Ukrain

Katja Boehm, Edzard Ernst and the CAM Cancer Consortium | Published 15/09/2020

Abstract and key points
What is it?
Does it work?
Is it safe?
References

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.

Numerous pre-clinical and clinical investigations seem to suggest that Ukrain is pharmacologically active and clinically effective. Data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, several limitations in the studies prevent any conclusion.

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.

Document history

Latest update: September 2020

Next update due: September 2023

Citation

Katja Boehm, Edzard Ernst, CAM Cancer Consortium. Ukrain [online document], August 25, 2020.

Acknowledgement

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

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 Asia1.

Ingredients/Components

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 from2.

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)2.

Serious doubts have been voiced concerning the chemical purity of the allegedly semi-synthetic mixed preparation from alkaloids of Chelidonium majus L and thiotepa3. 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 myelosuppression4. 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 extract5.

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.

History / providers

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. In 2004 and 2006, Nowicky was nominated for the Nobel Prize in Chemistry. The manufacturer of Ukrain is Nowicky Pharma, A-1040 Vienna, Austria.

Claims of efficacy / mechanisms of action / alleged indication

Several reports describe Eastern European clinical trials using Ukrain for people with various types of cancer.6 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 reported2,7,8.

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 induced9.

The antimitotic actions of Ukrain have been found to be reversible in low doses in vitro10. 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.

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 that11:

  • 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.

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 Australia12.

Dr Wassil Nowicky has submitted complaints to the European Court of Human Rights on account of “unlawful rejection of an approval application”13.

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 week14. For ten intravenous injections of 10-20 mg the total cost of medication itself is approximately (€2,900). This includes shipping, handling, bank transfer and prescription.

Controlled trials

There are seven RCTs assessing the efficacy of Ukrain for various cancer types15. 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 colorectal16,17, rectal18, bladder19, pancreatic20,21, and breast cancers22.

The results of the six trials carried out in Belarus suggest in all cases that Ukrain is effective in inhibiting cancer progression16-22. All of these six 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.

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 regimens23. Survival rates suggested that Ukrain was superior to gemcitabine alone. The results and authority of Gansauge et al's study were subsequently questioned24. 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 market25. The article also mentions financial sponsorship through the Ukrain manufacturer. Beger 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 Ukrain26. 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 cancer27. The authors report prolonged survival rates with this combination.

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.28-30 However, it must be noted that all case reports were published by the same team of authors.

Pre-clinical studies

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 Ukrain3,10. 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 tested31.

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 lines15,32-36.

Adverse events

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 found37. The researchers suggest there might be a probable relationship between liver injury and consumption of Chelidonium majus.

Contraindications

No contraindications of Ukrain have been given by providers, proponents or manufacturer11. Like with all orally applied medicines, the use of Ukrain during pregnancy and lactation are contraindicated.

Precautions/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.

Adverse effects

Soreness at injection site, nausea, diarrhoea, dizziness, fatigue, drowsiness, polydipsia, polyuria, and slight fever have been reported21,38. 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 treatment23. Liver toxicity has been observed39.

Interactions

None known but see comment above.

Quality issues

None known.

  1. Weiss RF. Herbal Medicine. Gothenburg, Sweden: Ab Arcanum and Beaconsfield, UK: Beaconsfield Publishers Ltd, 1985, 84–8.
  2. Panzer A, Hamel E, Joubert AM, Bianchi PC, Seegers JC. 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. Accessed 15th of September 2020.
  3. Panzer A, Joubert AM, Eloff JN, Albrecht CF, Erasmus E, Seegers JC. Chemical analyses of Ukrain, a semi-synthetic Chelidonium majus alkaloid derivative, fail to confirm its trimeric structure. Cancer Lett. 2000;160(2):237-41. Accessed 15th of September 2020.
  4. 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. Accessed 15th of September 2020.
  5. US 2006/0154947 A1 (2006-06-13) Wassyl Nowicky, Quaternary chelodine and alkaloid derivates, processes for their preparation and their use in manufacture of medicaments. [Patent]. Accessed 15th of September 2020.
  6. Susak YM, Zemskov VS, Yaremchuk OY, et al. Comparison of chemotherapy and x-ray therapy with Ukrain monotherapy for colorectal cancer. Drugs Exptl Clin Res 1996;22:115–22. Accessed 15th of September 2020.
  7. 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. Accessed 15th of September 2020.
  8. Colombo ML, Bosisio E. Pharmacological activities of Chelidonium majus L. (papaveracea). Pharmacol Res 1996;33:127-34. Accessed 15th of September 2020.
  9. 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. Accessed 15th of September 2020.
  10. Panzer A, Joubert AM, Bianchi PC, Seegers JC. The antimitotic effects of Ukrain, a Chelidonium majus alkaloid derivative, are reversible in vitro. Cancer Lett. 2000;150(1):85-92. Accessed 15th of September 2020.
  11. Ukrainian Ant Cancer Institute. Accessed 15th of September 2020.
  12. Ukrainian Anti Cancer Institute. Accessed 15th of September 2020.
  13. Hopf G. Ukrain® - Fortschritt oder Rückschritt in der medikamentösen Therapie onkologischer Erkrankungen? Deutsche Zeitschrift für Onkologie 2002;34:31-6. Accessed 15th of September 2020.
  14. Ernst E. Schmidt K. Ukrain – a new cancer cure? A systematic review of randomised clinical trials. BMC Cancer 2005;5:69-75. Accessed 15th of September 2020.
  15. 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. Accessed 15th of September 2020.
  16. 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. Accessed 15th of September 2020.
  17. 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. Accessed 15th of September 2020.
  18. Uglyanitsa KN, Nechiporenko NA, Nefyodov LI, Brzosko WJ. Ukrain therapy of stage T1NOMO bladder cancer patients. Drugs Exp Clin Res 1998;24:227-30. Accessed 15th of September 2020.
  19. 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. Accessed 15th of September 2020.
  20. 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.  Accessed 15th of September 2020.
  21. 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. Accessed 15th of September 2020.
  22. 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. Accessed 15th of September 2020.
  23. Arzneimittelbrief. Phase-II-Studie zur Behandlung des fortgeschrittenen, inoperablen Pankreaskarzinoms mit Ukrain. AMB 2002;(5):39a. Accessed 15th of September 2020.
  24. Der Spiegel (20. September 2008). Berühmter Chirurg soll wissenschaftliche Studien manipuliert haben. Spiegel 39/2008. Accessed 15th of September 2020.
  25. Aschhoff B. Retrospective study of Ukrain treatment in 203 patients with advanced-stage tumors. Drugs Exptl Clin Res 2000;25:249-52. Accessed 15th of September 2020.
  26. 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. Accessed 15th of September 2020.
  27. Prokopchuk OL, Zemskov SV, Susak YM. Ukrain treatment in a patient with metastatic renal cell carcinoma extending to the vena cava inferior. Case report. Drugs Exp Clin Res 2000;26:257-9. Accessed 15th of September 2020.
  28. Prokopchuk OL, Zemskov SV, Susak YM. Ukrain treatment of a patient with retroperitoneal synovial sarcoma. Case report. Drugs Exp Clin Res 2000;26:255-6. Accessed 15th of September 2020.
  29. Zemskov SV, Prokopchuk OL, Susak YM. Ukrain treatment in a patient with breast carcinoma. Case report. Drugs Exp Clin Res 2000;26:253-4. Accessed 15th of September 2020.
  30. Results from National Cancer Institute Austria, Human Tumor Cell Line Screen, Nowicky Pharma. Accessed 15th of September 2020.
  31. 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. Accessed 15th of September 2020.
  32. 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. Accessed 15th of September 2020.
  33. 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. Accessed 15th of September 2020.
  34. 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. Accessed 15th of September 2020.
  35. 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. Accessed 15th of September 2020.
  36. 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.
  37. Danysz A, Kokoschinegg M, Hamler F. Clinical studies of Ukrain in healthy volunteers (phase1). Drugs Exp Clin Res 1992;18:39-43.  Accessed 15th of September 2020.
  38. Stickel F, Seitz HK, Hahn EG, Schuppan D: [Liver toxicity of drugs of plant origin]. Z Gastroenterol 2001; 39(3):225-227. Accessed 15th of September 2020.

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