Ukrain is a semisynthetic compound consisting of alkaloids from Chelidonium majus L. conjugated to thiophosphoric acid, with immunomodulatory and therapeutic properties in cancer patients. The present in vitro studies demonstrate that Ukrain is an effective biological response modifier in that it augmented, by up to 48-fold, the lytic activity of spleen lymphocytes obtained from alloimmunized mice. The lytic activities of IL-2-treated spleen cells and peritoneal exudate lymphocytes were also increased significantly by the addition of Ukrain to the CML assay medium. The highest Ukrain-induced enhancement of spleen lymphocyte lytic activity in vitro was found to occur at 18 days after alloimmunization, was dose dependent and specific for the immunizing P815 tumor cells. Since Ukrain was present only during the CML assays, its mode of action is thought to be via direct activation of the effector cell's lytic mechanism(s).
The present study was undertaken to evaluate the influence of Ukrain on the free amino acids pool in blood plasma in ten patients with breast cancer, treated in the preoperative phase with the drug. The control group consisted of five patients of similar age and advancement of the disease, who did not receive Ukrain before mastectomy. The data obtained from these studies indicate that Ukrain positively influences the metabolism of amino acids and their derivatives. The most characteristic changes were increase of proline, taurine and glutamic acid.
The present study was undertaken to evaluate the influence of Ukrain on the amino acids pool and their derivatives in tumour tissue of ten patients with breast cancer, treated in the preoperative phase with Ukrain. The control group consisted of five patients of similar age and advancement of the disease, who did not receive Ukrain. The data obtained indicate that Ukrain influences cancerous tissue, as demonstrated at the level of amino acids. The most characteristic changes observed in cancerous tissue after treatment with Ukrain were increases in the levels of proline, taurine and glutamic acid.
The effects on different biophysiological parameters and subjective impressions were studied in a patient with breast cancer who was not previously given any therapy before receiving Ukrain. Daily measurements of pulse, blood pressure, temperature and various laboratory examinations were carried out. Development and course of subjective and objective phenomena seem to be typical for patients in whom Ukrain could induce long-term complete remission. The patient described here has had to data 12 years without any oncopathological symptoms.
A random group of 50 patients in tumor stages T1-3N0-2M0 was selected from breast cancer patients and given Ukrain therapy by intravenous injection. Twenty-five patients received a total dose of 50 mg Ukrain (5 mg every second day, 10 injections altogether). Twenty-five patients received a total dose of 100 mg Ukrain (10 mg every second day, 10 injections altogether).
Cystatin C is the best known extracellular endogenous cysteine proteinase inhibitor and has been studied as a possible index of tumor growth and as a marker of the effectiveness of antitumor therapy. The aim of this study was to evaluate cystatin C concentrations in murine tumor tissues (compared with other organs not directly involved with tumor development, such as the liver and spleen) during treatment with several antitumor drugs (Ukrain and/or cyclophosphane). Cystatin C concentrations in murine tissues and biological fluids was determined by enzyme-linked immunosorbent (ELISA) assay. The cystatin C ELISA test is a sandwich immunoassay, which uses immobilized rabbit antihuman cystatin C Pab and mouse antihuman cystatin C Mab-HRP (monoclonal antibodies, conjugated with horseradish peroxidase). We observed decreased serum cystatin C concentrations compared with controls in all nontreated tumor models: HA-1 hepatoma (solid and ascitic forms), lung adenocarcinoma (solid and ascitic forms) and LS lymphosarcoma. In the ascitic fluid of mice with HA-1 hepatoma the cystatin C concentration was much lower than in the serum of the same mice (about 20-fold lower). In the HA-1 model of hepatoma cells cystatin C concentration decreased about 2-3-fold compared with the control (intact liver) and Ukrain significantly increased the cystatin C concentration. Cyclophosphane treatment of LS lymphosarcoma significantly increased the cystatin C concentration in serum. Cyclophosphane treatment (50 mg/kg, single injection) increased cystatin C by up to 8-fold more in tumor issue. Ukrain treatment of LS lymphosarcoma was also followed by increased levels of cystatin C in tumor tissue (4-fold); cyclophosphane plus Ukrain had a similar positive effect. In the group with LS lymphosarcoma Ukrain or cyclophosphane plus Ukrain treatment induced a significant increase in cystatin C concentration in liver. Liver cystatin C concentration decreased in the HA-1 hepatoma group and treatment with Ukrain or carboxymethylated beta-1, 3-glucan (CMG) increased this index in both groups. Spleen cystatin C concentrations decreased about 5-fold in LS lymphosarcoma compared with controls and combined treatment with cyclophosphane plus Ukrain restored the index to the normal value. We can conclude that both murine tumors studied were characterized by low cystatin C concentrations in tumor tissues and decreased cystatin C concentrations (to a lesser degree) were also observed in liver and spleen as a result of the "toxic" effect of tumor bearing. Effective treatment in all cases (especially with Ukrain or a combination of cyclophosphane plus Ukrain) induced a significant increase in cystatin C. Obviously, the decrease in cystatin C concentration predominantly in tumor tissue was connected with tumor development and restoration of cystatin C level may be used as a marker of efficacy of antitumor therapy.
Development of murine HA-1 hepatoma was accompanied by increased activity of cathepsin B (in ascitic cells), cathepsin D (in ascitic fluid) and increased activity of procathepsin B. There were some changes of cysteine proteinases in liver and spleen, not involved directly into tumor growth. The most prominent changes included the decreased level of cysteine proteinase inhibitors cystatin C and stefin A in ascitic cells (and to a lesser degree in liver tissue). During tumor development serum cystatin C concentration decreased by 3-times compared to intact mice. Treatment by antitumor drug Ukraine increased life span of mice with HA-1 hepatoma (transplanted intravenously), decreased the increment of tumor weight. In ascite such treatment caused a decrease of number of tumor cells and an increase of number of macrophages. Ukraie (administered once or 5-times in a dose of 0.5 mg per mice) increased cystatin C level, revealing protective mechanism of action.
Ukrain, a semi-synthetic preparation obtained from Chelidonium majus L, is used in the treatment of cancer diseases. It has been observed to exert a protective influence in mice infected by influenza viruses. Recently, the influence of the preparation on the survival of mice infected by lethal doses of E. coli and S. aureus has been estimated. This preparation was administered to Balb/c mice subcutaneously in doses of 0.04, 0.4 and 4.0 mg/kg of body weight. Ukrain was given every second day during 20 days, or a short-term before-and-after method at 48, 24 and 2 h before the infection and or 2, 24 and 48 h after the infection of mice. The mice were infected intraperitoneally with E. coli or S. aureus in doses equivalent to 2LD50. Increased survival of mice, depending on the dose of the preparation and the kind of infecting bacterium was observed. The highest survival (50%) occurred in mice infected with E. coli and receiving the amount of the preparation corresponding to 0.4 mg/kg. The lowest survival was observed in mice infected by S. aureus and receiving the preparation in the amount of 4.0 mg/kg. Higher protective effectiveness of the Ukrain preparation was observed in mice when the preparation had been administered during 20 days as compared to the short-term before-and-after regime.
This study was carried out to determine the clinical and immune response of a stage IB voluminous uterine cervical cancer to thiophosphoric acid alkaloid derivatives from Chelidoniium majus L. (Ukrain). The drugs were administered 10 mg intramuscularly every other day, for up to 10 injections. The two largest diameters and tumour volumes were measured and laboratory and immunological tests were performed before and after Ukrain administration. The patients were then operated on with type III Piver's radical hysterectomy. Three out of nine eligible cases had partial responses while six cases remained stable. Decreased total B lymphocytes and suppressor T lymphocytes were observed as well as increased total numbers of T lymphocytes and helper T lymphocytes. There was no single case of clinical or haematological toxicity apart from mild nausea. Two patients were treated with adjuvant radiotherapy due to lymphatic involvement and all nine patients were still alive at least six months after follow-up.
Ukrain is a semisynthetic drug with immunomodulatory properties derived from Chelidonium majus L. alkaloids and thiophosphoric acid. It acts selectively in a lytic way on cancer cells. Its protective properties have been shown in mice infected by influenza viruses. In this paper, the studies made on the estimation of the direct activity of Ukrain preparation on viruses and bacteria E. coli and S. aureus are described. Viruses of different haemagglutination titres were incubated with different concentrations of the preparation during period of 1, 2 and 24 h. Afterwards the samples were collected and used for the infection of the allantoic cavity obtained from 10-day-old hen embryos. A second method was based on the introduction of the Ukrain preparation into the allantoic cavity of embryos before infection with influenza viruses and after the infection of embryos. In both the described methods, the embryos were incubated within 48 hours. Then the presence of influenza viruses in allantoic fluid was estimated using a haemagglutination reaction with 30% hen blood cells. The influence of the preparation on hen embryo was also studied. In order to estimate the antibacterial activity the following procedure was used. To the preparation diluted with the growth medium from 500 micrograms/ml to 1 microgram/ml a definite amount of the bacteria S. aureus or E. coli was added, and after 24 and 48 h of incubation at 37 degrees C the results were read off. In the second method, the bacteria were added to 1, 10, 100 and 500 micrograms of the preparation in 1.0 ml of 0.85% NaCl, and after 1, 2 and 24 of incubation at room temperature the samples were collected and inoculated on solid Mueller-Hinton medium. The presence of bacterial growth or medium turbidity after 24 and 48 h of incubation was taken as a positive result. Our studies have revealed that the above mentioned preparation does not exert any negative influence on hen embryos that could make it difficult to estimate replication of influenza viruses. This preparation did not show any direct influence on the inactivation of influenza viruses and the bacteria E. coli and S. aureus.
