ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryThe tumoricidal properties of an anti-human colon carcinoma monoclonal antibody (MAb), designated D612 (IgG2a), alone and in combination with IL-2-activated human lymphocytes were investigated in athymic mice bearing LS-174T colon tumor xenografts. Treatment of mice bearing LS-174T tumors (1 day, s.c.) with a single i.v. dose of 400 jig of D612 alone resulted in a significant inhibition of tumor growth. Lower doses of D612 had an intermediate effect on tumor growth. Similar inhibition of tumor growth was obtained when D612 was administered in three doses of 400 or 800 xg each during the first week after tumor implantation. Mouse macrophages but not splenocytes mediated antibody-dependent cellular cytotoxicity with D612, suggesting that tumor inhibition was due to the participation of host macrophages with D612. Human lymphokine-activated killer (LAK) cells were generated by incubating human peripheral blood mononuclear cells (PBLs) from normal donors with 100 U/ml of IL-2 for 24 h. An administration of human LAK cells did not significantly inhibit the growth of the human xenograft tumor. Adoptive transfer of a single dose of human LAK cells (2 x 107, i.v.) into mice treated with a suboptimal dose of D612 (200 |xg) significantly inhibited tumor growth compared to that obtained with either D612 or LAK cells alone. Similar results were obtained with three doses of D612 plus human LAK cells although there was a tendency for multiple doses of LAK cells alone to show some antitumor effects. LAK cells or PBLs had similar antitumor activities when used in conjunction with D612. When larger established tumors were treated, single or multiple doses of D612 or LAK cells alone were without effect; however, LAK cells plus D612 elicited significant growth inhibition. These results demonstrate that the tumoricidal properties of LAK cells and the D612 MAb can be augmented when used together in the immunotherapy of human colon cancer xenografts.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryThe purpose of these studies was to determine whether recombinant tumor necrosis factor (TNF) incorporated into liposomes produced enhanced antitumor effects against TNF-sensitive and TNF-resistant target cells. The lipid composition of liposomes influenced their binding to and endocytosis by target cells. Liposomes consisting of phosphatidylcholine and phosphatidylserine (7:3 molar ratio) bound to L929 cells and A375 human melanoma cells, albeit to different degrees. Liposomes retained encapsulated TNF for up to 48 h of incubation. TNF in liposomes lysed the TNF-sensitive A375 melanoma and L929 cells at levels similar to that mediated by free, unencapsulated TNF. Cells selected for resistance against free TNF were not sensitive to TNF in liposomes. Since liposomes concentrate in organs with high levels of reticuloendothelial activity, and TNF in liposomes retains antitumor activity, this delivery system may prove to be useful for treatment of lymph node and hepatic metastases

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryWe have examined the effects of synthetic dsRNA (poly rI:rC) treatment or of immunization with irradiated allogeneic cells on the expression in vivo of several interferon (IFN)-inducible genes. For this purpose, DBA/2 mice were injected i.p. once with poly rI:rC, or once and then again 3 weeks later, with irradiated C3H/He spleen cells and the effect of these treatments on the levels of the following mRNAs was determined: 202, 2',5'-oligoadenylate synthetase (2-5A synthetase), class I and class II major histocompatibility antigens, and (3-actin. After poly rI:rC treatment, the levels of the 202 and 2-5A synthetase mRNAs in the spleen and in the bone marrow peaked between 12 and 24 h and decreased thereafter. The class I mRNA levels started to increase at 12 h, peaked at 24 h, and declined thereafter. No increase in class II mRNA expression was observed after poly rI:rC injection, whereas p-actin levels remained unchanged. Pretreatment of DBA/2 mice with sheep anti-murine IFN-α/p antibodies before poly rI:rC injection strongly diminished the induction of 202 mRNA, indicating that IFN-a/p mediated this induction. When irradiated C3H/He spleen cells were injected into DBA/2 mice, the class I and class II mRNAs in the spleen, but not in the bone marrow, started to increase at 12 h, peaked between 48 and 96 h, and decreased thereafter. No increase in the levels of 202 and 2-5A synthetase mRNAs was detected, whereas p-actin levels remained unchanged. Pretreatment of DBA/2 mice with rat monoclonal anti-murine IFN-7 antibodies before allogeneic cell injection significantly decreased class II mRNA levels in the spleen, suggesting the involvement of IFN-7 in this induction. The above studies conducted in vivo (a) reveal differences in the tissue and gene specificity of gene activation between dsRNA and allogeneic cells and (b) indicate that gene activation by dsRNA is mediated at least in part by IFN-α/β, whereas gene activation by allogeneic cells is mediated at least in part by IFN-γ

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryWe have examined the antitumor and antimetastatic effects of native- type, glycosylated recombinant lymphotoxin (LT) on human and murine tumors transplanted in mice. The results reported here are as follows: (a) The in vivo antitumor spectrum of LT is not coincident with the in vitro study, and it has a wide antitumor spectrum and substantially inhibits the growth of human solid tumors, (b) When both syngeneic and nude mice are transplanted with Meth A tumor, the significant growth-inhibitory effect of LT is obtained in syngeneic mice, but the effect is quite small in nude mice regardless of the routes; LT attains the same degree of effectiveness as that in syngeneic mice, but at an 8 to 16 times higher dose. Furthermore, the pretreatment with antiasialo- GMl antibody inhibits the antitumor effects of LT in syngeneic mice, (c) In the pulmonary metastasis model induced by i.v. injection of Meth A cells, a high preventive effect of LT is obtained by systemic administration in syngeneic mice, but not in nude mice. In addition, the pretreatment with antiasialo- GMl antibody completely prevents the antimetastatic effect of LT, but also blocks that effect of control mice without LT treatment. In conclusion, LT appears to be a potent cytokine against tumor growth and metastasis in vivo. The differences between nude and syngeneic mice suggest the involvement of host immunity in the expression of LT function.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryIn a series of studies, recombinant interferon-α2a(rIFNα2a, Roferon- A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFNα2aranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFNα2aoffers important therapeutic benefit in a select group of patients with AIDS-related KS.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryIn vivo stimulation of pulmonary alveolar macrophages (PAMs) may enhance tumor cell cytotoxicity. A model using aerosolized γ-interferon (γ-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 7-IFN (104|ji,U/mouse) and LPS (100 |j.g/mouse). Other groups received either γ-IFN alone, LPS alone, or saline (control). Cells were harvested by bronchoalveolar lavage. Macrophage cell count demonstrated an increase in macrophage recruitment in the γ-IFN and LPS group. PAMs were evaluated for in vitro cytotoxicity against B16-F10 melanoma cells. Treatment groups demonstrated eγhanced cytotoxicity over controls, and the combination (γ-IFN plus LPS) was significantly better in cell killing than either treatment modality alone (p ≤ 0.02). Activated PAMs selectively killed tumor cells, but did not kill the 3T3 fibroblast cell line. Peritoneal macrophages from mice treated by inhalational γ-IFN + LPS were enhanced (indicating a systemic effect), but not to the same extent as PAMs. These studies suggest that inhalation of γ-IFN + LPS can selectively enhance in vivo cytotoxicity of murine PAMs. This may potentially be applicable to human tumor management.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryTwenty-nine patients with biopsy-confirmed metastatic melanoma (17) or metastatic renal cell carcinoma (12) were treated with escalating doses of recombinant human interleukin-2 (IL-2) administered as weekly 24-h intravenous infusions. Patients received from 3 to 12 x 106 C.U./m2(18-72 x 106 I.U./m2) weekly over a treatment period of 1 to 16 weeks, with a median of eight weekly cycles administered. Patients in all treatment groups experienced non-life-threatening systemic side effects consisting of fever, nausea, vomiting, fluid retention, and diarrhea. Grade III hypotension was seen in four of six patients (67%) at 12 x 106 C.U./m2, and represented the dose-limiting toxicity. Grade IV hypotension occurred in 1 of 14 patients at 6 x 106 C.U./m2; no other grade IV toxicities were observed. Grade III fever occurred in 3 of 11 patients (27%) treated at 3 x 106 C.U./m2, 3 of 14 patients (21%) at 6 x 106 C.U./m2, and 3 of 6 patients (50%) at 9 x 106 C.U./m2. An objective response was observed in 3 of 28 evaluable patients (10%): 1 complete response and 1 partial response in renal cell cancer, and 1 partial response in a melanoma patient. We conclude that for future studies, the recommended dose of IL-2 given as a weekly 24-h infusion is 9 x 106 C.U./m2and that a low rate of objective tumor response can be obtained in patients with melanoma and renal cell carcinoma using this regimen.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryFifteen patients with locally far advanced, nonpretreated head and neck squamous cell carcinoma were treated with low-dose recombinant interleukin- 2, using 10 daily perilymphatic injections. The therapy was well tolerated. No tumor regression was observed. Tumor biopsies were taken before and after treatment. Histopathological studies including evaluation of the mononuclear cell infiltrate and immunohistochemical detection of human leukocyte antigen (HLA) expression on tumor cells were performed. HLA class I was not detectable in 1 of 10 samples, and HLA class II expression was seen in 2 of 10 samples. As compared to pretreatment biopsies, no changes were found after treatment. This is in agreement with the lack of a clinical response.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryMice are relatively resistant to the lethal effects of endotoxin. Sensitivity to lipopolysaccharide (LPS) and monophosphoryl lipid A (MPL) can be enhanced by concurrently loading animals with D-galactosamine (D-gal). Significant diurnal variation in susceptibility to lethal toxicity was observed in D-gal loaded mice upon LPS or MPL immunostimulant challenge. In mice treated with either MPL or MPL plus D-gal, at the time of greatest toxic sensitivity, serum TNF levels were significantly higher than was seen in mice treated at a time of low sensitivity. Peritoneal exudate cells (PECs) harvested from mice treated with either D-gal or MPL displayed enhanced in vitro superoxide (SO) production. Simultaneous treatment with D-gal and MPL led to a synergistic enhancement of SO production above that induced by either xenobiotic alone. Pretreatment with the SO dismutase mimetic Cu(II) (diisopropyl salicylate)2 significantly protected mice from the lethal toxicity of Dgal- MPL challenge. PECs harvested from these same mice failed to display the elevated in vitro SO production reported above. SO elaboration in vivo, presumably by hepatocytes, PECs, and possibly other cells, subsequent to D-gal loading and LPS or MPL challenge, appears to play an important role in the lethal toxicity observed. The diurnal variation in toxicity reported in this animal model may result from TNF modulation of SO production in vivo.

ISSN:1524-9557    

出版商:OVID    

年代:1991

数据来源: OVID