Ukrain

Ukrain (NSC-631570) is claimed to be a semisynthetic compound of thiophosphoric acid (triaziridide) and the alkaloid chelidonine derived from the common weed, Chelidonium majus (greater celandine), which grows primarily in Europe and Asia.1 Ukrain is not a licensed drug in any of the EU countries. Information is lacking regarding the purity of the preparation.

Description of treatment method

Ukrain is most commonly administered intravenously. It is claimed that it consists of one molecule of thiophosphoric acid conjugated to three molecules of chelidonine.

History / providers

Ukrain was developed in 1978 by Dr. Wassil J. Nowicky, director of the Ukrain Anti-Cancer Institute of Vienna, Austria and first presented at the 13th International Congress of Chemotherapy in Vienna in August 1983. In 2004 and 2006, Nowicky was nominated for the Nobel Prize in Chemistry. The manufacturers of Ukrain is Nowicky Pharma, A-1040 Vienna, Austria.

Extracts from Chelidonium majus, a poisonous plant, were traditionally used for liver and gallbladder complaints, loss of appetite and gastroenteritis, although none of these indications are supported by trial evidence. Chelidonium majus contains a range of more than 30 alkaloids, most notably isochinolin derivatives (chelidonine, coptisine, berberin etc.). Chelidonine has antispasmodic, weak central analgesic and papaverine-like effects. Chelidonium majus extracts have been shown to stimulate production of bile and pancreatic digestive enzymes in human studies.2

Thiotepa is a chemotherapy drug and cancer chemotherapeutic member of the alkylating agent group and is derived from aziridine and thiophosphoryl chloride and its main toxicity is myelosuppression.37

Ukrain has been described as a semi-synthetic Chelidonium majus alkaloid derivative, consisting of three chelidonine alkaloids combined to triaziridide. Panzer et al found the actions of Ukrain to be similar to the Chelidonium majus alkaloids it is prepared from.8 Thus, they wanted to assess its chemical integrity. Chemical analyses of Ukrain was inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine).

In another study the same team found the antimitotic actions of Ukrain to be reversible in low doses in vitro.30 They suggest that the lack of adverse effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling cells to overcome the metaphase arrest and survive.

Serious doubts have been voiced concerning the chemical purity of the allegedly semi-synthetic mixed preparation from alkaloids of Chelidonium majus L and thiotepa.33 No thiotepa was contained in the Ukrain sample they investigated. Nowicky later on also claimed that the free thiotepa is removed out of the compound and that what is left is the Ukrain molecule and parts of the Chelidonium extract.41

Claim of efficacy / mechanisms of action / alleged indication

Several reports describe Eastern European clinical trials using Ukrain for people with various types of cancer.3 These findings cannot be applied to greater celandine because the alkaloids have been modified from their original form. The mechanism of action of Ukrain is unknown whereas the mechanism of action of thiotepa is known. The drug works by damaging the DNA of cells, leaving the cell unable to divide. Without cell division, the tumour cannot grow and spread.

Proposed activity of Ukrain includes cytotoxicity from effects on cellular oxygen consumption, inhibition of DNA, RNA, and protein synthesis, and induction of apoptosis. In vitro studies demonstrate weak inhibition of tubulin polymerization causing arrest at G2/M phase of the cell cycle. Limited in vitro data support the claim that Ukrain has selective cytotoxicity against cancer cells. Ukrain also is promoted for its claimed ability to increase total T-cell count and T-helper lymphocytes, while decreasing T-suppressor cells. In vitro activation of splenic lymphocytes also was reported.6 8 34

Various claims of efficacy of Ukrain exist, which have so far not been backed up by compelling scientific evidence. For instance, the producer of Ukrain claims that:

• It is toxic against cancer cells at the therapeutic dose but not against healthy cells.
• It accumulates at the site of the tumour very rapidly after injection and brings about the encapsulation of larger tumours through anti-angiogenesis, thereby increasing operability.
• It regenerates the immune system.

Antineoplastic and immunomodulatory effects have been suggested. For instance it has been suggested that the alkaloids interfering with the metabolism of cancer cells diminish synthesis of DNA, RNA and proteins. It has also been suggested that cellular oxygen consumption may be inhibited and thus a programmed cell death of malignant cells is thought to be induced.4

Prevalence of use

No data exist to estimate the prevalence of use of Ukrain by cancer patients.

Legal issues

Ukrain has no drug approval in the EU. In the UK, Ukrain neither has a marketing authorisation nor is it registered under the ‘traditional use’ label. It is not FDA-approved in the US but is approved in Mexico, and the United Arab Emirates as a standard anticancer medication. According to the manufacturer, NSC 631570 (=Ukrain) has drug licences in several states of the former Soviet Union (Ukraine, Georgia, Turkmenistan, Belarus/White Russia, Azerbaijan Republic, Tadshikistan, and the Ukraine. Ukrain has also been designated as an Orphan Drug for pancreatic cancer in the USA and in Australia.28

In 2006, Dr Wassil Nowicky submitted a complaint as set out in Article 34, European Convention on Human Rights to the President of the European Court of Human Rights of the European Council regarding a rejection for the application for authorisation of the preparation Ukrain as a cancer therapy.

Costs and expenditures

The costs of Ukrain therapy are high; one course costs €700 for the medication alone, and the total treatment costs have been estimated to be around €3,000 per week.22

For ten injections of 10-20 mg intravenously the total cost of medication itself is approximately $3,500.00 (€2,891). This includes shipping, handling, bank transfer and prescription.

Controlled trials

There are seven RCTs assessing the efficacy of Ukrain for various cancer types.5 The majority of these studies were published in two different journals between 1995 and 2002 by four different groups of authors, three from the Belarus and one from Germany. They relate to colorectal 14 15 rectal 16 bladder 17 pancreatic 18 20 and breast cancers.19

1. Manufacturer trials

The results of the 6 trials carried out in Belarus suggest in all cases that Ukrain is effective in inhibiting cancer progression. All of these 6 controlled trials were published with Ukrain manufacturers’ financial involvement. Severe limitations in methodological quality of these trials prevent any firm conclusions and independent replication of the results is needed.

Susak et al published an RCT in which 108 colorectal cancer patients received either Ukrain as a monotherapy or 5-fluororacil for an unspecified time duration.14 The results suggest that this was followed by non-progression of the malignancy in 88.8% of the patients in the experimental group compared to 27.7% in the control group. This study is only reported in abstract form. Numerous methodological details are therefore not accessible and the methodological quality of the design procedure cannot be assessed.

One year later, the same research group published a similar clinical trial, this time including 96 colorectal carcinoma patients. 15 Forty-eight patients received Ukrain as a monotherapy and 48 patients received 5-fluorouracil and X-ray therapy. The survival rate between the groups differed substantially. Two-year survival was 78.6% in the experimental group compared to 33.3% in the control group. This study, although not blinded, applied an appropriate method of randomisation.

Bondar et al treated 48 histologically verified rectal cancer patients either with X-ray therapy, chemotherapy and surgery (control group) or with Ukrain and surgery (experimental group).16 Before and after these treatments, the authors measured 19 different laboratory parameters including two tumour markers. In addition, the Karnofsky Index, tumour dimensions, and recurrences were monitored. All of these variables strongly favoured Ukrain therapy over conventional treatment. This study has, however, numerous limitations. For instance, the method of randomisation was not explained; the authors merely stated that “all patients were subdivided into two randomised groups”. Moreover, “tumour dimensions” were mentioned as an outcome measure but neither the methodology of measurement nor any results were provided. The recurrence rates are expressed as percentage figures and no test statistics seem to have been applied.

Uglyanitsa et al conducted a study with 28 patients suffering from bladder cancer.17 Their aim was “to evaluate the efficacy of Ukrain”. Patients were allocated to three groups treated with a total dose of 100, 200, or 300 mg Ukrain. Two weeks later tumour regression was verified through cytoscopy and ultrasound. Complete and partial regression were noted in 0/4 patients of group 1, 1/4 patients of group 2, and 2/6 patients of group 3. This study lacks many characteristics of a rigorous trial; its stated aims (to evaluate efficacy) cannot be achieved with the study design which essentially was that of an equivalence trial.

Zemskov and colleagues published a “pilot study” with 42 patients suffering from pancreatic cancer who had refused chemotherapy.18 They were randomised to receive either Vitamin C alone or with Ukrain (total dose 100 mg/patient). The primary endpoint (survival) strongly favoured the Ukrain group. The analysis seems to include 4 protocol violations (the description is unclear). Even though the randomisation procedure is mentioned (‘closed envelopes’) it is unusual that 21 patients ended up in both groups. The results are surprisingly good – much better than with any other treatment for that condition.

Uglyanitsa et al randomised (“by lottery”) 75 breast cancer patients into three groups of 25 patients each.19 They received either no specific treatment, a total dose of 50 mg or 100 mg Ukrain 5-7 days before mastectomy. The authors note that Ukrain rendered the primary tumour and the affected regional lymph nodes larger, harder and “more clearly defined”. They interpret this as Ukrain-induced tumour sclerosis. According to the investigators’ judgement, these changes facilitated the operative success. In addition, Ukrain was associated with remarkable symptomatic improvements, e.g. better appetite, more sleep, less weakness. The report is unclear in several respects. For instance, no details about statistical analyses are provided, the outcome measures seem subjective, no information regarding investigator blinding is given, and the randomisation procedure seems suspect.

Zemskov and colleagues randomised 42 patients with pancreatic cancer who had refused conventional therapy.20 They received either Ukrain (total dose 100 mg/patient) with Vitamin C or Vitamin C alone. The results confirmed this group’s earlier findings 18. Survival was remarkable in the Ukrain treated patients and symptoms responded well to this treatment. There are, however, numerous puzzling details, for instance do the authors call this a “pilot study”, a proper randomisation surprisingly resulted in two equally sized groups of 21. Furthermore, in the discussion section, the authors describe their earlier results as though this trial was conducted against 5-FU which, in fact, it was not 18.

2. Independent trials

One trial was carried out independently of the manufacturer's involvement.21 Gansauge et al reported a study of 90 patients with pancreatic cancer treated either with 1000 mg gemcitabine / m2 or 100 mg Ukrain or the combination of both regimens. Survival rates suggested that Ukrain was superior to gemcitabine alone. Remarkably, a direct comparison of the 12 month survival rates revealed large differences compared to the data from Zemskov et al 20 (29% vs 76% in the Ukrain-treated groups). The randomisation procedure was not explained and, again, the equal group sizes is noteworthy.

In a German publication the results and authority of Gansauge et al's study was questioned.39 Furthermore, in a recent publication in a German magazine scientific Professor Beger who led this investigation was accused of manipulating the outcome of this clinical study in order to push Ukrain on to the market.40 Berger is a specialist in pancreatic carcinomas. The article also mentions financial sponsorship through the Ukrain manufacturer. Professor Berger denied all accusations.

Uncontrolled trials

In an uncontrolled trial at a German clinic, 203 advanced cancer patients with different types of cancer were treated with Ukrain.12 Seventy-six patients (37.4%) were simultaneously treated with regional deep hyperthermia in which tumour tissue was heated to >42.5 degrees C. Several patients additionally received selenium, cimetidine, thymus extract and vitamin A. Forty-one patients (20.2%) achieved total remission, 122 (60.1%) partial remission and only 40 (19.7%) did not respond to treatment. The highest response rates were in patients with seminoma and in prostate cancer.

In 2007, Gansauge et al carried out an uncontrolled clinical trial to assess the clinical effects of adjuvant systemic chemotherapy with gemcitabine and NSC-631570 in patients with advanced pancreatic cancer.13 They included 30 patients in all of which a R0 resection and lymph node resection were performed. Adjuvant chemotherapy consisted of several cycles of weekly gemcitabine infusions (1000mg/sqm) and 20mg of NSC-631570 for 3 weeks followed by one week without treatment. Results showed that after more than 5 years follow-up, 6 patients were still alive without having been affected by disease recurrence. In 24 patients local recurrence or metastases were observed. The median relapse-free survival time was 21.7 months (76.6% after 1 year, 50% after 2 years, 30% after 3 years and 20% after 5 years). Survival rates were 86.7% after 1 year, 76.6% after 2 years, 46.7% after 3 years and 23.3% after 5 years.

Case series

Several case reports exist for the use of Ukrain in cancer patients. Invariably they suggest Ukrain to be effective in terms of antitumour activity.e.g.9 10 11 However, it must be noted, that all case reports were published by the same team of authors.

Pre-clinical studies

Animal experiments and in vitro studies have been carried out, many of which suggested that Ukrain has anticancer activity in a wide range of cell lines. At least 35 in-vitro and 45 animal experiments have been published that all assess the biological mechanism of Ukrain.5 In-vitro studies have demonstrated weak inhibition of tubulin polymerization, causing arrest at G2/M phase of the cell cycle.6 7 8

Habermehl et al carried out a study in order to elucidate the importance of apoptosis induction for antineoplastic activity of Ukrain, to define the molecular mechanisms of its cytotoxic effect and to identify its active constituents by mass-spectrometry. 36 For doing so they induced apoptosis into a T-lymphoma cell model. Results showed that Ukrain was a strong inducer of apoptosis but researchers suggest this is not due to the suggested so-called “Ukrain molecule” but to the cytotoxic efficiency of Chelidonium majus alkaloids induced chelidonine.

A German team of scientists compared the in vitro toxicity of Ukrain, thiotepa and Chelidonium majus alkaloids with the cytotoxicity of the standard anticancer drugs doxorubicin, cyclophosphamide and etoposide against 4 well-characterized human Ewing tumor cell lines.32 They found that doxorubicin was the most cytotoxic drug followed by cyclophosphamide. Ukrain and the Chelidonium majus alkaloids were slightly more cytotoxic than etoposide while thiotepa showed the lowest cytotoxicity. Those in vitro results indicate that the cytotoxicity of Ukrain against Ewing tumors is comparable to that of etoposide.

Finally, it was the aim of another German study to investigate the effects of different doses of Ukrain on cell survival, alteration of the cell cycle and induction of apopotosis and those were examined without and in combination with ionizing radiation (IR). 38 Researchers were using exponentially growing breast, pancreas, colorectal, glioblastoma, human skin and fibroblastic tumour cell lines and applied colony assays, flow cytometry and Western blotting. Results showed that Ukrain cytotoxicity was time- and dose-dependent. When combining Ukrain with IR enhanced toxicity was found in colorectal and glioblastoma cells only. A radioprotective effect was observed in normal human skin and lung fibroblast cells. The researchers suggest that Ukrain may have potential properties for clinical radiochemotherapy.

However, some studies suggest that there was no evidence to suggest selective cytotoxicity previously reported for Ukrain and that high-performance liquid chromatography and liquid chromatography-mass spectrometry was inconsistent with the proposed trimeric structure.30 33

Research carried out at the National Cancer Institute (Bethesda, Maryland, USA) where Ukrain was tested on the screening panel with 60 cell lines from eight human cancer types it was revealed to be cytotoxic against all the solid cancer cell lines tested.35

While common anticancer drugs are toxic both against cancer and normal cells (cytostatics), Ukrain is allegedly only toxic against cancer cells (“malignocytolytic”).

One of the main dangers with the application of Ukrain as is that conventional, possibly helpful treatment may not be sought, or onset of conventional treatment may be delayed. Ukrain is claimed to contain a derivative of thiophosphoric acid, which could cause severe and life-threatening adverse effects.

A literature review of possible cases caused by Chelidonium majus found that it may induce hepatitis and several cases of hepatitis-induced by consumption of Chelidonium majus were found. 31 The researchers suggest there might be a probable relationship between liver injury and consumption of Chelidonium majus and thus, there may be increased safety concerns about its oral use.

Contraindications

No contraindications of Ukrain have been given by providers, proponents or manufacturer but see above comments. Like with all orally applied medicines, the use of Ukrain during pregnancy and lactation are contraindicated.

Precautions/warnings

Extracts of Chelidonium majus have been implicated in causing hepatitis.24 25 26 Ukrain contains a derivative of thiophosphoric acid, which could cause adverse effects, contraindications and/or interactions associated with other hazardous drugs of this class of chemicals.

Adverse effects

Soreness at injection site, nausea, diarrhoea, dizziness, fatigue, drowsiness, polydipsia, polyuria, and slight fever have been reported.6 23 Haematological side effects and tumour bleeding were reported in a recent phase II trial. Severe bone marrow toxicity may occur after 15 to 20 days of treatment.21 Liver toxicity has been observed.27

Interactions

None known but see comment above.

Quality issues

None known.

Acknowledgement

The authors would like to thank Klara Rombauts for her valuable support during the update of the summary.