摘要:

Summary:A phase II trial of &agr;2b‐interferon in patients with relapsed or refractory Hodgkin's disease was conducted by the Cancer and Leukemia Group B. Nineteen patients were eligible for study. These patients had received at least two (median of four) previous chemotherapeutic programs and 79% had received prior radiation therapy. Three patients had undergone intensive chemotherapy and autologous bone marrow transplantation. The treatment regimen consisted of interferon‐&agr;2b10 × 106IU/m2subcutaneously three times per week. Only limited antineoplastic activity was seen in this heavily pretreated group of patients. There was one partial response and four patients had reduction in measurable disease not meeting the criteria for partial response. The drug was well tolerated. Toxicity was predominantly myelosuppression. Thrombocytopenia was particularly severe in patients with bone marrow involvement. The observed antineoplastic activity, albeit limited, in this heavily pretreated group of patients suggests a potential role for this agent in combination regimens in patients with earlier disease.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Peripheral blood lymphocytes obtained from cancer patients receiving interleukin‐2 (IL‐2) on two separate clinical protocols were evaluated for their in vitro responses to IL‐2, alloantigens, and PHA. IL‐2 in vivo induced enhanced in vitro proliferative responses to IL‐2 and diminished in vitro proliferative responses to phytohemagglutinin (PHA) and alloantigens. Alloinduced cytotoxic T cell responses were also depressed following in vivo IL‐2. We examined the kinetics of the in vitro proliferative response to PHA and IL‐2 and found that while the response of lymphocytes primed in vivo with IL‐2 to PHA was depressed at all times during the 2 week in vitro exposure, the response to IL‐2 peaked earlier and higher than did the response to IL‐2 by lymphocytes obtained prior to IL‐2 therapy. These contrasting effects on an‐tigen‐induced T cell responses vs. IL‐2 induced nonspecific proliferative and cytotoxic responses suggest the importance of dose and timing of IL‐2 administration when used to enhance antigen‐specific T cell responses or as an immune enhancing agent combined with vaccines.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:We have evaluated the effects of combinations of various cytokines on the reconstitution of natural killer (NK) cell activity and resistance to metastases from B16 melanoma, in lethally irradiated mice transplanted with syngeneic bone marrow. Treatment with some combinations of interleukin‐2 (IL‐2) and other cytokines (IL‐2 + IL‐1 + TNF&agr; or IL‐2 + IL‐1 + LT) induced appreciably greater and more rapid augmentation of NK cell regeneration than IL‐2 alone, as measured in vitro in the 4‐h51Cr release assay against YAC‐1 or in vivo in an assay of lung clearance of125IUdR‐labeled tumor cells. The same treatments also induced significant augmentation of in vivo resistance against pulmonary metastases in C57BL/6 mice injected with B16 melanoma cells. These data indicate that stimulation of NK activity in tumor‐bearing bone marrow transplanted recipients may be of value in the control of metastatic disease.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:A novel thiazolopyrimidine nucleoside, 5‐amino‐3‐&bgr;‐d‐ribo‐furanosylthiazolo [4, 5‐d]pyrimidine‐2, 7 (3H, 6H)‐dione (7‐thia‐8‐oxoguanosine), was evaluated for antiviral activity in rodent models, and at 50‐200 mg/kg prevented death in mice inoculated intraperitoneally (i.p.) with Semliki Forest, San Angelo, and banzi viruses when administered i.p. before virus challenge. Similarly, the nucleoside was effective against an intranasal challenge of rat coronavirus in suckling rats, with activity present when treatment started as late as 4 h after virus inoculation. Protection was observed against herpes type 1 and murine cytomegalovirus (both inoculated i.p.) infections, and encephalitis induced by intracerebral inoculation of a human coronavirus in mice. Friend leukemia virus splenomegaly was more severe in drug‐treated animals than in placebos. This immune modulator is promising for the treatment of animal and human diseases.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Some biological functions of macrophages can be stimulated by muramyl dipeptide (MDP) in vitro. Such stimulation is more efficient when MDP is bound to macromolecule carriers. The macrophage stimulation by MDP bound to glycosylated serum albumin (BSA) or bound to gluconoylated and glycosylated poly‐l‐lysine (PLK) is investigated. These two types of MDP conjugates are more efficient than free MDP in rendering mouse peritoneal and rat alveolar macrophages cytostatic against various tumor cells. However, the release of mitogenic factor or cytotoxic factor (CF) by activated macrophages varies according to the nature of the carrier (BSA or PLK) and to the nature and content of sugar residues bound to the macromolecule carrier (mannose or 6‐phosphomannose). Macrophages activated by MDP bound to glycosylated BSA release mitogenic factor and CF into the medium; anti‐recombinant tumor necrosis factor (rTNF) totally inhibits the cytotoxicity of the supernatant. On the contrary, MDP bound to glycosylated PLK induces no secretion of mitogenic factor and a very small amount of CF in the culture medium. The role of CF in the cytostatic activity of activated macrophages is discussed. The released CF is not involved in the cytostatic activity, but TNF‐like molecules, expressed at the membrane level, could be implied because anti‐rTNF abrogates 40% of the cytostatic activity of the macrophages.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Prostatic carcinoma represents the second leading cause of cancer mortality in men and is responsible for over 25,000 deaths each year. Currently, no curative therapy is available for metastatic carcinoma of the prostate. The present studies were undertaken to assess the efficacy of recombinant tumor necrosis factor &agr; (TNF) in the therapy of experimental prostatic carcinoma. TNF was cytotoxic to the prostate cancer cell lines PC3, DU145, and LNCAP but not benign prostatic epithelial and stromal cells in vitro. The sensitivity of the prostatic carcinoma lines to TNF‐mediated cytotoxicity was enhanced by the presence of actinomycin D. Intravenous administration of TNF (50‐100 &mgr;g/kg) to nude mice bearing subcutaneous PC3 tumors resulted in significant inhibition of primary tumor growth compared to control. TNF was also effective in reducing the growth of intraabdominal PC3 tumors induced by intrasplenic injection of PC3. Furthermore, the incidence of microscopic PC3 foci in the spleen, liver, lung, and diaphragm was diminished in mice receiving TNF therapy. These studies demonstrate the potential of TNF in the therapy of human prostatic carcinoma.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Tumor‐infiltrating lymphocytes (TILs) comprise a subpopulation of lymphoid cells that infiltrate into growing tumors. These cells can be activated in vitro with recombinant interleukin‐2 (rIL‐2) to become highly cytotoxic against fresh tumor targets in vitro and against a variety of systemic metastases in vivo. OK‐432 is a well‐known inducer of NK cells and immune effector T cells. This study was designed to evaluate the effects of OK‐432 on (a) the generation and (b) the cytotoxic potential of rIL‐2‐induced TILs. When TILs obtained from a murine colon adenocarcinoma (the MC‐38 tumor) were cultured in complete media supplemented with 100 U of rIL‐2/ml and 1.0 &mgr;g of OK‐432/ml, the number of TILs generated was greater than that seen with rIL‐2 or OK‐432 alone (number of TILs on day 15 of culture: 100 U of rIL‐2/ml: 268 × 105TILs; 1.0 &mgr;g of OK‐432/ml: 30 × 105TILs; 100 U of rIL‐2/ml + 1.0 &mgr;g of OK‐432/ml: 528 × 105TILs). Higher concentrations of OK‐432 had deleterious effects on TIL growth characteristics. TILs generated in 100 U of rIL‐2 and 1.0 &mgr;g of OK‐432/ml of complete media demonstrated greater tumor lysis compared to rIL‐2 alone (% lysis against MCA‐102 target; 100 U of rIL‐2/ml: 12%; 100 U of rIL‐2/ml and 1.0 &mgr;g of OK‐432/ml: 50%; effector target ratio 20:1;p< 0.001). Similar results were seen against the NK‐sensitive YAC‐1 lymphoma target. An analysis of cell surface antigenic expression revealed that cells grown in OK‐432 and rIL‐2 had a greater expression of the Thy 1.2 and Lyt‐2 antigens compared to rIL‐2 or OK‐432 alone. These findings demonstrate that, with the proper culture conditions, OK‐432 can act synergistically with rIL‐2 to enhance growth and cytotoxicity of MC‐38 TILs.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:CL 246,738 is a synthetic heterocyclic of the acridine class that has immunomodulating, interferon (IFN)‐inducing, and antitumor activity by the oral route in mice. We have completed a phase I ascending dose trial to determine the maximum tolerated oral dose and biologic modifying effects. Twenty‐three patients received CL 246,738 orally at five dose levels, escalating from 5 to 50 mg/kg. The major side effects were gastrointestinal disturbances such as nausea, vomiting, and diarrhea. No hematologic, hepatic, or symptomatic dose‐limiting toxicities were encountered. The mean half‐life of CL 246,738 in whole blood was at least 300 h and remained relatively constant over the dose range studied. Higher doses resulted in increased whole blood levels. Biologic response modification included stimulation of the IFN‐induced proteins, 2',5'‐oligoadenylate synthetase and &bgr;2‐microglobulin, at higher doses of CL 246,738, and enhanced T‐cell proliferation to alloantigens at lower doses. Increases in lymphocytes bearing the Leu‐7 phenotypic marker were observed and some patients had enhanced natural killer (NK) cell cytotoxicity. Enhanced NK cell cytotoxicity was demonstrated in vitro. Thus, CL 246, 738 was orally relatively well tolerated and has immunomodulating properties in humans.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Patients with metastatic solid tumors were treated with six escalating doses of weekly intralymphatically injected recombinant interleukin 2 (i.l. IL‐2). Nine patients completed the treatment and were evaluated for immunologic features of their peripheral blood lymphocytes (PBLs). The patients' PBL counts increased 4 days after the first i.l. IL‐2 injection. The cell counts remained higher than baseline in week 6 prior to the last i.l. IL‐2 injection. However, the PBL number decreased below baseline 1 day after the sixth injection, and recovered to normal levels after 3 days more. Natural killer (NK) activity showed similar changes when calculated as total activity per ml of blood. In vitro 1 h treatment of PBLs with IL‐2 greatly enhanced NK cyto‐toxicity. The enhancement was only slight in the first week of i.l. IL‐2 treatment, but was significantly greater on day 35 (7 days after dose 5) and day 39 (4 days after dose 6). In contrast, the increase was similar to the baseline on day 36, the day after the sixth injection. No lymphokine‐activated killer activity was detected in the patients' PBLs with or without short‐term in vitro IL‐2 treatment. Besides the NK cytotoxic function, lymphoid subpopulations were evaluated numerically for total T cells (CD3/OKT3), T‐cell subsets (CD4/OKT4 and CD8/OKT8), B cells (OKB7), NK cells (CD56/NKH1/Leu19, CD16/Leu11), and monocytes/NK cells (CD11b/OKM1). The activation markers (HLA‐DR, CD25/Tac, and CD38/OKT10/Leu17) were also included. Intralymphatic IL‐2 treatment had no effect on the PBL surface marker expression in the first week of treatment. However, by week 6, the percentages of cell populations expressing the NK‐associated antigens CD56, CD16, and CD11b were significantly increased. In contrast, the percentage of CD3‐positive T cells showed no change or a marginal decrease. Prior to and after i.l. IL‐2 treatment, the CD56‐positive cells in the PBLs were predominantly CD16 positive and CD3 negative. The i.l. IL‐2 treatment did not induce PBL proliferation, or changes in the expression of CD25 (Tac), HLA‐DR, CD38, CD4, CD8, CD57, or OKB7 in the patients' PBL. These results indicate that i.l. IL‐2 treatment does affect the total number of PBLs, the cells expressing NK activity, and NK‐associated surface markers.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Interleukin‐2 (recombinant methionyl human interleukin‐2 alanine 125; IL‐2) was administered intralymphatically to 12 patients with advanced cancer in a phase I trial. Doses were administered once a week for 6 weeks in a dosage escalation schedule; patients were entered in four groups at successively higher starting dosages. Toxicity occurred in a profile similar to that seen with intravenous IL‐2. The maximum tolerated dose with this route/schedule was 275,000 units/kg, a figure not higher than expected with intravenous administration.T1/2&agr;was prolonged to 54 min from the 13 min figure we obtained with IL‐2 given intravenously. Granulocytosis and eosinophilia were seen, along with lymphocytosis following initial lymphopenia. Anti‐IL‐2 anti‐bodies were seen in 42% of patients (compared to 16% with this agent given intravenously), suggesting increased immunogenicity of this route/schedule. No clinical response was achieved. Immunologic effects will be reported separately but are summarized.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID