摘要:

SummaryThe effects of human recombinant γ-interferon (γ-IFN) on the levels of carcinoembryonic antigen (CEA) expression were investigated in vitro in three human colon adenocarcinoma cell lines (WiDr, HT29, and SW403). Sub- confluent cultures were exposed continuously to IFN at concentrations of 1–1,000 antiviral units/ml for up to 6 consecutive days. IFN resulted in a significant increase in CEA levels when assayed by cellular enzyme-linked immunosorbent assay (ELISA), with higher concentrations and longer exposure times resulting in greater CEA enhancement. A three to five-fold enhancement of CEA was observed after 5–6 days of continuous exposures at concentrations of 100–1,000 antiviral units/ml. CEA levels returned to baseline over a 4-day period after discontinuation of IFN. Levels of IFN that resulted in CEA enhancement also resulted in cell growth inhibition, with a direct correlation observed. Flow cytometric studies, which evaluated changes in CEA membrane expression of only the viable cells remaining after IFN exposure, gave similar results to cellular ELISA. Quantitative CEA ELISA, which quantitated changes in total cellular CEA content, demonstrated greater increase in CEA than predicted by cellular ELISA. Continuous IFN exposures for 5–6 days at 1,000 U/ml led to a 96-, 26-, and 5-fold increase in total CEA for the WiDr, HT29, and SW403 cell lines, respectively. WiDr cells exposed to daily 6-h IFN pulses demonstrated intermediate increases in CEA compared with cells exposed continuously to IFN. In summary, the present study demonstrates that γ-IFN can significantly enhance CEA expression of human colon cancer cells and that the levels that produce the greatest degree of enhancement also result in a significant cytotoxic effect. The results from this study make a strong argument for use of IFN as an adjunct to radioimmunotherapy in future trials.

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

SummaryHyperthermia can strikingly enhance tumor necrosis factor-α (TNF-α) cytotoxicity in vitro and in vivo. Other forms of TNF may have tumor therapeutic applications and their interaction with hyperthermia should also be assessed. We have compared the effect of heat on the in vitro cytotoxic response of murine L929 and EMT-6 and human T24 tumor cells to three TNF forms; recombinant human TNF-α, TNF-β (lymphotoxin), and TNF-SAM2. A neutral red assay was used to measure toxicity at 18–20 h after initiating the heat treatment. TNF treatment preceded heating by 0–4 h or followed it by 2 h. Heating was done at 39 or 40.5°C for 24 h, 40.5 or 42°C for 1 h, or 43°C for 1–1.5 h. We found that both TNF-p and TNF-SAM2 toxicities, like that of TNF-α, were markedly enhanced by hyperthermia. Neither EMT-6 nor T24 cells responded consistently to any of these TNFs at heat doses up to 1 h at 43°C, but an increment of only 15 min more at 43°C sensitized EMT-6 cells and 1.5 h at 43°C resulted in extensive EMT-6 cell killing. The T24 cells remained resistant except for variable responses at the highest TNF and heat doses. If TNF treatment was begun immediately before or 2 h after beginning to heat the EMT-6 cells, sensitization was reduced or eliminated, respectively, for all three TNF forms relative to protocols in which TNF was added 1, 2, or 4 h before heating. These results show that, like TNF-α, other recombinant TNF forms have cytotoxic interactions with hyperthermia that are dependent on treatment sequence and dose and that TNFs constructed to reduce systemic toxicity and enhance antitumor efficacy (TNF-SAM2) may retain therapeuti- cally advantageous cytotoxic interactions with hyperthermia.

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

SummaryIn this Phase I trial, the feasibility of sequential administration of continuous intravenous recombinant interleukin-2 (rIL-2) at 18 ± 106IU/m2/ day for 6 days, followed by three daily bolus intravenous recombinant tumor necrosis factor (rTNF) infusions at doses escalating between 10 and 120 μg/ m2/day, was investigated in 31 patients with metastatic malignancies. Prophylactic use of indomethacin prior to and during rTNF administration was found to significantly reduce toxicity. However, despite prophylactic indomethacin, a maximum tolerated dose of rTNF of 120 μg/m2was reached. The limiting toxicity was hypotension. Predictable flu-like toxicities (i.e., fever/chills, hypotension, gastrointestinal toxicity, edema, malaise) were seen in most patients. These started during the rIL-2 infusion and continued during rTNF administration, particularly in the absence of indomethacin. Hematological, renal, and hepatic toxicities were not dose limiting. These toxicities were all reversible after treatment interruption. Pulmonary toxicity [i.e., anaphylactic- like reactions, bronchospasms, and adult respiratory distress syndrome (ARDS)] was seen in several patients immediately after rTNF infusions, irrespective of the rTNF dose or treatment cycle, and mainly in patients with extensive pulmonary metastases. The combined effect of treatment-related ARDS, lung metastases, and a Guillain-Barré syndrome led to the death of one patient. Two partial responses were seen in this study (i.e., breast and renal cancer). Based on these results, a Phase II trial of rIL-2 followed by rTNF has been initiated in metastatic breast cancer patients.

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

SummaryTwenty patients with advanced cancer for which there was no effective standard therapy or whose disease was refractory to standard therapy were treated with recombinant macrophage colony-stimulating factor (rM- CSF). The rM-CSF was administered by intravenous bolus infusion for 5 consecutive days every other week for 2 treatment weeks. The doses administered ranged from 30 to 33,000 μg/m2/day. There was no intrapatient dose escalation. There were minimal to no systemic side effects seen, except for acute dyspnea noted in three patients. The dyspnea was felt to be related to the rate of infusion and did not recur in one patient given additional rM-CSF at a slower infusion rate. The major hematologic effect seen was a mild decrease in platelet count, which began to recover while the patients continued to receive the rM-CSF. The clearance of rM-CSF was dose dependent. Lower doses resulted in a saturable mechanism felt to represent cellular uptake. Clearance at higher doses demonstrated both a first-order mechanism at high serum rM-CSF concentrations, representing renal clearance, as well as a saturable mechanism at low serum concentrations. The maximum mean serum half-life was reached at dose levels of ≥3,690 μg/m2and was in the range of 234–258 min. By this route of administration, rises in absolute monocyte count were slight and seen only at doses of ≥450 μg/m2during the second therapy week. The maximum tolerated dose was not reached in this study because of lack of availability of rM-CSF.

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

SummaryUsing an enzyme-linked immunosorbent assay (ELISA), we have measured serum levels of a soluble form of the p55 subunit of the interleukin-2 receptor complex, soluble CD25 (sCD25), at regular intervals in the sera of 51 pediatric and adult cancer patients receiving recombinant human interleukin-2 (IL-2). The IL-2 was administered in repetitive weekly cycles alone or in combination with lymphokine-activated killer (LAK) cells. Levels of CD25 correlated with clinical toxicities reflected by nadir blood pressures, percentages of weight gained, and minimum Karnofsky performances during IL-2 therapy. Coadministration of autologous in vitro activated LAK cells together with IL-2 did not significantly affect the pattern of sCD25 release relative to administration of IL-2 alone. Examination of sCD25 release in response to different doses of IL-2 revealed a statistically significant dose effect of IL-2 on the sCD25 levels in patient sera. In addition, the level of sCD25 in patient sera also correlated strongly with expression of CD25 on the surface of peripheral blood lymphocytes (PBL) obtained from patients following IL-2 therapy. These studies demonstrate the utility of the sCD25 ELISA as a clinical tool for monitoring patients on treatment regimens that include IL-2.

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1992

数据来源: OVID