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)

Interleukin-4 is a highly pleiotropic T-cell derived lymphokine that has been reported to stimulate a host cell-mediated antitumor response. Recombinant human interleukin-4 (rhuIL-4) is currently undergoing clinical phase I trials. We have studied the growth modulating effects of rhuIL-4 on a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 0.1 to 10 ng/ml were used in continuous incubation experiments. Of 147 specimens, 73 (50%) were evaluable for the determination of tumor growth modulating activity. The most common tumor types recruited included breast, non-small cell lung, ovarian cancer and melanoma. Stimulation of tumor colony forming units (colony formation > or = 1.5 x controls) was observed in 0/73 tumors. Similarly, only 1/73 (1.3%) specimens (a non-small cell lung cancer) had a significant decrease in tumor colony forming units (colony formation < or = 0.5 x controls) at 1 ng/ml. We conclude that rhuIL-4 is not a direct modulator of tumor colony formation in vitro. However, antitumor effects could perhaps be achieved in vivo via the immune-modulating effects of Interleukin-4.
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PMID:Lack of effects of recombinant human interleukin-4 on in vitro colony formation of freshly explanted human tumor cells. 148

Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by isolation perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.
Melanoma Res 1992 Nov
PMID:Treatment of recurrent in transit metastases from cutaneous melanoma by isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study. 149 Jan 14

To determine if intensive chemotherapy consisting of cyclophosphamide (C), etoposide (E), and cisplatin (P) (CEP) may be usefully combined with recombinant human interleukin-2 (rhIL-2), we examined a murine tumor model designed to approximate a common clinical situation: macroscopic, drug-resistant cancer. Using C57BL/6 mice with extensive tumor burden 10 days after intravenous B16 melanoma cell injection, we observed (1) C, E, and P synergize to enhance survival but do not cure mice at the highest tolerable dose (C = 200 mg/kg, E = 60 mg/kg, and P = 3 mg/kg); (2) rhIL-2 at 3 x 10(5) U (subcutaneously) daily for 4 days administered 10-18 days after B16 injection significantly improves survival; (3) CEP plus rhIL-2 is more effective than CEP alone only when rhIL-2 is administered before CEP; (4) CEP suppresses IL-2-induced lymphokine-activated killer cell activity in the spleen; and (5) rhIL-2 protects mice incompletely from the immunologic and hematologic suppression of CEP. Our results suggest that intensive chemotherapy combined with rhIL-2 may be beneficial. The success of any such combination may be schedule dependent.
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PMID:Modulation of hematologic and immunologic effects of high dose chemotherapy by interleukin-2 in a murine tumor model. 151 98

The cytolytic and/or cytostatic effects of hyperthermia, lymphokine-activated killer cells (LAK cells) and the combination of both were assayed using F1 and F10 B16 melanoma cell lines. F10 cells with a high metastatic potential showed a greater sensitivity to hyperthermia than F1 cells which have low metastatic potential. The F10 cells were lysed to a lesser extent by LAK cells than the F1-B16 cells. When the cell lines were subjected to hyperthermia at 43 degrees C for 3 h and then interacted with LAK cells, the maximum cytolysis reached almost 100%. When the interaction with LAK cells was followed by hyperthermia at 43 degrees C, the total release of 51Cr from the cell lines was 75-85%. The extent of 51Cr release from the B16 melanoma cell lines was inversely correlated with the survival rate as calculated by the plating efficiency of the incubated cells. The survival rate of mice intravenously injected with B16-F10 cells and subjected to hyperthermia at 41 degrees C for 3 h in vitro increased compared to that of controls. This was further increased by the simultaneous administration of LAK cells.
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PMID:Responses of B16 melanoma cell lines, F1 and F10, to hyperthermia, lymphokine-activated killer cells and a combination of both in vitro. 153 78

A patient with liver metastases of human lymphocyte antigen (HLA) class II-negative malignant melanoma was treated with several cycles of adoptive immunotherapy with interleukin-2 and lymphokine-activated killer (LAK) cells. The authors evaluated the efficacy of regional transfer of LAK cells versus systemic intravenous administration. Initially, the patient was treated according to a regional treatment protocol, consisting of perfusion of the spleen with interleukin-2 and transfer of LAK cells into the portal vein; a partial remission was observed. Because of technical problems, interleukin-2 and LAK cells were administered intravenously in a second treatment cycle. This systemic treatment course resulted only in a minor mixed response of the hepatic metastases. A third treatment course was administered with the use of intravenous interleukin-2 infusion and arterial perfusion of the liver with LAK cells. The patient had separate hepatic arteries to both lobes of the liver as an anatomic variation. Because most of the tumor mass was present in the right lobe of the liver, a third of the LAK cells were injected into the right hepatic artery and the remaining cells were administered intravenously. The lesions in the right lobe of the liver regressed, but disease progression occurred in the left lobe. A fourth treatment cycle, consisting of intravenous infusion of interleukin-2 and arterial perfusion of both lobes of the liver with LAK cells, resulted in a complete response of all hepatic lesions, which has lasted 18 months to date. Because, in this patient, tumor regression was observed only in anatomic areas of the liver, which were perfused with LAK cells, it is suggested that the regional administration of LAK cells was essential for successful treatment.
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PMID:Regional administration of lymphokine-activated killer cells can be superior to intravenous application. 154 23

The IA4 mAb was identified among a series of antibodies raised in BALB/c mice after immunization against a HLA class I-deficient, lymphokine-activated killer (LAK)-susceptible EBV-B lymphocyte line. The IA4 antibody was selected because of its high expression, in the range of 10(5) to 25 x 10(5) sites/cell, on several B lymphocyte lines (EBV-transformed or Burkitt) and monocytic lines such as HL60 and U937, and because its expression was correlated with both target susceptibility to LAK lysis and reduced expression of HLA class I surface Ag on two pairs of EBV-B-transformed cell lines (721/721.134 and MM/10F2). Despite the strategy followed to raise the mAb and the correlation mentioned above, no direct role of the IA4 molecules in LAK susceptibility has been established, since the IA4 molecule is poorly expressed on the sensitive targets Daudi and K562; moreover, the IA4 antibody did not affect reproducibly the in vitro killing of positive target cells by LAK effectors. The IA4 antibody was poorly immunoprecipitating and the surface molecule recognized was identified by gene cloning following an expression strategy using a U937 cDNA library transfected in COS cells, and a screening strategy based on membrane expression of IA4 molecule. The IA4 cDNA is virtually identical to "R2," a mRNA species previously identified in activated human T cells by subtractive hybridization. The IA4 cDNA contains an open reading frame coding for a protein 267 amino acids long with four potential transmembrane domains and one large external hydrophilic domain of about 110 amino acids, possibly glycosylated. The encoded protein belongs to a family of surface molecules, the tetra spans transmembrane protein superfamily, all displaying the four transmembrane domains, expressed on various cell types including lymphocytes (CD9, CD37, CD53, TAPA-1), melanoma cells (ME491), and intestinal cells (CO-029). These molecules have been reported to be involved in cell activation and cell death. Surprisingly, the Schistosoma mansoni Ag Sm23 displays significant homologies with this family. The IA4 molecule is a widely distributed surface marker expressed on circulating lymphocytes and monocytes, newborn thymocytes, and the cell lines mentioned above. The IA4 molecule expression is up-regulated upon cell activation. Weakly expressed on resting peripheral T and B lymphocytes and large granular lymphocytes (NK), its expression roughly doubles after activation by PHA, staphylococcus aureus Cowan I, and IL-2, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A member of the tetra spans transmembrane protein superfamily is recognized by a monoclonal antibody raised against an HLA class I-deficient, lymphokine-activated killer-susceptible, B lymphocyte line. Cloning and preliminary functional studies. 157 70

Interleukin 2 (IL-2) has been demonstrated to generate lymphokine-activated killer (LAK) cells from normal human peripheral blood lymphocytes (PBL). Such LAK cells have demonstrated lytic activities on certain tumor cell targets including melanoma, renal carcinoma, and other tumor targets. B lymphoblastoid cell lines such as Raji cells are routinely employed to assess functional LAK cell activity. In our studies we have assessed the effect of various cytokines that affect lymphocyte cell growth and differentiation, including rIL-2, interleukin 4 (rIL-4), interleukin 6 (rIL-6), interferon alpha and gamma (rIFN-alpha and -gamma) and tumor necrosis factors alpha and beta (rTNF-alpha, rTNF-beta), for their ability to generate functional LAK cell activity. Our data confirm that rIFN-alpha and -gamma singularly are capable of inducing LAK cell activity (55 +/- 21 and 40 +/- 10, respectively, in comparison to rIL-2 at 1000 units/ml) whereas rIL-4, rIL-6, BCGF, rTNF-alpha, or rTNF-beta failed to generate the functional LAK cell activity from human PBL. Interferon alpha, itself capable of generating LAK cell activity, was augmentative in its effect with rIL-2 for the generation of functional LAK cell activity. Conversely, rIL-4 inhibited LAK cell activity induced by either rIL-2 alone or the combination of rIL-2 and rIFN-alpha. Furthermore, the increased effects of rIFN-alpha with rIL-2 on LAK cell activity are partly abrogated by as much as 30 or 52% by delaying the addition of either rIL-2 or rIFN-alpha, respectively, for more than 24 h. These results suggest a regulatory role for certain cytokines on LAK cell functions.
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PMID:Lymphokine-activated effector cells: modulation of activity by cytokines. 158 19

The antitumor effects of chemotherapy, recombinant human interleukin-2 (IL-2), recombinant human interferon alpha A/D (IFN alpha), allogeneic human lymphokine-activated killer (LAK) cells, and antitumor monoclonal antibody (mAb), administered alone and in various combinations, were tested in athymic nude mice carrying human tumor xenografts. Treatment began 6-18 days after i.v. or i.p. inoculation of colorectal carcinoma or melanoma cell lines, when macroscopic growths were evident. Chemotherapy consisted of two or three courses of 5-fluorouracil (5-FU) or dacarbazine. IL-2 and/or IFN alpha were administered three to five times weekly for 1-3 weeks, usually starting 2-5 days after chemotherapy. Human LAK cells were infused once or twice weekly for 2 or 3 weeks concurrently with IL-2. In some experiments, murine anticolorectal carcinoma mAb (SF25) was administered. In both tumor systems, chemotherapy alone or immunotherapy alone (IL-2, IL-2 + LAK cells, IFN alpha, IL-2 + IFN alpha +/- LAK cells) had little or no therapeutic effects. Additive effects were obtained by combining chemotherapy with IL-2 and LAK cells or with IL-2 and IFN alpha. In the majority of the experiments, the most effective combination was chemotherapy + IL-2 + IFN alpha + LAK cells. Treatment with mAb was beneficial in the colorectal carcinoma system when combined with 5-FU + IL-2 or 5-FU + IL-2 + IFN alpha. Homing experiments with radiolabeled human and mouse LAK cells injected i.v. showed increased early accumulation in the liver and lungs, whereas freshly explanted mouse splenocytes localized mostly in the spleen and liver. The tissue distribution pattern of human LAK cells was similar in normal and tumor-bearing mice (with lung metastases). These findings suggest that combination of chemotherapy with cytokines and LAK cells can be partially effective for advanced solid human tumors even in the absence of the host's T-cell immune response. Preliminary experiments showed that tumor-specific, anti-melanoma T-cell clones were effective in local (s.c.) tumor growth inhibition (Winn assay) following coinjection with the autologous tumor cells.
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PMID:Chemo-adoptive immunotherapy of nude mice implanted with human colorectal carcinoma and melanoma cell lines. 159 37

The effects of purified protein A from Staphylococcus aureus Cowan I stain on induction of lymphokine (IL-2) activated killer (LAK) activity were studied in normal as well as melanoma patient's lymphocyte. The coculture of peripheral blood mononuclear cells (PBMC) with various doses of protein A (0.001, 0.01 and 0.1 microgram/ml) and IL-2 (100 U/ml) for 4 days produced synergistic effect on the LAK cells mediated cytotoxicity. The potentiation of cytotoxicity and lytic ability of LAK cells against NK sensitive (K-562) and NK-resistant (M14) tumor cells were observed. Further there was potentiation of DNA synthesis in PBMC after 4 days culture. Similar results were found when PBMC from melanoma patients were cultured with PA and IL-2. The potentiation of LAK cell induction associated with its cytotoxic and lytic potential by low doses of IL-2/PA regiment may be helpful in the development of LAK immunotherapy of the cancer patients.
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PMID:Protein A potentiates lymphokine-activated killer cell induction in normal and melanoma patient lymphocytes. 159 62

The aim of the present study was to examine the phenotypic heterogeneity of murine and human melanoma cell lines with particular reference to anticancer drug sensitivity, growth pattern and susceptibility to lysis by lymphokine (rIL2) activated killer (LAK cells). Clones selected for a different drug sensitivity were tested to evaluate the stability of such properties after different in vitro passages. A possible relationship between drug sensitivity and LAK susceptibility was also analyzed. The results indicated a high heterogeneity in murine and in human melanoma clones for all the parameters. However, drug sensitivity, which was stable although for only a few passages in an untreated human melanoma, was highly unstable in murine naturally or drug-induced resistant cells. Finally, whereas human drug-resistant clones were sensitive to lysis by LAK cells and an inverse correlation was found with the level of drug resistance, murine clones appeared to be LAK sensitive, and no correlation was found between the level of drug resistance and LAK sensitivity. Our data indicate a different stability in drug response of human and murine cells and a different behaviour of human and murine drug-resistant cells in response to LAK lysis.
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PMID:Heterogeneity and phenotypic instability of chemotherapeutic and immunologic sensitivity in murine and human melanoma cell clones. 160 62


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