Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new approach to cancer therapy has been developed based on the adoptive transfer of autologous lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (IL-2). Forty-one patients with advanced cancer who have failed all standard treatments were treated in this experimental protocol. Fourteen patients experienced an objective regression of cancer, including one patient with metastatic melanoma who underwent a complete regression. Objective responses were seen in patients with colorectal cancer, renal cell cancer, melanoma, and lung adenocarcinoma. The sites of tumor regression included subcutaneous tissue, lung, and liver. The major side effect of therapy resulted from the administration of high-dose IL-2 and was manifested primarily as fluid retention, resulting in a generalized capillary permeability leak syndrome. This approach to adoptive immunotherapy represents a promising approach to the therapy of patients with metastatic cancer. Attempts to increase the potency and decrease the toxicity of therapy and extend this treatment to patients with smaller tumor burdens are in progress.
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PMID:A new approach to the therapy of cancer based on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2. 352 4

We describe here the preliminary results of the systemic administration of autologous lymphokine-activated killer (LAK) cells and the recombinant-derived lymphokine interleukin-2 to patients with advanced cancer. This regimen was based on animal models in which the systemic administration of LAK cells plus interleukin-2 mediated the regression of established pulmonary and hepatic metastases from a variety of murine tumors in several strains of mice. We treated 25 patients with metastatic cancer in whom standard therapy had failed. Patients received both 1.8 to 18.4 X 10(10) autologous LAK cells, generated from lymphocytes obtained through multiple leukaphereses, and up to 90 doses of interleukin-2. Objective regression of cancer (more than 50 per cent of volume) was observed in 11 of the 25 patients: complete tumor regression occurred in one patient with metastatic melanoma and has been sustained for up to 10 months after therapy, and partial responses occurred in nine patients with pulmonary or hepatic metastases from melanoma, colon cancer, or renal-cell cancer and in one patient with a primary unresectable lung adenocarcinoma. Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped. Further development of this approach and additional patient follow-up are required before conclusions about its therapeutic value can be drawn.
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PMID:Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. 390 8

The combination of chemotherapy and immunotherapy seems to improve response rate in metastatic melanoma. We investigated the effects on toxicity and immunological effects of a single dose of dacarbacin (DTIC; 850 mg/m2) or cisplatin (CDDP; 100 mg/m2) added to subsequent immunotherapy with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). Twelve patients, who did not respond to IFN-alpha/IL-2 alone were studied. Six received DTIC and IFN-alpha/IL-2, and six received CDDP and IFN-alpha/IL-2. DTIC did not add significant toxicity except for nausea. Significant thrombocytopenia was observed in two patients after CDDP. Although CDDP led to grade 3 nephrotoxicity in two patients, the IL-2-induced fluid retention was less severe than with IFN-alpha/IL-2 alone. Pharmacokinetics of IL-2 were not altered by DTIC, but higher IL-2 serum levels were found in patients with grade 3 nephrotoxicity after CDDP. The IL-2-related induction of secondary mediators (interferon-gamma, tumour necrosis factor-alpha, soluble CD25) was not impaired by chemotherapy and the induction of neopterin was significantly higher after addition of CDDP. One partial response was observed after addition of DTIC to IFN-alpha/IL-2, and one after addition of CDDP. The addition of a single dose of DTIC or CDDP to IFN-alpha/IL-2 is fairly well tolerated and does not abolish induction of secondary mediators. Randomized trials are necessary to test the clinical efficacy.
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PMID:Addition of dacarbazine or cisplatin to interferon-alpha/interleukin-2 in metastatic melanoma: toxicity and immunological effects. 749 66

Hematopoietic recovery in 115 patients with metastatic breast cancer or metastatic melanoma, enrolled in phase-I studies of recombinant growth factors while undergoing treatment with high-dose chemotherapy with autologous bone marrow support, was examined with assays of bone marrow progenitor cells and peripheral blood progenitor cells, and by evaluation of peripheral blood counts. Groups of patients receiving hematopoietic cytokine support [with interleukin-1 (IL-1), interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or monocyte CSF (M-CSF)] post marrow infusion were compared with contemporaneous control patients not receiving growth factor support. Patients receiving GM-CSF demonstrated statistically significant increases in the growth of granulocyte/macrophage colony-forming units (CFU-GM) in the bone marrow and peripheral blood compared with control patients. The effect of GM-CSF was dose dependent in the early period post marrow infusion (day +6) with bone marrow CFU-GM colonies at doses 8-16 micrograms/kg/day 34 times those measured in controls. Significant increases in bone marrow multipotential progenitor cells (CFU-GEMM) were seen in patients receiving GM-CSF day +21 post marrow infusion. Patients receiving IL-1 demonstrated significant increases in bone marrow CFU-GM at day +21, maximal at dosages of 24-32 ng/kg/day. There were no significant increases in burst forming unit-erythroid (BFU-E) among any study group. Patients receiving G-CSF had significantly increased absolute neutrophil counts (ANC) and total white blood cell counts (WBC) by day +11 post transplant compared with control patients. Patients receiving GM-CSF demonstrated significantly increased WBC (greater than 2000/mm3) at day +11 and ANC greater than 500/mm3 at day +16. Optimal dose of G-CSF and GM-CSF to stimulate neutrophil recovery post transplant was 4-8 micrograms/kg/day and 8-16 micrograms/kg/day, respectively. Platelet recovery did not differ among the six study groups. These data demonstrate accelerated myeloid recovery after high-dose chemotherapy and autologous bone marrow support in patients receiving either G-CSF or GM-CSF. Moreover, GM-CSF and IL-1 stimulate myelopoiesis at the level of bone marrow CFU-GM, while G-CSF causes earlier neutrophil recovery peripherally.
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PMID:Hematopoietic recovery following high-dose combined alkylating-agent chemotherapy and autologous bone marrow support in patients in phase-I clinical trials of colony-stimulating factors: G-CSF, GM-CSF, IL-1, IL-2, M-CSF. 750 80

Tamoxifen (TAM) has been reported to enhance cisplatin (CDDP) cytotoxicity in experimental and clinical melanoma studies. Based on our previous experience with sequential cisplatin-interleukin-2 (IL2)-interferon (IFN), we performed a phase II study of TAM combined with our original CDDP-IL2-IFN regimen in 22 pretreated metastatic melanoma patients. With a 41% response rate (95% CI, 21-61) we confirmed the interesting antitumor activity of CDDP-IL2-IFN combination; however, TAM enhanced neither the response rate nor the duration of response, but appeared to induce significantly more myelotoxicity, as compared to our previous results with CDDP-IL2-IFN alone. Whereas mechanisms by which TAM may modulate CDDP cytotoxicity in melanoma tumors remain unknown, the exact place of TAM, if any, and its safety in chemotherapeutic or chemoimmunotherapeutic combinations require further investigations.
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PMID:A phase II study of tamoxifen combined with cisplatin-interleukin 2 and alpha-interferon in metastatic melanoma. 757 60

There is a worldwide increasing incidence of all forms of skin cancer among Whites as a result of increased sun exposure. Basal cell and squamous cell carcinomas, the most common tumours of the head and neck, are relatively benign neoplasms of elderly individuals. Malignant melanoma, however, has the potential for early metastasis and may occur in early adult life. The increase in malignant melanoma is particularly disturbing, and is a clear indication for skin screening clinics. Although surgical excision is the primary treatment of choice for skin tumours, various drugs may be of therapeutic value. Fluorouracil cream is a useful treatment for solar keratoses. Retinoids are particularly suitable for patients with large numbers of nonmelanoma skin cancer lesions and solar keratoses. For malignant melanoma, arterial limb perfusion with high concentrations of cytotoxic drugs may be performed both as an adjunctive and therapeutic manoeuvre. Treatment of metastatic melanoma with cytotoxic agents is associated with low response rates and high toxicity. However, trials with combined interferon-alpha, interleukin-2 and cytostatic drugs have produced promising preliminary results.
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PMID:Skin cancer. Recognition and treatment. 758 89

Cytokines have been tested in the treatment of different skin cancers during the last decade, and treatment schedules have been established or proposed for several malignant skin tumors. Preferentially, the interferons and interleukin-2 were found to be effective in treating skin cancers. Interferons alpha and beta have been approved for the treatment of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma, cutaneous T cell lymphoma, and malignant melanoma in several countries. Interferon alpha was found to be most effective in cutaneous T cell lymphoma with 40%-60% overall responses. When combining interferon alpha with psoralens and ultraviolet A (PUVA) or with retinoids, even higher response rates up to 60%-90% were reported, and long-term remissions have been described. A considerable activity of interferon alpha was found in HIV-associated Kaposi's sarcoma with response rates of 30%-50%. The effectiveness of Kaposi's sarcoma's treatment was further improved by combining interferon alpha and zidovudine. Responses to interferon alpha in metastatic malignant melanoma are rather seldom (10%-15%), but a stabilization of the disease with prolonged survival was reported after interferon alpha treatment. Additionally, interleukin-2 was found to be active in metastatic melanoma, with overall response rates of about 20%, and both biological agents were found to have an additive efficacy in combination. Several combined regimens of interferon alpha, interleukin-2, and polychemotherapy have been described in metastatic melanoma, and overall response rates higher than 50% were found with these combined treatment modalities. Interferon alpha and beta were also intralesionally injected into basal cell carcinomas and other epithelial skin cancers, and complete responses were found in more than 80% of tumors treated. Local applications of interferons and interleukin-2 were likewise found to be effective in the treatment of cutaneous melanoma metastases and cutaneous manifestations of Kaposi's sarcoma. Cytokines and their combination with other treatment modalities has greatly enriched the treatment facilities in malignant skin tumors during recent years, and additional new cytokines will be introduced in skin cancer treatment in near future.
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PMID:Perspectives of cytokine treatment in malignant skin tumors. 759 3

Metastatic or tumor-draining lymph nodes from six of nine melanoma patients undergoing lymph node dissection for metastatic melanoma generated cytotoxic T cells against autologous melanoma when these lymph node cells were treated by in vitro sensitization and recombinant interleukin-2 (IL-2). During the initial lymphocyte culture (2-6 weeks), cross-reactivity with autologous tumor cells, K562 and Daudi cells was usually noted. Cold-target inhibition assay with K562 and Daudi showed K562/Daudi-associated antigens on melanoma cells. During the later phase of lymphocyte culture with repeated in vitro sensitization (over 6-10 weeks), cytotoxicity was noted against autologous and allogeneic melanoma cells but not against K562. Daudi cells or autologous fibroblasts. Repeated in vitro sensitization resulted in the selection of specific cytotoxic lymphocytes against melanoma. Cold-target inhibition assay with autologous and allogeneic melanoma cells revealed shared and individual antigens. Using blocking monoclonal antibodies, MHC-restricted killing was noted in the autologous system. Further, both the autologous and allogeneic systems could be mediated through adhesion molecules such as ICAM-1 and LFA-3 on melanoma cells and LFA-1 on T cells. This study suggests that a constellation of cytotoxic effector cells and melanoma-associated antigens may be pivotal in tumor killing. Thus, future adoptive immunotherapy should modulate and enhance this complex interaction.
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PMID:Generation of cytotoxic effector cells against human melanoma. 762 96

Both chemotherapy and interleukin-2 and/or interferon-alpha produce objective responses in a proportion of advanced malignant melanoma patients. While duration of response to chemotherapy is short, i.e. usually below 4 months, immunotherapy has resulted in a small number of long-lasting remissions in patients with metastatic melanoma. In two consecutive phase II trials in a total of 67 patients, we assessed the potential synergism between both modalities, i.e. chemo- and immunotherapy. Treatment consisted of intravenous (i.v.) carboplatin (CBDCA, 400 mg/m2) and dacarbazine (DTIC, 750 mg/m2) given twice (i.v. bolus over 30 min) at 3-week intervals, or 4 cycles of DTIC (220 mg/m2 i.v. 3 days), cisplatin (DDP, 35 mg/m2 i.v. 3 days), carmustine (BCNU, 150 mg/m2 i.v. cycles 1 and 3) and tamoxifen (TAM, 20 mg oral/daily) at 3-week intervals. Chemotherapy was followed by immunotherapy with combined subcutaneous (s.c.) interleukin-2 (rIL-2) and SC interferon-alpha 2 (rIFN-alpha). Among 40 patients who received a full cycle of chemotherapy with CBDCA/DTIC and sequential immunotherapy, there were 3 (7.5%) complete remissions (CRs) with a median duration of 19 months (range 13-26+). Partial remissions (PRs) were noted in 11 (27.5%) patients with a median response duration of 8 (range 5-14) months. Among 27 patients who received DTIC/DDP/BCNU/TAM and rIL-2/rIFN-alpha, there were 3 (11%) complete remissions and 12 (44.5%) partial remissions. Duration of complete and partial remissions ranged from 9+ to 13+ (median, 11+), and 5 to 15+ (median, 7+) months, respectively. Chemotherapy produced mostly moderate toxicity. Thrombocytopenia was common with the nadir after a median time of 18 days following start of CBDCA/DTIC and DTIC/DDP/BCNU, respectively. 10 patients required transfusion of thrombocytes. Nausea and vomiting due to chemotherapy were well tolerated using concomitant ondansetrone (8 mg i.v.). Immunotherapy was self-administered at home with mild to moderate side effects; malaise, fever, chills, nausea/vomiting, diarrhoea, anorexia and arthralgias were most frequent, but were spontaneously reversible after ending rIL-2/IFN-alpha. A mean 87 and 88% of the projected doses of rIL-2 and rIFN-alpha were administered on either protocol. There were no life-threatening complications and no treatment-related deaths. The sequential combination of chemotherapy and rIL-2 plus rIFN-alpha had at least additive therapeutic activity against metastatic malignant melanoma. The schedules produced long-lasting remissions and were tolerated well overall. These trials substantiate a potential role for low to intermediate dose immunotherapy in maintaining and consolidating therapeutic effects of chemotherapy in metastatic melanoma.
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PMID:Chemoimmunotherapy of advanced malignant melanoma: sequential administration of subcutaneous interleukin-2 and interferon-alpha after intravenous dacarbazine and carboplatin or intravenous dacarbazine, cisplatin, carmustine and tamoxifen. 764 14

Treatment of metastatic melanoma with cytotoxic drugs is still associated with low response rates and high toxicity. The most effective single agents in metastatic melanoma produce response rates between 15 and 20%. Combined schedules based on dacarbazine (DTIC), carmustine (BCNU), cisplatin and vinca alkaloids produced objective response rates between 25% and more than 40%; adverse effects, however, were severe and prolongation of survival remains uncertain. Cytokines were therefore introduced as melanoma treatment, with initial high expectations. Interferon (IFN)-alpha as a single treatment produced an overall response rate of 10-15% in melanoma patients. Clinical and experimental results suggest that the antitumour activity of IFN is mainly related to its antiproliferative effect; immunomodulatory effects were not substantiated in clinical investigations. Adoptive immunotherapy of metastatic melanoma has been established by use of lymphokine-activated killer (LAK) cells plus interleukin-2 (IL-2) or high dose IL-2 alone. Clinical trials of adoptive immunotherapy showed objective response rates of 20-25% in disseminated melanoma, and response rates could be further improved by the combination of IL-2 with IFN-alpha. Clinical trials with combined IFN or/and IL-2 and cytostatic drug therapy started a few years ago and have yielded promising initial results. The combination of IFN-alpha with dacarbazine was effective in over 50% of treated patients, leading to complete or partial remissions in 28% and stabilization of the disease in an additional 28% of more than 400 patients treated so far. Recently, a new generation of multidrug combinations including IFN-alpha and/or IL-2 has been initiated with overall response rates of more than 50% in several reports.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chemotherapy and chemoimmunotherapy in disseminated malignant melanoma. 769 93


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