Surgery, chemotherapy and radiotherapy are the three most important types of cancer treatment. However, each of them have their limitations and as well as considerable adverse effects. Surgery is the oldest treatment option and, if possible, is still frequently the method of first choice. Unfortunately curative surgical intervention is only possible in few cases; the residual tumour usually remains unrecognised, leading to tumour recurrence and metastazing. Additional treatment then comes into consideration.
Both radiation and chemotherapy do not have a selective effect against tumour cells, they are themselves carcinogenic (they cause cancer) and mutagenic (they damage chromosomes and change the genetic make-up).
Radiation therapy works by damaging the DNA of cancerous cells. This DNA damage is then passed on through cell division, accumulating damage to the cancer cell's DNA, causing them to die or reproduce more slowly. Radiotherapy causes varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after re-treatment (cumulative side effects).
The first use of drugs to treat cancer was in the early 20th century. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. It was reasoned that this agent might have a similar effect on cancer. In 1942 mechlorethamine was first used as a cytostatic agent for cancer therapy. Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that it also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract and hair follicles; this results in the most common side effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss). Moreover, various groups of cytostatic agents cause other specific adverse effects. Many of anticancer drugs are cancerogenic and mutagenic.
Complex concomitant therapies have being used now to alleviate adverse effects of the chemotherapy, i.e. corticosteroids, antiemetic agents etc. Still, a part of chemotherapy cycles must be performed with reduced dose, postponed or stopped.
It is clear that the problem of the immense adverse effects of chemotherapy cannot be solved in a customary way. This could only be achieved by preparations which only kill cancer cells while leaving healthy cells undamaged, in other words which act selectively against cancer cells.
An article in Der Spiegel of 15 May 2010 shows how unsatisfactory current results of chemotherapy are (http://www.spiegel.de/spiegel/print/d-70501026.html). Each day around 20,000 people in the world die as a result of cancer.
It is evident that it has always been the greatest wish of all scientists and cancer researchers to find a preparation which kills only cancer cells and leaves healthy cells undamaged. In other words, a preparation with a selective effect only against cancer cells but not against healthy cells. All the efforts of scientists all over the world have been unsuccessful – there was the strong conviction that this problem was insoluble because the difference between a healthy cell and a cancer cell is too small.
Cancer cells can be killed without damaging healthy cells
A new preparation was presented at the 13th International Congress of Chemotherapy in Vienna in August-September 1983 – thiophosphoric acid derivative of alkaloids from greater celandine (Ukrain, NSC 631570). The development of this preparation was the first significant step on the way to solving the problem. In vitro tests showed that after incubation with Ukrain normal liver cells and Ehrilch tumour ascitic cells demonstrate different oxygen consumption: after an initial increase oxygen consumption in cancer cells falls to zero whereas oxygen consumption in normal cells returns to normal and the cells remain undamaged (38). This study brought the first indications that, in contrast to its starting substances thiotepa (a well known cytostatic agent) and greater celandine alkaloids, Ukrain is in fact only toxic against cancer cells and not against normal cells.
The second indication was provided by clinical use, where Ukrain caused no noteworthy side-effects (21). It improved patients’ general condition as well as their immune status which had previously been impaired by chemotherapy (22).
The third indication was provided by a study at the University of Miami, based upon which the therapeutic index of Ukrain was calculated to be 1250 (26). This is unusually high for an anti-cancer preparation. The therapeutic index is the ratio of the toxic dose to the therapeutic dose and reflects the level of safety of a medicine. The therapeutic index of conventional cytostatic preparations is in the range of 1.4-1.8 meaning that an overdose can have fatal consequences. There is no risk of an overdosage with Ukrain on account of its very high therapeutic index of 1250.
The development of Ukrain was a trail-blazing discovery. The preparation has shown that the problem can be solved and has changed our ideas about healthy and cancer cells.
The presentation at the congress was greeted both by scepticism and great interest. Many reputed research institutes such as the National Cancer Institute (USA), EORTC, the University of Miami, the Rochester University (USA), and University of Tübingen (Germany) began to test the preparation to better explain its unique properties and anticancer potential. In the NCI test model, in contrast to conventional cytostatic preparations which caused the growth inhibition only in some cancer cell lines, like thiotepa inhibited the growth of MLI-09 (non-small lung cancer) and UOK-57LN (renal cancer), Ukrain killed all 60 tested cancer cell lines, which represent the eight important human tumours, including the cell lines which were resistant to the strongest cytostatic drug at the time, cisplatin.
This generated still more interest in scientific circles. Leading scientists examined Ukrain, each group with the method available. Thanks to this variety of experimentation the fine mechanisms of action of Ukrain at different levels could be deciphered: firstly at cellular level with oxygen consumption (effect on mitochondria), then on the level of chromosomes (effect on DNS and RNS), cell organelles and molecules. These experiments produced extremely interesting results and not only confirmed the selective effect of Ukrain but thoroughly destroyed all doubt on the matter. This means that Ukrain can differentiate between healthy and malignant cells, a feature not yet managed by other anti-cancer drugs. Interest in Ukrain is growing and research is continuing.
Researchers at the University of Natural Resources and Life Sciences, Vienna compared Ukrain’s inhibitive effect on the reproduction of malignant and normal cells. In order to achieve 50% growth inhibition a tenfold concentration of NSC 631570 had to be administered to normal endothelial cells in comparison to a human osteosarcoma cell line. Laser scanning microscopy showed a high capacity to absorb Ukrain in malignant cells while absorption in normal cells was considerable lower under the same experimental conditions (36).
In a study of the effect of Ukrain on K-562 erythroleucemia cells it was found that the preparation causes bimodal cell death. At lower Ukrain concentrations malignant cells die as a result of apoptosis, at higher concentrations the formation of microtubules is prevented und polyploidy occurs (62).
In 1998 a group around Anne Panzer (University of Pretoria, South Africa) proved the selective effect of Ukrain on molecular level. Tests on human cervical carcinoma cells HeLa, squamous cell carcinoma WHCO5 and normal equine lung cell lines demonstrated that Ukrain is selectively toxic against cancer cells. It causes a metaphase block which is characterised by an abnormal distribution of chromosomes and the formation of micronuclei and results in apoptosis. Normal cells are not influenced in the process (139).
In 2000 in a study of cell proliferation after absorption of BrdU in the cell lines AsPC1, BxPC3, MiaPaCa2, Jurkat and THP-1 and the cell cycle phases – with the help of Giemsa staining, researchers from Ulm found that 10 µg/ml UKRAIN causes a clear accumulation of cancer cells in phase G2/M. Interestingly no difference was seen in the rate of apoptosis in normal peripheral mononuclear cells treated with Ukrain compared to those untreated. The blastogenic response of mitogen-stimulated lymphocytes was even significantly increased. The authors showed that Ukrain blocks pancreas cancer cells in the prophase by inhibiting tubulin polymerisation (181). This study confirmed that Ukrain exerts no influence on normal cells.
Also in 2000 researchers at Rochester University (USA) examined the effect of NSC 631570 on concentrations of cyclins and cyclin-dependent kinases in epidermoid carcinoma cell lines ME180 and A431 as well as the prostate cancer cell line LNCaP. Changes were found in the concentrations of mitotic cyclins A and B1 as well as CDK1 and CDK2. The researchers also observed increased expression of the CDK-inhibitor p27 in both cell lines, which led to the accumulation of cancer cells but not normal cells in the G2/M phase (147, 149).
In another study in 2000 researchers from South Africa found that Ukrain inhibits the polymerisation of tubulin (185).
In 2002 scientists at the Eberhard-Karls-Universität (Tübingen, Germany) examined the effect of NSC 631570, alone or combined with radiation (1-10 Gy), on cell survival, the modification of the cell cycle and the induction of apoptosis in the exponentially growing human tumour cell lines MDA-MB-231 (breast cancer), PA-TU-8902 (pancreatic cancer), CCL-221 (colonic cancer), U-138MG (glioblastoma) and the human skin fibroblasts HSF1, HSF2 and lung fibroblasts CCD32-LU. Without radiation NSC 631570 had a time and dose dependent cytotoxic effect which was more pronounced in cancer cells than in normal cells. Combined with radiation NSC 631570 resulted in increased cytotoxicity against colonic cancer and glioblastoma cell lines but not against breast cancer and pancreatic cancer cell lines. By means of flow cytometry it was shown that NSC 631570 modulated the toxic effect of radiation on these human cancer cell lines by causing their accumulation in the G2/M phase of the cell cycle. Its protective effect on normal human fibroblasts speaks in favour of its use in combined radio-chemotherapy (184).
In 2005 the ability of Ukrain to induce apoptosis was studied on a Jurkat lymphoma model. Ukrain proved itself to be a strong inducer of apoptosis. More detailed investigations showed that it caused the depolarisation of mitochondrial membranes and as a result the activation of caspases (246).
In 2006 researchers at the Institut Nacional de Cancerologia (Mexico City, Mexico) found that Ukrain triggers apoptosis in a series of cancer cell lines (human cervical carcinoma HeLa, HeKB, HeKS32, HeBcll3, HeNFR and HelKK, colonic cancer SW480, kidney cancer HEK293, osteosarcoma MG 63) by activating the intrinsic cell death pathway. Interestingly the non-transformed fibroblast cell line hTERT was not sensitive to this drug (255).
The cytotoxic effect of NSC 631570 was examined on two primary pancreatic cancer cell lines (PPTCC), fibroblasts from ductal pancreatic cancer tissue samples (F-PDAC) and an immortalised ductal epithelial pancreas cell line (HPNE). Cytotoxicity was established by means of CellTiter 96 kit. The modulation of NSC 631570 absorption in the medium was determined with the help of the fluorescence of NSC 631570 under UV light. The cytotoxic effect of NSC 631570 on pancreatic cancer cell lines was considerably higher than on the fibroblasts and epithelial cells (20% as against 80% living cells). In addition the fluorescence test showed that PPTCC cells absorbed more of the preparation than F-PDAC and HPNE cells. These results show a selective effect of NSC 631570 on the pancreatic cancer cells, which indicates different transport systems or a higher rate of metabolism of the preparation in the PDAC cells (265).
As can be seen, many aspects of the effect of Ukrain on cancer and normal cells have so far been studied. Nevertheless, the possibility exists that these effects are merely the results of an as yet unknown process which Ukrain induces in cancer cells but not in normal cells. As Ukrain killed in the tests almost all cancer cell lines, it can be suggested that a factor occurs when a normal cell becomes a cancer cell. This factor is affected with Ukrain. If this phenomenon can be deciphered it could provide very important indicators for the significant difference between normal cells and cancer cells, point towards the real cause of cancer and open up completely new perspectives for the development of new anti-cancer drugs, not only for treatment but also for use in cancer prevention.
These studies on the selective effect of Ukrain clearly revealed cancer cells can be killed without any damage to the health tissues. This is the most important discovery in the whole story of anti-cancer drugs.
The inhibition of the angiogenesis
Another important feature of Ukrain is the inhibition of the formation of the new blood vessels supplying a tumor. Due to these antiangiogenic properties Ukrain administered before surgery brings about better demarcation of the tumor from surrounding tissue and the tumor encapsulation. This alleviates the surgical removal of tumors what has been confirmed in breast cancer studies (68-73, 114). In tests in vitro, Ukrain inhibited in a dose-dependent manner the proliferation of human endothelial cells without exerting cytotoxic effect. The angiogenesis inhibition was observed on the capillary formation model (136).
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