Cancer immunotherapy by fusions of dendritic and tumour cells and rh-IL-12.

BACKGROUND: Vaccination with fusion cells (FCs) comprising dendritic cells and tumour cells as well as administration of interleukin-12 (IL-12) showed a significant therapeutic effect against established tumours in mouse experimental models. We conducted immunotherapy against various malignant tumours using the FCs and rhIL-12, and investigated the safety and efficacy of the therapy. MATERIALS AND METHODS: Patients' DCs were mixed with autologous irradiated tumour cells and treated with 50% polyethylene glycol to generate FCs. The FCs were inoculated intradermally, and then 30 ng kg(-1) of rhIL-12 was injected at the same sites 2 and 6 days later. This process was carried out as one cycle, and three of these cycles were repeated at 1-week intervals to comprise one course. After completing the course, its safety and therapeutic effects were estimated. RESULTS: The most frequently observed adverse event was fever, observed in 26% of patients in the first cycle. Decrease in white blood cell and an increase in serum ALT were observed in 28% and 25%, respectively. Three out of 12 patients with a malignant brain tumour (25%) achieved a partial response (PR), but other patients with a malignant tumour showed no regression of their tumours. Thirteen out of 16 patients with a brain tumour (81%) showed cutaneous delayed hypersensitivity responses. However, only one of 16 patients (6%) with a malignant tumour other than a brain tumour developed such responses. CONCLUSIONS: Immunotherapy using a FC vaccine and rhIL-12 induced no serious adverse reactions, and provided good therapeutic responses in some of the patients with a brain tumour.

Recombinant human interleukin-11 decreases severity of acute necrotizing pancreatitis in mice.

Interleukin (IL)-11 has anti-inflammatory activity in animal models of gut inflammation, endotoxemia, and radiation-induced thoracic injury. The aim of the present study was to investigate the protective role of IL-11 in a model of acute necrotizing pancreatitis in mice. Acute pancreatitis was induced by administration of seven intraperitoneal injections of cerulein (50 microg/kg) at hourly intervals. Lipopolysaccharide (LPS) was injected 5 hours after the first cerulein injection. Treatment with recombinant human IL-11 (rhIL-11) was started 30 minutes before the first cerulein injection and repeated 4 hours later. Serum levels of amylase, lipase, and tumor necrosis factor (TNF)-alpha were measured at the end of the experiments. The severity of pancreatitis was evaluated by histological scoring using a semiquantitative analysis of hematoxylin and eosin-stained sections of the pancreas. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed to quantify the intrapancreatic TNF-alpha mRNA levels. Serum amylase and lipase levels progressively increased with a maximum reached between 8 and 11 hours. Treatment with rhIL-11 significantly decreased amylase and lipase levels at 6 and 8 hours. Serum TNF-alpha peaked at 6 hours and rapidly decreased thereafter. The elevation of serum TNF-alpha was markedly inhibited by treatment with rhIL-11. Histologically, treatment of rhIL-11 reduced the severity of pancreatic injury including edema, inflammatory cell infiltration, and hemorrhage at 6 hours. Intrapancreatic TNF-alpha mRNA levels were reduced by >50% in the rhIL-11-treated group at 6 hours. In conclusion, rhIL-11 decreased the severity of experimental pancreatitis early on but not later and inhibited the intrapancreatic TNF mRNA expression in vivo, suggesting that the protective effect of IL-11 during the early stage of acute pancreatitis may be mediated, at least in part, through modulation of TNF production.

Differential interleukin 12 responsiveness for interferon gamma production in advanced stages of cancer patients correlates with performance status.

Interleukin 12 (IL-12) has been shown to exhibit potent antitumor activity in murine tumor models through various mechanisms including the capacity to stimulate IFN-gamma production by T cells and natural killer cells. The aim of the present study was to examine the efficacy of IL-12 in inducing IFN-gamma secretion in cancer patients. A comparison was made between healthy individuals who served as controls and cancer patients for IFN-gamma production induced after the stimulation of whole blood samples with 1000 pg/ml IL-12. Samples from all healthy individuals showed positive IL-12 responsiveness. Approximately half of the samples from patients displayed levels of IFN-gamma production comparable to those observed for controls, whereas the rest of the samples exhibited almost-null responses. The incidences for reduced capacity of IFN-gamma production and null IL-12 responsiveness in cancer patients at all cancer stages or at a given advanced stage (stage IV) increased along with performance status. However, these correlated with neither the number of lymphocytes contained in the blood samples nor the tumor types. When peripheral blood mononuclear cells were isolated from patient blood samples showing null/marginal responses, and their responsiveness was examined, 7 of 13 samples exhibited positive responses. Whereas enhanced tumor necrosis factor alpha production was also observed in some patients after IL-12 stimulation, the elevation of tumor necrosis factor alpha was induced only in blood samples that showed IL-12-stimulated IFN-gamma production. These observations indicate that a remarkable difference exists in IL-12 reactivity among cancer patients, and that differential IL-12 responsiveness depends largely on performance status.

[Study on anti-tumour effects of interleukin 12 for spontaneously arose murine renal cell carcinoma].

BACKGROUND: We studied on the anti-tumour effects of recently cloned cytokine interleukin-12 (IL-12) for murine renal cell carcinoma (RC-2) with special reference to the difference of its activity based upon the different method of administration. MATERIALS AND METHODS: Ten days after RC-2 inoculation to subcutaneous of BALB/C mice, the recombinant murine IL-12 (rMu-IL-12 was administered (0.5 microgram/mouse, 1.0 microgram/mouse and 2.0 micrograms/mouse) 5 times per week for 3 weeks. Two administration methods were applied: intraperitoneal administration (i.p.) and subcutaneous administration near grown tumour (s.c.). We evaluated the efficacy of IL-12 for the RC-2 by means of the ratio of relative mean tumour weight (TRW/CRW), the degree of histological degeneration and the survival time of tumour-bearing mice. Furthermore, the serial body weight of mice excluding the tumour weight was monitored in order to evaluate the side effect of IL-12. RESULTS: 1) The ratio of TRW/CRW: As to the experiment of IL-12 injected at 0.5 microgram/mouse, the anti-growth effect was more potent in the i.p. group than in the s.c. group. On the other hand, as to the higher dose groups including 1.0 microgram/mouse and 2.0 micrograms/ mouse groups, the s.c. groups showed more potent anti-tumour growth effects than the i.p. groups. 2) The histological effect: All examined groups showed the degree of grade II degeneration which meant the existence of viable tumour cells after the treatment had been finished. Furthermore, we found out the different pattern of degeneration between the two administration groups (i.p. and s.c.). Namely, there observed sporadicaly degeneration in the i.p. groups, and also observed uniform degeneration close to the injected area in the s.c. groups. 3) Survival time: All treated groups showed a significant prolongation of survival compared with the control, but no significant difference was observed between these two different injected groups. 4) Side effects: Through monitoring serial changes of body weight of treated mice, no significant decrease of body weight due to the administration of IL-12 was observed in all experiments. CONCLUSION: The anti-tumour effects of IL-12 for murine renal cell carcinoma with special reference to the difference of anti-tumour effect based upon the different method of administration shows that more potent anti-tumor growth effects are observed in the i.p. group dosed at 0.5 microgram/mouse than in the s.c. group. On the other hand, as to the escalating doses, more potent anti-tumour effects are observed in the s.c. groups than in the i.p. groups. Through all treatment groups, no complete regression of the tumour is observed. Therefore, further precise study to clarify the immunological reaction between tumour and its host derived from the administration of IL-12 must be needed in order to establish more effective treatment with IL-12 in the future.

[Dental management of the medically compromised patient. A study of 162 cases].

Dental management of 162 cases of medically compromised patients was reviewed. Over the past 3 years and 2 months, 130 patients with certain medical problems underwent 162 cases of dental treatment under local anesthesia. In the present study, research was done chiefly on intraoperative management of these patients. The following results were obtained: 1) In the population of 130 patients, those in their 7th decade were the most numerous. Among the subjects, essential hypertension was the most common underlying disease, and the majority of the patients had accompanying cardio-vascular diseases. 2) When the pre- and post-65-year-old patient groups were compared, the latter group had a higher frequency of multiple medical problems. 3) It is suggested that, to manage patients having hypertension or ischemic heart diseases as a complication, continuous blood pressure measurement and ECG monitoring are essential. 4) Among several local anesthetics, 3% prilocaine with 0.03 U/ml felypressin was used most frequently, especially for those with cardiovascular diseases. 5) In the management of hypertensive and ischemic heart patients, nitrous oxide inhalation sedation was effective. 6) For those who required vasodilation, administration of nifedipine or nitroglycerin was effective. 7) Although one case of syncope and another in which dental treatment procedure had to be suspended were found, no severe complications were encountered.

[Studies on the anti-ulcer effects of isoprenyl flavonoids (1). The anti-ulcer effects of isoprenyl chalcone extracted from Sophora subprostrata (author's transl)].

A series of extracted fractions from sophora subprostrata was screened by determining anti-ulcer effects in pylorus ligated and stressed rats. Fr. [C-2] had the most potent anti-ulcer effects of all fractions extracted. Sophoradin and sophoranone which were isolated from Fr. [C-2] were also found to have inhibitory effects on ulcer formation in pylorus ligated and stressed rats. The anti-ulcer effect of sophoradin was relatively potent in comparison with that of sophoranone and/or Fr. [C-2]. The anti-ulcer effect of sophoranone was approximately the same as that of Fr. [C-2]. The authors examined the effects of sophoradin and sophoranone on gastric secretion in pylorus ligated rats. Sophoradin and sophoranone significantly reduced the volume of gastric juice. Sophoradin but not sophoranone inhibited the free and total acid output of gastric juice. The effect of sophoradin was examined on various secretagogues which induced gastric secretions in rats with acute fistula. Sophoradin showed a tendency to inhibit tetragastrin- and insulin-induced gastric acid secretion, but there were no effects on methacholine- and histamine-induced secretions. These results suggest that sophoradin may have marked anti-ulcer and inhibitory effects on gastric secretion.