Ukrain is the first and only anticancer drug which accumulates in cancer cells minutes after administration. In contrast to chemotherapy the drug destroys only cancer cells by inducing apoptosis (programmed cell death) while leaving healthy cells undamaged.

This drug has been approved as standard anticancer medication in some countries of Europe and Asia (for example, Ukraine: first approval on October 18, 1998, #3641, re-approval on September 2, 2003, #3641; United Arab Emirates: registration no. 4987-6179-1), Mexico (No. 036M2005 SSA). Ukrain has also been designated as an Orphan Drug for pancreatic cancer in the USA (Designation Request #03-1693) and also in Australia (File 004/009839).

Ukrain has saved the lives of many cancer patients. This is proved by the fact that patients who were the first to use the preparation as monotherapy against metastasising tumours have lived for 25 years without relapse. Ukrain causes the full regression of the main tumour and also of metastases. Many clinical studies have proved this, such as those of the work group led by Prof. Berger in Germany with pancreatic cancer. At therapeutic dose the product has no appreciable side-effects and does not damage healthy cells but only attacks cancer cells.

Due to its very high therapeutic index of 1250 – in contrast to common cytostatics with a low TI of 1.4-1.8 – there is no danger of an overdose with Ukrain therapy (therapeutic index - ratio of toxic dose to the therapeutic dose). Ukrain also does not cause necroses with intramuscular administration.

Through its antiangiogenic properties this medicine encapsulates tumours, thereby making them accessible to surgery. If possible, it is recommended to reduce the tumour burden within 10-14 days after the start of therapy.

The destruction of cancer cells with Ukrain is dose dependent. The higher the dose the more cancer cells are killed. Tumour degradation products such as amino acids, milk acid and others can release and induce transient local pain which can be treated with local sodium hydrogen carbonate compresses or oral intake of small quantities of sodium hydrogen carbonate solution (soda on knife top approx. 100-150 mg diluted in 250 ml water).

This pain can be also treated with sodium bicarbonate solution as an infusion, see
http://www.orthopaedie-dr-woelffle.de/neuraltherapie_neu_ulm.html
http://www.neuraltherapy.com/,   http://www.neuraltherapybook.com/

At small doses, this preparation has an immune-modulating effect and significantly enhances malignotoxic activity of macrophages, lymphocytes and NK-cells against various cancer cells, i.e. it has properties related to cell mediated immunity. Due to these immune effects it improves the general condition of patients. It is recommended to administer small doses of Ukrain immediately after surgery (during 3-5 days, 5 mg a day). It helps to regenerate the immune function, improve wound healing and rehabilitation and to prevent keloid scarring.

For successful treatment large doses of Ukrain should be alternated with small ones: large doses destroy tumours, small doses help to eliminate tumour degradation products. Therefore alternate doses are used in the course of Ukrain therapy, e.g. Monday 5 mg - Thursday 20 mg, or 5 – 30 mg, 5 – 40 mg, twice a week, with a two-day break after a small dose and a three-day break after a large one.

The mechanism of action of Ukrain has been tested on more than 100 cancer cell lines so far, including cisplatin-resistant lines, but also on normal cell lines. Ukrain has been proven to be effective against all cancer lines whereas normal lines were unaffected. In contrast to conventional cytostatics, which are toxic both against cancer and normal cells, Ukrain is toxic only against cancer cells and has been described as a malignotoxic agent.

Among other in vitro studies, Ukrain has been tested at the National Cancer Institute, Bethesda, Maryland, USA, on 60 cell lines representing eight important human malignant tumours: brain, ovarian, kidney, small cell and non-small cell lung carcinomas, colon cancer, leukaemia and melanoma. Ukrain was effective against all cell lines. In comparison with 5-fluorouracil (5-FU) and gemcitabine, two standard cytostatics in the treatment of abdominal carcinomas, Ukrain achieved better results having caused not only growth inhibition of cell lines but also reduction of cell mass. This advantage of Ukrain over 5-FU and gemcitabine was confirmed with clear clinical benefits in several randomised clinical studies.

96 patients with colorectal carcinomas were included in a randomised study conducted by Prof. Susak et al. from the National Medical University Kiev, Ukraine. 48 patients were treated with UKRAIN (15 of them with metastasing and 33 with non-metastasing colorectal tumours) and 48 patients were treated with 5-FU and radiotherapy. The survival rate after 21 months was 78.6% in the group treated with UKRAIN and 33.3% in the group treated with 5-FU and radiotherapy (Susak et al, 1996).

48 patients with rectal carcinomas participated in a randomised study carried out by Prof. Bondar et al. from the Regional Cancer Center, Donetsk, Ukraine. 24 patients received high-dosage radiotherapy and 5-FU before surgery, and another 24 patients received one series of UKRAIN therapy before surgery (10 mg on alternate days, up to a total dose of 60 mg) and one series after surgery (up to a total dose of 40 mg). During the following 14 months, 25% of patients who had received 5-FU and radiotherapy had relapses but only 8.3% of patients who had received UKRAIN. During the following two years, 33.3% of patients who had received 5-FU and radiotherapy had relapses but only 16.7% of the patients who had been treated with UKRAIN (Bondar et al, 1998).

90 patients with histologically verified advanced pancreatic cancer were treated in a controlled randomised study by Prof. Beger et al. at the University of Ulm, Germany. Patients in group A received gemcitabine 1000 mg/m2, those in group B received 20 mg UKRAIN, and those in group C received 1000 mg/m2 gemcitabine followed by 20 mg UKRAIN per week. Survival rates after six months were 26% in group A, 65% in group B and 74% in group C. The results showed that in inoperable advanced pancreatic cancer, survival rates were doubled using UKRAIN in combination with gemcitabine (Gansauge et al, 2002).
Patients were further observed after the conclusion of the study and it was noted that UKRAIN was well tolerated and could be administered without problem to all patients. UKRAIN brought about a significant increase in survival time in comparison to therapy with gemcitabine alone. Combination therapy with gemcitabine and UKRAIN showed no advantage over monotherapy with UKRAIN. The longest survival in the gemcitabine group was 19 months, 21 months in the gemcitabine+Ukrain group, and in the Ukrain group a patient was still alive after 28 months.

As one may gather from the study of Gansauge et al, 2003, from the University of Ulm: “as a result of this study we highly recommend the treatment of patients suffering from advanced pancreatic cancer with Ukrin.

The recent clinical study by the same group provided additional data on the benefit of a combined adjuvant treatment with Ukrain and gemcitabine. The relapse-free survival time was 21.7 months, and median survival 33.8 months which is clearly better than results reported in the literature, for example 20.4 months in the study by Kurosaki et al, 2004. The actuarial survival rates were 86.7% after one year, 76.6% after two years, 46.7% after three years and 23.3% after five years (these patients are still alive). Again, this publication supports the efficacy (and safety) of the use of Ukrain as it demonstrates a considerable prolongation of survival compared to what is known from other clinical studies (Gansauge et al, 2007).

The selective effect of Ukrain has been proven in many studies by researchers from various countries, for example:

• Hohenwarter et al, 1992
• Panzer and Seegers, 1998
• Roublevskaia et al, 2000
• Cordes et al, 2002
• Gagliano et al, 2007
• Mendoza et al, 2007.

In the study by Hohenwarter et al. the inhibitory effect of Ukrain on malignant and normal cells was compared. To obtain a 50% growth inhibition, a tenfold concentration had to be used with normal endothelial cells compared to a human osteosarcoma cell line. Laser scanning microscopy showed a high uptake of Ukrain in malignant cells while the content in normal cells under the same experimental conditions was substantially lower (Hohenwarter et al, 1992; used cell lines: human osteosarcoma and melanoma cell lines; human endothelial cells from umbilical vein).

At the 89th annual meeting of the American Association for Cancer Research in New Orleans, March 28 – April 1, 1998 A. Panzer and J.C. Seegers (University of Pretoria, South Africa) presented their work on the selective effect of Ukrain on various cancer cell lines. The authors concluded “that Ukrain is selectively toxic to malignant cells by causing a metaphase block which is characterised by abnormal chromosomal distribution, and results in the formation of micronuclei and in apoptosis” (Panzer and Seegers, 1998; used cell lines: human cervical carcinoma HeLa and human foreskin fibroblasts Hs27, squamous oesophageal cancer WHCO5; transformed human embryonic kidney Graham 293, and transformed African green monkey kidney Vero).

In the tests on epidermoid carcinoma cells A431 and ME180 as well as prostate cancer cell lines LNCaP, Roublevskaya et al. from Rochester University, USA revealed Ukrain to induce the G2M accumulation of cancer cells but not of normal cells. The researchers also observed an upregulation of CDK inhibitor p27 in cancer cell lines (Roublevskaya et al., 2000, 2000a; used cell lines: epidermoid carcinoma ME180 and A431, prostate cancer LNCaP; normal human keratinocytes HaCaT).

Cordes et al. from Eberhard-Karls-University Tubingen, Germany, investigated the effects of Ukrain on cell survival, alteration of the cell cycle and induction of apoptosis without and in combination with ionising radiation (IR). Ukrain modulated radiation toxicity of human cancer cell lines and protected normal cells from radiation. The combination of Ukrain plus IR gave enhanced toxicity in CCL-221 and U-138MG cells but not in MDA-MB-231 and PA-TU-8902 cells. A radioprotective effect was found in normal human skin and lung fibroblasts (Cordes et al, 2002; used human cell lines: breast carcinoma MDA-MB-231, pancreas carcinoma PA-TU-8902, colorectal cancer CCL-221, glioblastoma U-138MG; skin fibroblasts HSF1, HSF2, and lung fibroblasts CCD32-LU).

An Italian research group, Gagliano et al. from the University of Milan, used RT-PCR, Western blot and SDS-zymography to investigate the effects of Ukrain on the expression of genes and proteins involved in the extracellular matrix remodelling associated with tumour invasion in human cultured glioblastoma cells. There was a significant, dose-related decrease in glioblastoma cell proliferation and a tendency to the downregulation of SPARC (secreted protein acidic and rich in cysteine) after treatment with Ukrain, suggesting ‘the drug may be a useful therapeutic tool for brain tumours’ (Gagliano et al, 2006; used cell lines: human glioblastoma MI lines T60, T63, and GBM).

Researchers at the Instituto Nacional de Cancerologia, Mexico City, Mexico ‘revealed that Ukrain induced apoptosis in a panel of cancer cell lines by activating the intrinsic cell death pathway. Interestingly, nontransformed fibroblasts (hTERT) cell line was insensitive to the drug.’ (Mendoza et al, 2007; used cell lines: cervical cancer HeLa, HeKB, HeKS32, HeBcl3, HeNFR and HeIKK, human colon cancer SW480, human renal carcinoma HEK293, human osteosarcoma MG-63, and immortalised human fibroblasts hTERT).

In 2000 the group from South Africa published another article in which the selective mode of action of Ukrain was denied (Panzer et al, 2000). The authors did not explain the contradiction in the results of their two studies. The Ukrain opponents called the authors' group ‘independent’; however, the results of the second study could not be reproduced by any other research group.

This selective effect of Ukrain on cancer cells has been proven not only with autofluorescence under UV-light and pharmacokinetics but also in many in vitro experiments and several clinical studies.

The biggest wish of all oncologists has been to develop an agent that is only toxic against cancer cells. For a long time this aim was considered impossible. The drug Ukrain makes the dream a reality and has taken the first big step towards the solution of this problem.

The wide spectrum of cancer cell lines where Ukrain is effective explains its use in the treatment of various malignant tumours. In Ukraine, for example, Ukrain is officially registered for the treatment of various types of cancer.

Thanks to the unique properties of the preparation the inventor of this medicament was nominated for the Nobel Prize in 2005 (see www.ukrin.com/docs/lettertonobel.pdf) and for the Alternative Nobel Prize in 2007 (see www.ukrin.com/enclosures/nordfors.pdf).