, these data indicate that major-histocompatibility-complex-independent lysis of autologous tumor cells and of natural killer reference targets by the same alloreactive T cell clone are activities related at the level of target recognition but distinct at the level of the lytic hit. Thus, efficient lysis of autologous tumor cells results from a complex mechanism based upon direct effector-target interaction as well as on cytokine-mediated cytolytic effects.
 ...
PMID:T lymphocytes can mediate lysis of autologous melanoma cells by multiple mechanisms: evidence with a single T cell clone. 214 69

Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days. Eight patients responded objectively and six patients (6%) had a complete response. The median duration of complete response was 11 months. Patients achieving complete response had only cutaneous, nodal, or pulmonary disease; some had extensive prior therapy; some could tolerate no more than three million units per day. Few patients could tolerate the target dose of 36 million units daily for 70 days. Limiting toxicity was primarily fatigue. Interferon in tolerable doses is effective in a small subset of patients with melanoma. Comparison of published trials of dacarbazine and recombinant alpha interferon indicates the two drugs have similar activity.
 ...
PMID:Phase II study of recombinant alpha-interferon in malignant melanoma. 223 1


<< Previous 1 2 3 4 5 6 7 8 9 10