摘要:

Murine splenocytes immunized in vitro against syngeneic adult kidney fibroblasts coupled sequentially with a glycylglycylcystamide spacer, and the p-nitrophenyl ester of muramyl dipeptide developed direct cell-mediated cytotoxicity to the immunizing cells which cross-reacted against syngeneic fibrosarcoma cells. These results extended previous observations showing the reverse pattern of cross-reactivity. Derivatized kidney fibroblasts also gave protection in an in vivo protection-challenge experiment performed with the tumor cells. A hypothesis is presented relating this kind of autoimmunity to tumor immunity.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Fifty-three patients with metastatic renal cell carcinoma received treatment with combinations of recombinant alpha (rIFN-alpha-2a) and gamma (rIFN-gamma) interferons on three different treatment schedules. On treatment schedule A, 13 patients received i.m. rIFN-alpha-2a and rIFN-gamma simultaneously at a 1:1 ratio by dose units (2 ± 106U/m2), equivalent to a 1:10 ratio by protein weight. Results included severe constitutional symptoms in 62% of the patients and no partial remissions (PR) or complete remissions among 10 evaluable patients. On treatment schedule B, 25 patients received an i.m. injection of rIFN-alpha-2a and rIFN-gamma simultaneously at a 1:1 ratio by protein weight (2 ± 106U/m2and 2 ± 105U/m2, respectively). This schedule was well tolerated, allowing a 25–50% increment in over 75% of the patients. Four patients (16%) achieved PR. On treatment schedule C, 15 patients received alternating weekly therapy, first rIFN-gamma (5 ± 106U/m2daily for 7 days) followed by rIFN-alpha-2a (10 ± 106U/m2daily for 7 days). One of 13 evaluable patients in treatment schedule C achieved an 80% tumor reduction and was rendered free of disease after the primary tumor was resected. Toxicity was similar in nature to that of rIFN-alpha-2a or rIFN-gamma separately. The toxicity of treatment schedule A suggested additive toxic effects. No distinct synergistic antitumor effect was observed.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Consensus interferon (r-metHuIFN-Con1) is the product of a gene constructed to code for the most frequent amino acid residues known to occur in subspecies of alpha interferons. Twenty-one patients with advanced malignancy entered this phase I trial with dosing levels of 3, 7.5, 15, 30, and 45 mcg/m2/day given intramuscularly on days 1–5 and 8–10 of each 28-day cycle. The initial dose was randomly given by intravenous, intramuscular, or subcutaneous injection to facilitate pharmacokinetic studies. Vomiting and diarrhea were dose-limiting at 45 mcg/m2/day, preventing completion of therapy. Malaise, flu-like symptoms, nausea, and headache were frequent but tolerable at a dose of 30 mcg/m2/day. Patients were able to escalate to 45 mg/m2/day, suggesting tachyphlaxis to these toxicities. The initial distribution phase (T1/2α) was 4.9–9.0 minutes with a T1/2β of 34–415 minutes in three patients for whom sequential values could be determined. r-MetHuIFN-Con, was absorbed after both subcutaneous and intramuscular administration. 2'5'-Synthetase levels increased following treatment, although no consistent pattern was noted. One partial response was seen in a patient with gastrointestinal carcinoma. The recommended phase II starting dose of r-metHuIFN-Con, is 30 mg/m2/day using this schedule by any of these routes of administration.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

The capacity of null cells, enriched in natural killer cells and lymphokine-activated killer (LAK) cell precursors, and T cells to conjugate with tumor targets was analyzed using a flow cytometric assay. Both purified null and T lymphocytes had a similar capacity to conjugate with uncultured and cultured tumor targets prior to interleukin-2 (IL-2) stimulation. In addition, the frequency of conjugation did not correlate with the cytotoxicity expressed by these purified lymphocyte subpopulations, as null but not T cells were highly lytic for the K562 target. Following incubation in IL-2, however, the level of conjugation with tumor targets of both null and T lymphocytes was increased. Both effector populations formed stable conjugates within 6 min at 37°C. The promotion of conjugation was associated with the induction of LAK activity by null but not T lymphocytes. No differences were apparent between the capacity of either IL-2-activated null or IL-2-activated T lymphocytes to conjugate with tumor targets, although only the former efficiently lysed them. Conjugation of both null and T effectors with tumor targets required the presence of Mg2+cations because it was inhibited by the presence of EDTA (38–72% inhibition) but not EGTA. Conjugation was also inhibited by an antibody (MHM 23) recognizing the β-chain shared by LFA-1, MAC-1, and P150/95 molecules. These observations demonstrate that both null and T lymphocytes responded to IL-2 with an increase in their ability to conjugate with tumor targets. The frequent formation of stable conjugates under these conditions by cells with both cytolytic and noncytolytic capacity failed to define conjugation as the only major condition proximate to LAK lysis.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Analysis of chemically cross-linked recombinant human tumor necrosis factor (rTNF) on sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed the presence of three distinct molecular forms which correspond to trimers, dimers, and monomers. The cross-linking procedure appeared to enhance the antigenicity of these molecular forms of rTNF as determined by Western blot analysis. Cross-linking was unaffected by 2% Nonidet P-40. high concentrations of human serum albumin, or 60% normal human serum. Sodium dodecyl sulfate (0.08%) completely abolished the cross-linking of rTNF. This paper demonstrates that rTNF. at a concentration as low as 0.8 ng/ml, exists solely in the trimeric form in solution under nondenaturing conditions.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

The existence of a tumor necrosis factor (TNF) receptor on KYM human myosarcoma cells was elucidated by Scatchard plot and cross-linking analysis. The average number of specific binding sites per cell was 15,300 and the apparent dissociation constant Kdwas 4.0 ± 10−10M. The estimated relative molecular mass of a TNF receptor on KYM cell was approximately 95,000.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

We have studied the function of interferon-gamma (IFN-γ) on human B cell proliferation and differentiation. When B cell subpopulations were separated by Percoll gradient centrifugation and stimulated by Staphylococcus aureus Cowan I (SAC), these subpopulations responded differently to lymphokines. Small B cells (60/80% Percell) were stimulated to proliferate by IFN-γ alone. Large B cells (50/60% Percoll) did not respond to IFN-γ but proliferated in response to B cell growth factor (BCGF) free of interleukin-2 (IL-2) and IFN-γ. Although IFN-γ alone could not induce the differentiation of SAC-activated B cells and did not support the growth of large B cells, it enhanced the proliferation and differentiation of both subpopulations in the presence of BCGF and IL-2. Also, IFN-γ induced the expression of IL-2 receptor on B cells. Pretreatment of B cells with IFN-γ for 48 h had a minor effect on the proliferation but significantly enhanced the differentiation in the presence of BCGF and IL-2; therefore, IFN-γ may act as a differentiation factor. However, in a late stage of culture, IFN-γ inhibited B cell differentiation. Our experimental data suggest that IFN-γ is a growth factor for distinct subpopulation of SAC-activated human B cells and enhances the proliferation and differentiation and the expression of IL-2 receptor on B cells.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

White-type polysaccharide preparation (WPS) obtained from Serratia marcescens bacteria by hot 0.2 N acetic acid extraction was shown to have antitumor effects. These were manifested by enhanced resistance to the take of TA3 transplantable murine adenocarcinoma and by the induction of regression of Meth A sarcoma in mice. Optimal conditions for the liberation and isolation of these substances were sought to achieve the highest antitumor activity and the lowest endotoxin (ET) content. Simultaneously, the activities of the WPS preparations were tested in various tests which are frequently used as in vitro correlates of in vivo antitumor effects, such as the activation of macrophage cytotoxicity, activation of natural killer (NK) cells, and tumor necrosis factor (TNF) generation. We found that the enhanced resistance to the take of TA3 tumor correlated with ET content of the WPS preparations. Preparations with reduced or no ET content showed diminishing activity in this assay or were without any measurable effect. The induction of TNF production and NK activation did not show such close relationship with the ET content. This was particularly evident if testing WPS samples obtained after 60 or 120 min hydrolysis at 90°C. The greatest discrepancy was found between ET content and the Meth A regression induction. Samples with no detectable ET content and no activity in the macrophage, NK, or TNF tests were potent inducers of Meth A regression. Partial purification of such WPS samples could be achieved and a preparation was obtained with high Meth A regression capacity. Preliminary chemical analysis of this preparation showed 25.5% amino acid, 53.7% neutral carbohydrate, <0.4% KDO, 0.8% hexosamine, <0.1% phosphorous, and <1.0% long-chain carboxylic acid content. The above chemical analytical data are not consistent with designating such preparations as ET or ET derivatives, such as Lipid A or its split products. This conclusion was confirmed by the lack of endotoxic properties as determined by biological assays on this preparation.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

We report a Phase I study in 39 cancer patients of the tolerance and biologic activity of 47 intravenous (i.v.), intramuscular (i.m.), and subcutaneous (s.c.) treatments with recombinant methional gamma interferon (IFN-γ4A) which most closely resembles the natural material produced by T lymphocytes. Patients were treated with IFN-γ4A5 days a week for 2 weeks. After a 2-week rest period, patients were placed on the same dose of drug three times a week. The most common side effects—fever, chills, malaise, myalgias, and nausea and vomiting—were seen with all routes of administration. Reversible increases in hepatic transaminase and decrease in granulocytes counts were seen. The dose-limiting toxicities observed were malaise and orthostatic hypotension. The maximum tolerated dose was 500–1,000 μg/M2/day. The t1/2of IFN-γ4Ain the circulation was 20 min after i.v. injection. No blood levels were detected after i.m. or s.c. injection. Antibody against IFN-γ4Aincreased in three patients. A complete response was observed in one patient with pulmonary metastases from renal cell carcinoma.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Interferon has been reported to have activity in the treatment of multiple myeloma. We studied 24 myeloma patients treated with human lymphoblastoid interferon (Wellferon) by intramuscular injection twice weekly at an initial dose of 3 MU/M2 (three patients) or 15 MU/M2 (21 patients). One of 17 evaluable patients achieved a partial remission, three others were stable over a 16-week period of treatment, and 13 others had progressive disease. Subjective toxicity was frequent and substantial, particularly at the 15 MU dose level. Hematologic toxicity was mild and reversible. Two patients experienced acute renal failure. The low rate of response (69c) and substantial level of toxicity fail to support further exploration of these schedules of interferon as a single agent in myeloma.

ISSN:0732-6580    

出版商:OVID    

年代:1988

数据来源: OVID