Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural killer (NK) cells and NK cell activity were determined in three groups (newly diagnosed [n = 21], on therapy [n = 21], and off therapy [n = 18]) of children with various types of malignant solid tumors and in a control group (n = 26) by means of Leu-7 and Leu-11b monoclonal antibodies and a 4-hour 51Cr-release assay, respectively. The erythroleukemia cell line K562 was used as a target cell. The newly diagnosed group included eight patients with localized disease (Stage I-II), ten with bulky but nonmetastatic disease (Stage III), and three with metastases (Stage IV). The mean percent of NK cell activity in the newly diagnosed group was significantly higher than that of the control group. Children with Stage III tumors at diagnosis had higher mean NK cell function than those with Stage I-II and Stage IV. On therapy patients had significantly fewer NK cells and lower NK cell cytotoxicity than those in the other groups studied. We also studied the following: (1) the in vitro effect of recombinant interferon-alpha (rIFN-alpha) and recombinant interleukin-2 (rIL-2) on NK cell function of peripheral blood lymphocytes (PBL) from children with solid malignancies; and (2) the susceptibility of neuroblastoma-derived (CHP-126 and SKNSH) and rhabdomyosarcoma-derived (A-204) cell lines to NK cell lysis. Both rIFN-alpha and rIL-2 enhanced NK cell activity of PBL from children with malignancies and healthy children against K562 and solid tumor cell lines. The enhancing effect or rIL-2 was greater than that of rIFN-alpha. CHP-126 and SKNSH cell lines were susceptible to NK cell lysis mediated by the PBL of children with neuroblastoma and the control group. The A-204 cell line was less sensitive than K562 to NK cell cytotoxicity. Our results suggest a potential therapeutic role for both cytokines in the treatment of malignant solid tumors of childhood.
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PMID:Natural killer cells in children with malignant solid tumors. Effect of recombinant interferon-alpha and interleukin-2 on natural killer cell function against tumor cell lines. 278 77

In a murine pulmonary metastases model, interleukin-2 (IL-2), a lymphokine capable of expanding all classes of T lymphocytes, synergizes with interferon-alpha (IFN-alpha) to reduce established metastases and prolong survival. We tested whether indomethacin (INDO), which inhibits synthesis of prostaglandin E2 (a potent immunosuppressor), could further augment the antitumor efficacy of these lymphokines. Age-matched C57BL/6 mice bearing pulmonary micrometastases of a weakly immunogenic fibrosarcoma MCA-106 were treated intraperitoneally for 6 consecutive days, starting on day 3 with (1) saline solution, (2) IL-2 (50,000 units twice a day), (3) IFN-alpha A/D (50,000 units per day), and (4) IL-2 and IFN-alpha A/D. Half of each treatment group was given plain water and the rest INDO-treated (14 micrograms/cc) drinking water throughout the duration of the experiment. Pulmonary metastases were enumerated on day 21. IFN or INDO alone had little effect, whereas IL-2 reduced metastases and prolonged survival. All combination treatments, including INDO/IFN, decreased metastases and prolonged survival except INDO/IL-2/IFN in which several early deaths negated any significant survival prolongation. Early mortality (less than 21 days) was seen with IFN/INDO (8.3%), IL-2/IFN (7.7%), and IL-2/IFN/INDO (8.3%) indicating toxicity of these treatments. Spontaneous proliferation of splenocytes from non-tumor-bearing mice treated for 5 days showed that INDO combined with IL-2 or IFN enhanced proliferation measured 3 days after cessation or treatments. A striking reduction in T-cell marker (Thy 1.2+) in groups treated with IL-2/IFN, INDO/IL-2, INDO/IFN, and INDO/IL-2/IFN 3 days after cessation of IL-2 and IFN suggests that a non-T-cell is amplified when INDO is combined with IL-2 or IFN. These results show that INDO can enhance efficacy of IL-2 or IL-2/IFN. Furthermore, INDO/IFN offers an equi-efficacious, albeit similarly toxic, alternative to IL-2 treatment of tumors and may be useful clinically.
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PMID:Indomethacin-enhanced immunotherapy of pulmonary metastases using IL-2 and IFN-alpha. 278 16

Twenty-seven patients with metastatic cancer were treated with a daily continuous intravenous (IV) infusion of recombinant human interleukin-2 (rhIL-2) along with daily intramuscular recombinant interferon-alpha-2a (rIFN-alpha-2a) 4 days per week for 4 weeks with repeated treatment after 2 to 4 weeks of rest. The maximum-tolerated dose (MTD) was 3 million U/m2/d of rhIL-2 with 5 to 10 million U/m2/d of rIFN-alpha-2a. The dose-limiting toxicities are moderate hypotension requiring low doses of pressors and chronic fatigue associated with decreased performance status. Other common side effects included fever, chills, fluid retention, nausea/vomiting, erythrodermia, weight loss, elevated liver transminase levels, anemia, thrombocytopenia, and CNS toxic effects. There were seven objective responses among 25 evaluable patients. Four major responses (one complete response and three partial responses) were observed among 10 patients with melanoma treated with the MTD level. These data suggest that for cancer patients, concomitant rhIL-2 and rIFN-alpha-2a therapy is tolerable and has manageable side effects. Further phase II studies will be needed to define the antitumor activity of this combination.
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PMID:Concomitant administration of recombinant human interleukin-2 and recombinant interferon alpha-2A in cancer patients: a phase I study. 280 85

Human blood monocytes from healthy volunteers, separated by centrifugal elutriation, were not cytotoxic to allogeneic A 375 melanoma cells. The monocytes were rendered tumoricidal by incubation for 24 h with natural interferon-alpha and beta or recombinant interferon-alpha A and alpha A/D (more than 100 U/ml) or with interferon-gamma (more than 1 U/ml). Liposome-MTP-PE at concentrations of more than 50 nmol/ml also induced tumoricidal activity of monocytes. When a combination of subthreshold concentrations of these IFNs and liposome-MTP-PE were added to monocyte cultures, IFN-alpha and beta acted additively in monocyte activation, while IFN-gamma acted synergistically. The synergism for monocyte activation required that monocytes be incubated first with IFN-gamma and then with liposome-MTP-PE. These findings suggest that the synergistic effect of IFN-gamma and liposome-MTP-PE can decrease the necessary clinical doses of these agents for malignant diseases, and may have therapeutic availability in the treatment of metastatic cancer in humans.
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PMID:[Induction of tumoricidal properties in human monocytes by synergism between interferon-gamma and liposome-entrapped muramyl tripeptide]. 309 16

Both interferon-alpha (IFN-alpha) and alpha-difluoromethylornithine (DFMO) have shown modest activity as single-agent therapy in the treatment of malignant melanoma. Several investigators have demonstrated true synergism in vitro of the combination of DFMO and IFN-alpha against human tumor cells, including melanoma. We have investigated this combination in 17 patients with malignant melanoma in a Phase I trial. Patients were treated with 4 or 6 g/m2/day of oral DFMO in 3 divided doses for 11 days, followed by a 3-day rest period. Concomitant administration of 1.5, 3.0, 6.0 or 9.0 x 10(6) U/m2 IFN-alpha intramuscularly was given. The maximum tolerated dose was 4 g/m2/day of DFMO plus 6 x 10(6) U/m2/day of IFN-alpha. Dose-limiting toxicity occurred in 3 of 3 patients receiving 9 x 10(6) U/m2 IFN-alpha and consisted of leukopenia, fatigue, and weight loss. Other toxicities were mild and included reversible hearing loss, diarrhea, nausea, and vomiting. Three responses were seen, including one partial response (PR) of soft tissue metastases, one PR of lung and liver, and one complete response of liver metastases without clearance of carcinomatous meningitis. A Phase II trial has been initiated based on these encouraging results.
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PMID:A phase I trial of recombinant interferon-alpha and alpha-difluoromethylornithine in metastatic melanoma. 313 43

We investigated the antitumor effects of combined immunotherapy with recombinant human interleukin-2 (rhIL-2) and the recombinant human interferon-alpha (rhIFN-alpha) A/D hybrid in the treatment of established single or multiple murine hepatic metastases. Mice bearing either weakly immunogenic MCA-106 or nonimmunogenic MCA-102 were treated with rhIL-2 alone, rhIFN-alpha alone, or the combination of lymphokines. Therapy was initiated on Day 3 or 10 and continued for 3-4 consecutive days. In the treatment of 3- and 10-day multiple MCA-106 liver metastases, significant reductions in the number of metastases, often more than 90%, were observed with the combination of rhIL-2 and rhIFN-alpha at doses of each lymphokine which had no effect when given alone. This decrease in the number of metastases resulted in a survival benefit that was seen in the combination therapy groups in a dose-dependent manner. Similarly, substantial reductions in tumor weight were seen when the combination of rhIL-2 and rhIFN-alpha was administered to mice with single large hepatic metastases. The decreases in both single and multiple metastatic tumor deposits by the combination of lymphokines were more than that predicted by the additive effect of each treatment alone. With the nonimmunogenic tumor, MCA-102, however, no benefit was derived from the addition of rhIFN-alpha to rhIL-2 therapy. Immunotherapy with recombinant murine interferon-gamma and rhIL-2 was directly compared to therapy with rhIL-2 and rhIFN-alpha. The combination of rhIL-2 and rhIFN-alpha again was found to be effective while recombinant murine interferon-gamma added toxicity but no therapeutic benefit to immunotherapy with rhIL-2 alone. The synergy between rhIL-2 and rhIFN-alpha was shown to be dependent on the host's intact immune system since mice immunosuppressed by sublethal irradiation prior to inoculation of tumor did not respond to the combined treatment. Possible mechanisms of the in vivo synergy between rhIL-2 and rhIFN-alpha are discussed.
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PMID:Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid alpha-interferon in the treatment of established murine hepatic metastases. 326 13

General surgical procedures are followed by a period of generalized immunosuppression that may favour the deposition of metastases seeded at operation in patients with malignant disease. In an attempt to prevent the suppression of host-antitumour immune mechanisms following surgery we have studied the immunological effects of low-dose perioperative interferon-alpha (r-HuIFN alpha). Patients were randomly allocated pre-operatively to the control (n = 15) or treatment group (n = 15). Patients in the treatment arm received a 1-week course of subcutaneous recombinant human interferon-alpha 2a (Roferon-A) at a dose of 2 megaunits daily starting on the evening before surgery. Natural killer cell, lymphokine activated killer cell cytotoxicities and endogenous interleukin 2 production were measured 1 day before surgery and on the first, third, fifth and tenth postoperative days. Treatment with r-HuIFN alpha did not prevent the postoperative impairment of interleukin 2 production or lymphokine activated killer cell cytotoxicity. However it prevented the fall in natural killer cell activity normally observed following surgery. This may have important consequences in controlling metastatic dissemination of tumour in this vulnerable period.
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PMID:Effects of low dose perioperative interferon on the surgically induced suppression of antitumour immune responses. 326 47

The effects of recombinant human interferon-alpha A/D (rIFN-alpha A/D, a subtype of recombinant human leukocyte interferon with biological activities against murine tumor cells) on the growth of murine tumors were studied. rIFN-alpha A/D significantly inhibited the growth of mouse M5076 reticulum cell sarcoma, MOPC-104E myeloma, colon carcinoma 26 and Meth A fibrosarcoma by dose-dependent fashion. rIFN-alpha A/D also inhibited the metastases and growth of Lewis lung carcinoma and showed a synergistic effect with combination of cyclophosphamide. The antitumor activity of rIFN-alpha A/D was observed by intra-muscular, intravenous, subcutaneous, intraperitoneal injections or by the injection at the site of the tumors.
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PMID:[Effects of recombinant human interferon-alpha A/D on the growth of experimental tumors in mice]. 330 69

A combined treatment of alpha interferon (INF), 8 MHz radiofrequency (RF) hyperthermia using Thermotron-RF Model 8 and/or irradiation was performed on a patient with advanced renal cancer. The patient was a 52-year-old male, who had received arterial embolization with a gelatin sponge and 60 mg of adriamycin for the right renal tumor in January, 1985. He was referred to our clinic in April, 1985. Computed tomography showed a right renal tumor, 120 x 105 x 80 mm. Histological examination revealed clear cell carcinoma of the right kidney. The tumor was unresectable because of the huge tumor size, invasion into the right lobe of the liver, multiple pulmonary metastases and severe dysproteinemia. From the beginning of May, 1985, administration of 3 x 10(6) units interferon-alpha (INF) daily and radiofrequency (RF)hyperthermia for one hour twice a week were started. By June 11, 1985, 10 sessions of RF-hyperthermia were performed. Thereafter, hyperthermia for the renal tumor was maintained once a week until June, 1986. From the middle of June, 1985, a gradual improvement of dysproteinemia and appetite loss, and a decrease of the right renal tumor size as well as disappearance of febrile attacks were attained. In November, 1985, mediastinal lymph node swelling developed. A combined therapy of RF-hyperthermia twice a week and irradiation with 2.0 Gy daily 5 times a week was started. A total of 14 sessions of RF-hyperthermia and 30 Gy of irradiation were delivered until January, 1986. Intratumoral temperature of the renal tumor reached 44.0 degrees C during the heating.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[A combined treatment of interferon-alpha, 8 MHz radiofrequency hyperthermia and/or irradiation in a patient with advanced renal cancer]. 344 69

Recent developments in biotechnology have resulted in a substantial renewal of cancer immunotherapy. In particular, the availability of murine monoclonal antibodies and recombinant biological response modifiers by genetic manipulation has made it possible to re-test abandoned concepts of adoptive humoral and cellular immunotherapy and to reconsider the biomodulation of the patient's immune system. Thus, the utilization of monoclonal antibodies to purge ex vivo autologous marrow from residual tumor cells has reached an advanced stage of clinical investigation in the field of autologous bone marrow transplantation for leukemia or lymphoma. Numerous promising clinical trials are being performed by the injection of monoclonal antibodies directed at tumor-associated antigens, coupled with cytotoxic agents (isotopes, drugs, toxins). In the area of recombinant technology, interferon-alpha has become the drug of choice for a particular form of chronic leukemia (hairy-cell leukemia). Interleukin-2 administered in conjunction with autologous activated lymphocytes has been shown to mediate significant anti-tumor activity in metastatic cancer patients. This review briefly describes recent clinical results obtained in cancer immunotherapy and discusses the potential of these new approaches.
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PMID:[Current possibilities in immunotherapy of cancer]. 355 Oct 61


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