Pre-Clinical Investigations on Ukrain

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Effect on Glioblastoma
Glioblastoma is a very dangerous brain tumor with small chances of survival. Ukrain modulates the activation of certain genes and proteins involved in tumor invasion. After treatment with high dose Ukrain, the concentration of the so-called glial fibrillary acidic protein increased within the cancer cells. There was no effect on the Connexin 43 protein. Ukrain-induced programmed cancer cell death(Apoptosis) were in 4.63 % in low concentration, 10.9 % at medium concentration and 28.9% in high concentration. The Apoptosis was likely to be mediated by release of the substance cytochrome c in the cell cytoplasm(Cell fluids).

Stimulation of immune defence
Ukrain stimulates the immune defence and has cell killing and growth inhibition effects on various cancer cells. Ukrain induced programmed cancer cell death in womb cancer cells cultures by activating the so-called intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.

Active Substance?
Habermehl with co-workers found Ukrain to be a potent inducer of apoptosis. However, mass spectrometric analysis of Ukrain failed to detect the suggested Ukrain molecule that has been postulated yto mediate the effect of Ukrain. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain.
The potent proapoptotic effects of Ukrain seems not to be due to the suggested "Ukrain-molecule" but to the cytotoxic efficacy of Chelidonium majus L. alkaloids including chelidonine.Panzer[/b]] with co-researchers also made a study, were
chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry failed to demonstrate the proposed trimeric structure of Ukrain.

Ewing tumors
Using the MTT assay, the cytotoxicity of Ukrain was compared with the cytotoxicity of Chelidonium majus L. alkaloids, and the cancer drugs thiothepa, doxorubicin, cyclophosphamide and etoposide against four human [url=Ewing tumor cell cultures. The sensitivity profile of Ukrain was comparable to that of the C. majus L. alkaloids, and different from that of thioTEPA, cyclophosphamide, etoposide and doxorubicin. This indicates that ukrain might be of use in the treatment of Ewing tumors.

Antidepressant ant anti-dementia effect?
Chelidomium Majus alkaloids, Ukrain and the pharmaceutical compound Sanguirythrine seems to diminish the breakdown of the Neurotransmitters Serotonin and Acetylcholin. This could be a theorethical explanation to the many reported about better mood and concentration ability when taking Ukrain, as this is typical actions for antidepressants and anti dementia medicines.

MAO-inhibiting effect
It has been shown that the major alkaloids from plants Chelidonium majus L. and Macleaya (Bocconia) are irreversible inhibitors of oxidative deamination reaction of serotonin and tyramine as substrates, catalyzed by rat liver mitochondrial monoamine oxidase (MAO). Among the examined agents, alkaloid chelidonine and drug "Ukrain" were the strongest inhibitors of the reaction. As it is well known, the MAO inhibitors appear to be, as a rule, pronounced antidepressants. The combination of malignotoxicity and antidepressive activity in drug "Ukrain" seems to be favourable for its clinical applications.

Resistance to ionizing radiation
This studydata give the first mechanistic insights into specific cellular resistance mechanisms behind the cytotoxic and radiosensitivity-modifying effects of the drug Ukrain by showing that fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain in human tumour and normal cells in vitro.

Radioprotective properties on normal cells, but not on cancer cells.
Exponentially growing human tumour cell lines from breast, pancreas, colorectal, glioblastoma, and human skin and lung fibroblastic cells when exposed to Ukrain and radiation,
Ukrain cytotoxicity was time- and dose-dependent. The combination of Ukrain plus radiation gave enhanced toxicity in colorectal cancer and glioblastoma cells, but not in breast cancer and pancreatic cancer cells. Most strikingly, Ukrain managed to protect normal skin and lung cells from the harmful effects of radiation.

Effect on alcohol dehydregonase
Ukrain seems to inhibit the enzyme thay breaks down alcohol. This means that there is reason to be careful when combining alcohol and Ukrain.

induktion of apoptosis
The induction of apoptosis by Ukrain was studied in Chinese hamster ovary cells. Ukrain was found to be capable of the in vitro induction of apoptosis in the cell lines studied. The effect was less expressed in cells with multiple drug resistance. Ukrain enhanced the effects of etoposide, i.e., the combined effect of both agents was evident at significantly reduced concentrations. This suggests that pharmacological compositions of the drugs may reduce the effective doses used in chemotherapy and thus significantly diminish its toxic side effects.

Exposure of a prostate cancer cells culture to Ukrain resulted in cell growth inhibition which is concomitant with apoptosis. After 24 h treatment with 3.5 microM of Ukrain as many as 73% cells were found in a state of beginning apoptosis. The rate of apoptotic cells rose steadily with increased drug concentration in a dose-dependent manner and reached 20% at a dosage of 17.5 microM.

A method for determination of Ukrain in blood plasma
the main fluorescent component of Ukrain was determined by liquid chromatography . Ukrain was resolved from fluorescent peaks of the sum of alkaloids of Chelidonium majus L. although several peaks of alkaloids were retained in Ukrain as traces. The height of the main peak was nearly constant, while the alkaloid peaks varied depending on the series of the preparation; chelidonine and ThioTEPA gave no peaks. Ukrain possesses neither significant stable binding to plasma proteins nor adsorption in blood cells.

Acute toxicity in rats
The acute toxicity of Ukrain was determined after a single intravenous, intramuscular or oral administration in rats. It was found that the intravenous LD50 was greater than 43 mg active ingredient/kg body weight in the males and 76 mg active ingredient/kg body weight in the females. . In both sexes the intramuscular LD50 was greater than 165 mg active ingredient/kg body weight.

Selective toxicity for cancer cells
Ukrain selectively inhibits growth of ME180 and A431 cancer cells at a concentration range from 3.5 microM to 7.0 microM and induces apoptosis. In contrast, normal human skin cells showed no damaging effect of Ukrain.
Exposure of cultured carcinoma cells to Ukrain resulted in cell growth inhibition and apoptosis at doses as low as 7 microM. In contrast, the same drug concentrations were not affective towards normal human keratinocytes. In order to investigate whether cell cycle control mechanisms are effected in response to Ukrain, we analyzed cell cycle distribution and levels of cyclins and cyclin-dependent kinases in drug treated carcinoma cells. We found alterations in levels of mitotic cyclins A and B1, and cyclin-dependent kinases CDK1 and CDK2, after treatment. We also observed an upregulation of CDK inhibitor p27 in both cancer cell lines which may lead to the G2/M cells accumulation, which in turn leads to apoptosis.

Selective cytotoxic effect on cancer cells
The inhibitory effect of Ukrain on malignant cells and on normal cells, in vitro,
has been compared. To obtain a 50% inhibition of cell growth, a tenfold
concentration had to be used with normal endothelial cells compared to a human
osteosarcoma cell line. A laser scanning microscope showed a high uptake of
Ukrain in malignant cells, while the content in normal cells under the same
experimental conditions was substantially lower.

No selective toxicity for Chelidonine
Chelidonine is one of the major alkaoids found in Greater Celandine.
The effects of chelidonine in two normal (monkey kidney and Hs27), two transformed (Vero and Graham 293) and two malignant (WHCO5 and HeLa) cell lines, were examined. Chelidonine proved to be a weak inhibitor of cell growth, but no evidence for selective cytotoxicity was found in this study.

No selective toxicity for Ukrain?
Ukrain is alleged to be an effective chemotherapeutic drug which causes minimal side-effects as a result of selective toxicity towards malignant cells only. Panzer previously failed to confirm this claim and found Ukrain to be equally toxic to normal, transformed and malignant cell lines by causing a metaphase arrest. In this study Panzer have found the antimitotic actions of Ukrain to be reversible in low doses in vitro. He hypothesizes that the lack of side-effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling normal cells to overcome the metaphase arrest and survive.

In vitro effect on multiple tumors
A comparative in vitro study between the effects of Ukrain and antitumor drugs cyclophosphamid and cisplatin on total thiol content in Guerin carcinoma, Guerin/cis-DDP carcinoma, and in animal livers was carried out. The cancer cell cytotoxicity of Ukrain was found similar to that of known antitumor drugs.

Effect of Glucose, succinate and temperature on Ukrain activity
The influence of glucose, succinate, and the pH of the medium on the cytotoxic activity of the preparation Ukrain was studied. It was established that glucose (5 mmol) reduces the cytotoxic activity of Ukrain, while succinate (5 mmol) increases it. The activity of the preparation was practically absent at pH 6.1-6.7 of the incubation medium and was at a maximum at pH 7.3-8.0. A temperature of 41.5 degrees C has no influence on the effectiveness of Ukrain.

Therapeutic Substance(s):