Ukrain

Ukrain is a drug based on the extract of the plant Chelidonium majus L (greater chelandine). It is claimed to be effective against a range of cancers.

Anticancer treatment

  • Disease progression: The evidence (1 SR of 7 RCTs) is unclear; although the results of 7 RCTs suggest that Ukrain is effective in inhibiting cancer progressions, all trials have severe methodological limitations.

No serious adverse effects are on record for Ukrain but warning must be given for certain components of Ukrain. These include Chelidonium majus (greater celandine) for which reports of hepatitis exist, and thiophosphoric acid. Mild to severe adverse events such as tumour bleeding and liver toxicity have been reported.

Citation

Wider B, Mora D, CAM Cancer Collaboration. Ukrain [online document], Oct 26, 2023.

Document history

Last revised in October 2023 by Barbara Wider and Dana Mora. Assessed as up to date in September 2020, January 2019, February 2017, February 2015 and February 2013 by Barbara Wider. Updated in February 2012 by Katja Boehm. First authored in May 2009 by Katja Boehm. Next update due: October 2026

Description

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 chelandine), which grows primarily in Europe and Asia (Weiss 1985).

Ukrain was developed in 1978 by Dr. Wassil J. Nowicky, director of the Ukrainian Anti-Cancer Institute of Vienna, Austria and first presented at the 13th International Congress of Chemotherapy in Vienna in August 1983. The manufacturer of Ukrain is Nowicky Pharma, Vienna, Austria (UACI 2023).

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

Ingredients and quality issues

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 (Panzer 2000a).

Chelidonium majus contains a range of more than 30 alkaloids, most notably isochinolin derivatives (chelidonine, coptisine, berberin etc.). Chemical analyses of Ukrain were 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) (Panzer 2000a). Serious doubts have been voiced concerning the chemical purity of the allegedly semi-synthetic mixed preparation from alkaloids of Chelidonium majus L and thiotepa (Panzer 2000b). 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 (van Maanen 2001). 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 (Nowicky 2006).

Alleged indications

The website of Ukrain’s manufacturer Nowitzky Pharma makes several claims for Ukrain which have so far not been backed up by compelling scientific evidence:

- treats cancer
- is the only drug which accumulates quickly and only in cancer tissue
- makes each metastasis visible due to autofluorescence.

At least 35 in-vitro and 45 animal experiments have been published that all assess the biological mechanism of Ukrain which suggest that Ukrain has anticancer activity in a wide range of cell lines (Habermehl 2006, Cordes 2002, Susak 2010, Barnerjee 2010, Funel  2010)

While common anticancer drugs are toxic both against cancer and normal cells (cytostatics), Ukrain is allegedly only toxic against cancer cells (“malignocytolytic”). Some studies suggest that there was no evidence to suggest selective cytotoxicity previously reported for Ukrain (Panzer 2000b, Panzer 2000c) . Research carried out at the National Cancer Institute 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 (NCIA 1990).

Application and dosage

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

Mechanisms of action

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.

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 (Panzer 2000a, Uglyanitsa 2000, Colombo 1996) .

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 (Jagiello-Wojtowicz 1998).

The antimitotic actions of Ukrain have been found to be reversible in low doses in vitro (Panzer 2000c). They suggest that the lack of adverse effects observed in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling cells to overcome the metaphase arrest and survive.

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, and has been designated as an Orphan Drug for pancreatic cancer in the USA and in Australia (Nowicky Pharma).

There are seven RCTs available assessing the efficacy of Ukrain for various cancer types (Ernst 2005). They relate to colorectal (Susak 1995, Susak 1996), rectal (Bondar 1998), bladder (Uglyanitsa 1990), pancreatic (Zemskov 2000, Uglyanitsa 2000), and breast cancers (Zemskov 2002). The majority of these studies were published in two different journals between 1995 and 2002 by four different groups of authors, three from Belarus and one from Germany. All of these trials were published with Ukrain manufacturers’ financial involvement.

Description of included studies

The systematic review on Ukrain for cancer treatment (Ernst 2005) reports that the results of the six controlled trials carried out in Belarus suggest in all cases that Ukrain is effective in inhibiting cancer progression (Susak 1995, Susak 1996, Bondar 1998, Zemskov 2000, Uglyanitsa 2000, Zemskov 2002).  Severe limitations in methodological quality of these trials prevent any firm conclusions and independent replication of the results is needed. (Ernst 2005)

The study by Gansauge et al reported a study of 90 patients with pancreatic cancer treated either with 1000mg gemcitabine/m2 or 100mg Ukrain or the combination of both regimens (Gansauge 2002). Survival rates suggested that Ukrain was superior to gemcitabine alone. The results and authority of Gansauge et al's study were subsequently questioned (Arzneimittelbrief 2002). The principal investigator, Hans G Beger, a specialist in pancreatic carcinomas was accused of manipulating the outcome of this clinical study in order to push Ukrain on to the market (Der Spiegel 2008). The article also mentions financial sponsorship through the Ukrain manufacturer. Beger denied all accusations.

In an uncontrolled trial at a German clinic, 203 advanced cancer patients with different types of cancer were treated with Ukrain (Aschhoff 2000). The authors report surprising remission rates with the highest response rates observed in patients with seminoma and prostate cancer. Some patients were, however, concomitantly treated with regional deep hyperthermia, selenium, cimetidine, thymus extract and vitamin A.

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 30 patients with advanced pancreatic cancer (Gansauge 2007). The authors report prolonged survival rates with this combination.

Adverse effects

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 (Moro 2009). The researchers suggest there might be a probable relationship between liver injury and consumption of Chelidonium majus.

Soreness at injection site, nausea, diarrhoea, dizziness, fatigue, drowsiness, polydipsia, polyuria, and slight fever have been reported (Uglyanitsa 2000, Danysz 1992, 1992). Haematological side effects and tumour bleeding were reported in a phase II trial. Severe bone marrow toxicity may occur after 15 to 20 days of treatment (Gansauge 2000). Liver toxicity has been observed (Stickel 2001).

Contraindications

No contraindications of Ukrain have been given by providers, proponents or manufacturer (UACI 2023). Like with all orally applied medicines, the use of Ukrain during pregnancy and lactation are contraindicated.

Interactions

None known but see comment above.

Warnings

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.

Arzneimittelbrief. Phase-II-Studie zur Behandlung des fortgeschrittenen, inoperablen Pankreaskarzinoms mit Ukrain. AMB 2002;(5):39a. Accessed 15th of September 2020.

Aschhoff B. Retrospective study of Ukrain treatment in 203 patients with advanced-stage tumors. Drugs Exptl Clin Res 2000;25:249-52. 

Banerjee A, Pathak S, Biswas SJ, Roy-Karmakar S, Boujedaini N, Belon P et al. Chelidonium majus 30C and 200C in induced hepato-toxicity in rats. Homeopathy: the Journal of the Faculty of Homeopathy 2010; 99(3):167-176. 

Bondar GV, Borota AV, Yakovets YI, Zolotukhin SE. Comparative evaluation of the complex treatment of rectal cancer patients (chemotherapy and X-ray therapy, Ukrain monotherapy). Drugs Exp Clin Res 1998;24:221-6. 

Colombo ML, Bosisio E. Pharmacological activities of Chelidonium majus L. (papaveracea). Pharmacol Res 1996;33:127-34. 

Cordes N, Plasswilm L, Bamberg M, Rodemann HP. Ukrain, an alkaloid thiophosphoric acid derivative of Chelidonium majus L. protects human fibroblasts but not human tumour cells in vitro against ionizing radiation. Int J Radiat Biol 2002;78(1):17-27. 

Danysz A, Kokoschinegg M, Hamler F. Clinical studies of Ukrain in healthy volunteers (phase1). Drugs Exp Clin Res 1992;18:39-43.  

Der Spiegel (20. September 2008). Berühmter Chirurg soll wissenschaftliche Studien manipuliert haben. Spiegel 39/2008. Accessed Accessed 25th October 203.

Ernst E. Schmidt K. Ukrain – a new cancer cure? A systematic review of randomised clinical trials. BMC Cancer 2005;5:69-75. 

Funel N, Costa F, Pettinari L, Taddeo A, Sala A, Chiriva-Internati M et al. Ukrain affects pancreas cancer cell phenotype in vitro by targeting MMP-9 and intra-/extracellular SPARC expression. Pancreatology 2010; 10(5):545-552. 

Gansauge F, Ramadani M, Pressmar J, Gansauge S, Muehling B, Stecker K, Cammerer G, Leder G, Beger HG. NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer. Results of a phase II trial. Langenbecks Arch Surg 2002;386:570-4. 

Gansauge F, Ramadani M, Schwarz M, Beger HG, Lotspeich E, Poch B. The clinical efficacy of adjuvant systemtic chemotherapy with gemcitabine and NSC-631570 in advanced pancreatic cancer. Hepato-Gastroenterology 2007;54:917-20. 

Habermehl D, Kammerer B, Handrick R, Eldh T, Gruber C, Cordes Net al. Proapoptotic activity of Ukrain is based on Chelidonium majus L. alkaloids and mediated via a mitochondrial death pathway. BMC Cancer 2006;6:14. 

Hopf G. Ukrain® - Fortschritt oder Rückschritt in der medikamentösen Therapie onkologischer Erkrankungen? Deutsche Zeitschrift für Onkologie 2002;34:31-6. 

Jagiello-Wojtowicz E, Kleinrok Z, Urbanska EM. Ukrain (NSC-631570) in experimental and clinical studies: a review. Drugs Exp Clin Res 1998;24:213-9. 

Moro PA, Cassetti F, Giugliano G, Falce MT, Mazzanti G, Menniti-Ippolito Fet al. Hepatitis from Greater celandine (Chelidonium majus L.): Review of literature and report of a new case. J Ethnopharmacol 2009;124(2):328-32. Accessed 15th of September 2020.

National Cancer Institute Austria (NCIA) Results,  Human Tumor Cell Line Screen, Nowicky Pharma.1990 

Nowicky Pharma, Accessed 24th of October 2023.

Nowicky W (2006), Quaternary chelodine and alkaloid derivates, processes for their preparation and their use in manufacture of medicaments. (US 2006/0154947 A1 (2006-06-13) [Patent]. 

Panzer A, Hamel E, Joubert AM, Bianchi PC, Seegers JC. (2000a). Ukrain (TM), a semisynthetic Chelidonium majus alkaloid derivative, acts by inhibition of tubulin polymerization in normal and malignant cell lines. Cancer Lett 2000;160(2):149-57.

Panzer A, Joubert AM, Eloff JN, Albrecht CF, Erasmus E, Seegers JC. (2000b). Chemical analyses of Ukrain, a semi-synthetic Chelidonium majus alkaloid derivative, fail to confirm its trimeric structure. Cancer Lett. 2000;160(2):237-41. 

Panzer A, Joubert AM, Bianchi PC, Seegers JC. (2000c) The antimitotic effects of Ukrain, a Chelidonium majus alkaloid derivative, are reversible in vitro. Cancer Lett. 2000;150(1):85-92. 

Stickel F, Seitz HK, Hahn EG, Schuppan D: [Liver toxicity of drugs of plant origin]. Z Gastroenterol 2001; 39(3):225-227.

Susak YM, Skivka LM, Rudik MP, Pozur VV, Liubunya AV, Susak YM et al. Comparative investigation of the effect of Ukrain on growth of ascite and solid forms of Ehrlich's carcinoma. Experimental Oncology 2010; 32(2):107-110. 

Susak YM, Yaremchuk OY, Zemskov VS, Kravchenko OB, Liepins A, Yatsyk IM et al. Randomised clinical study of Ukrain on colorectal cancer. Eur J Cancer 1995;31:S153 Abstract 733. 

Susak YM, Zemskov SV, Yaremchuk OY, Kravchenko OV, Yatsyk IM, Korsh OB. Comparison of chemotherapy and X-ray therapy with Ukrain monotherapy for colorectal cancer. Drugs Exp Clin Res 1996;22:115-22. 

Uglyanitsa KN, Nechiporenko NA, Nefyodov LI, Brzosko WJ. Ukrain therapy of stage T1NOMO bladder cancer patients. Drugs Exp Clin Res 1998;24:227-30. 

Uglyanitsa KN, Nefyodov LI, Brzosko WJ. Comparative evaluation of the efficiency of various Ukrain doses in the combined treatment of breast cancer. Report I. Clinical aspects of Ukrain application. Drugs Exp Clin Res 2000;26:223-30.  

Uglyanitsa KN, Nefyodov LI, Doroshenko YM, Nowicky JW, Volchek IV, Brzosko WJ, Hodysh YJ. Ukrain: a novel antitumour drug. Drugs Exp Clin Res 2000;56:347-56. 

Ukrainian Anti Cancer Institute (UACI). Accessed 15th of September 2023.

van Maanen MJ, Huitema AD, Rodenhuis S, Beijnen JH. "Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin". Anticancer Drugs 2001;12 (6): 519–24. 

Weiss RF. Herbal Medicine. Gothenburg, Sweden: Ab Arcanum and Beaconsfield, UK: Beaconsfield Publishers Ltd, 1985, 84–8.

Zemskov SV, Prokopchuk O, Susak Y, Zemskov S, Tkachenko O, Hodysh Y et al. Efficacy of Ukrain in the treatment of pancreatic cancer. Langenbecks Arch Surg 2002;387:84-9. 

Zemskov VS, Procopchuk OL, Susak YM, Zemskov SV, Hodysh YY, Zemskova MV. Ukrain (NSC-631570) in the treatment of pancreas cancer. Drugs Exp Clin Res 2000;26:179-90. 

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