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NSC631570 - A PROMISING CANCER CURE (SEMISYNTHETIC COMPOUND FROM THE ALKALOIDS OF CHELIDONIUM MAJUS L.)
Romanchuk V.O.
Graduate Student Lviv National Ivan Franko University Henerala Chuprynky Street, 49, 79044, Lviv, Ukraine https://orcid.org/0000-0003-1594-3995
Abstract
NSC631570 (Ukrain) is an anticancer medical preparation on the basis of the extract of the plant Chelidonium majus L. and Thiotepa. Numerous pre-clinical and clinical studies seem to suggest that NSC631570 is pharmacologically active and clinically effective. It has curative effects on a range of cancer types. Thus, it has a big potential as an anticancer drug. The studies on this preparation started about 40 years ago. Meanwhile, numerous in-vitro studies, animal experiments and case reports have emerged. All these data suggest that NSC631570 has a strong anticancer activity in a wide range of cell lines.
Keywords: cancer, NSC631570, Chelidonium Majus L., alkaloids, selective action, cancer cells, healthy cells, clinical study, research, cancer patients, autofluorescense, patient cases, results.
Malignant tumors belong to the greatest problems of our present. The number of cancer diseases with a fatal end is constantly increasing. According to the European Commission, every fourth person living in the European Union is dying of cancer (each year -837,000 Europeans), and in the world about 4 million new cases of oncological diseases are recorded. This kind of the disease is diagnosed in all groups of population: men, women, elderly people and children. The most common among the oncological diseases are: cancer of lungs, skin, breast, gastrointestinal tract, prostate, ovaries, cervix of the uterus and thyroid gland. Among malignant tumors in children prevail leukemia, malignant tumors of the brain and lymphoma. (www.unicef.org/ukraine/ukr/onko.pdf). And every year, these statistics are getting worse.
With this illness all over the world doctors fight primarily with help of surgical operations but also with
radiation therapy and chemical preparations that exhaust the immune system and negatively affect healthy cells.
However, there is an alternative treatment of cancer diseases.
It is an effective anticancer preparation NSC631570 (Ukrain) developed in 1976 by Dr. Wassil Nowicky, an Austrian scientist of Ukrainian origin. This anticancer drug is based on the extract of the plant Chelidonium majus L. and Thiotepa. Numerous pre-clinical and clinical investigations seem to suggest that NSC631570 is pharmacologically active and clinically effective. This drug destroys only cancer cells, leaving healthy cells undamaged. This means that the NSC631570 has a selective effect, confirmed by a number of scientific studies.
Cancer cells can be killed without harming healthy ones
At the 13 th International Congress for Chemotherapy in Vienna in August-September 1983, a new agent - thiophosphoric acid derivative of the alkaloids from celandine (NSC631570) was presented (35). The development of this preparation was the first and very important step on the way to the development of a preparation that kills only cancer cells, but not healthy ones.
The in vitro investigations confirmed a different oxygen consumption in normal liver cells and cancer cells: after an initial increase, the oxygen consumption in the tumor cells fell to zero. In normal liver cells, oxygen consumption normalized and they remained undamaged (6). This study provided initial indications that NSC631570, in contrast to its starting materials Thiotepa and celandine alkaloids, is actually only toxic to cancer cells and not to normal cells.
The second indication was achieved from clinical use, where NSC631570 caused no significant side effects (31). Besides, this preparation improved the general condition of patients and their immunological status, which was damaged as a result of the previous chemotherapy (10).
The third sign came from the study from the University of Miami (USA). In this study the therapeutic index of NSC631570 was calculated - 1250 (41). That's unusually high for a cancer drug. Therapeutic index (TI) is the ratio of the toxic dose to the therapeutic and reflects the safety of a drug. The therapeutic index of conventional cytostatic preparations, to which Thio-tepa also belongs, is in the range 1.4-1.8 and therefore overdosing it can have fatal consequences. Because of the very high TI value of 1250, there is no risk of overdosing with the NSC631570.
After that many well-known research institutions, e.g. the National Cancer Institute (USA), EORTC, University of Miami (USA), Rochester University (USA), University of Tübingen (Germany) have started to test the preparation in order to better understand its unique properties and therapeutic potential. In contrast to conventional cytostatic preparations, NSC631570 has all 60 cancer cell lines tested, which represent 8 important human tumors, were killed (32), including those cell lines which were resistant to the then strongest known cytostatic agent Cisplatinum.
This has arisen even more interest in the scientific community. Leading scientists tested NSC631570, each group using the method available to them. Thanks to this variety of experiments, the fine mechanisms of the action of NSC631570 could be deciphered at different levels: at the cellular level with oxygen consumption, at the level of the chromosomes, cell organelles and molecules. These studies have brought extremely interesting results and not only confirmed the selective effect of NSC631570 several times, but also thoroughly eliminated any doubts that it only kills cancer cells but does not harm healthy cells in any way. This means that NSC631570 can differentiate between healthy and malignant cells - this property is not available to the other cancer drugs developed to date. Scientific interest in NSC631570 is growing and research continues (39; 47; 40; 13; 14; 15).
In the study on the effect of NSC631570 carried out at St. John's Memorial University (Newfoundland, Canada) under the direction of Prof. Andrejs Liepins, it was found that this preparation causes bimodal cancer cell death. (27).
In 1998, Anne Panzer's group (University of Pretoria, South Africa) demonstrated the selective effect of NSC631570 at the molecular level. The scientists investigated that NSC631570 is selectively toxic to cancer cells by causing a metaphase block. The normal cells were not affected (37).
In 2000, the Ulm researchers found that 10 ^g / ml NSC631570 after 24 hours causes a significant accumulation of cancer cells in phase G2/ M. The authors showed that NSC631570 blocks pancreatic cancer cells in prophase by inhibiting tubulin polymerization (16). This work confirmed that NSC631570 does not affect normal cells.
Normal human fibroblasts were later used in their experiments by the scientists at the Eberhard-KarlsUniversität Tübingen (Germany) and the Instituto Nacional de Cancerologia (Mexico City, Mexico) (9; 30). Neither research group found any toxic effects of NSC631570 on these normal cell lines.
In 2002, the scientists at the Eberhard Karls University of Tübingen (Germany) examined the effect of NSC 631570 alone or combined with radiation on cell survival, the modification of the cell cycle and the induction of apoptosis in the exponentially growing human tumor cell lines MDA-MB-231 (Breast cancer), PA-TU-8902 (pancreatic cancer), CCL-221 (colon cancer), U-138MG (glioblastoma), and in human skin fibroblasts HSF1, HSF2 and lung CCD32-LU. Without irradiation, NSC 631570 caused time- and dose-dependent cytotoxic effects, which were more pronounced on cancer cells than on normal cells. Combined with radiation, NSC 631570 caused increased cy-totoxicity to colon cancer and glioblastoma cell lines, but not to the breast cancer and pancreatic cancer cell lines. Using flow cytometry, NSC 631570 was shown to modulate the toxic effects of radiation on these human cancer cell lines by inducing their accumulation in the G2/ M phase of the cell cycle. Its protective effect on normal human fibroblasts suggests that it can be used in combined radio- and chemotherapy (9).
These innovative openings have caused even greater interest in the scientific world:
Until now, to the NSC631570 their works have devoted more than 260 scientists from 24 countries in 60 universities and research institutes. Their work was described in more than 300 scientific publications, majority of which are available on the www.pubmed.org First patients and clinical use Dr. Prof. J.-A. Musianowycz from Paris (France) in 1977 was the first who applied the NSC631570 in the treatment of incurable patients. In 1979 he presented 17 patients cases of clinical use. He prescribed to the NSC631570 to incurable cancer patients, primarily with breast and skin cancers. In some of them Prof. Musianowycz noted the decline in the growth of metastases, and in some even their disappearance. Patients put on weight and pain decreased. Prof. Musianowycz noted that this medicine deserves a deeper scientific
study and conduct of experiments. (https://ukrin.com/docs/Musianowycz 1979.pdf ).
Doctors reports
Here are some quotes from the reports of the treatment of cancer patients with NSC631570 (https://www.ukrm. com/docs/erfahrungsberichte.pdf).
In 1996 Dr. Alois Denk wrote: "From a medical view it would be preferably to investigate the action of NSC631570 and tell the wider public about the relevant results."
In the same 1996, Associate Professor of the University of Dr. Hubert Denz informed: "In one case of pancreas cancer with the help of computer tomography, we established a temporary decrease of the tumor (...) Side effects were insignificant, namely there was a light feeling of heat, but in general the treatment was carried out simply great (...) It is worth to plan and to carry out appropriate clinical studies of the medicine, which will provide the standardized dosage, application form, duration of treatment and documentation with results. (...) First of all, it seems to be appropriate to use the NSC631570 in the treatment of pancreatic cancer, since by this time, the results after chemotherapy are very modest, and in the most weakened patients there are significant side effects. In addition, there are some more positive reports on the therapy with NSC671570 of this type of tumor."
Dr. Siegfrid Wagner: "The preparation NSC631570 has been in my ordination for about 2 years. (...) So far, 40-50 patients with various tumor diseases and of different ages have been treated with it. Depending on the initial position of the disease process, success could be recorded in every case of the treatment with NSC631570, whereby the growth stagnation and remission-like conditions of the tumor were also recognizable. No undesirable side effects whatsoever were observed during treatment with NSC631570".
The Chief Doctor Hans-Jörg Klein: "In the majority of my cases, NSC631570 is an adjunct therapy to chemotherapy and/or radiation therapy. Particularly noticeable successes were achieved with it as mono-therapy in around 10% of cases. In adenocarcinomas, for example, remission-like stages and considerable metastasis regressions were observed. (...) In all cases of NSC631570 therapy there was a significant improvement in the quality of life of cancer patients".
Dr. Uta Konstantopulos stated: "Onepatient with an inoperable carcinoma of bile duct and metastases in the liver after a small surgical intervention (artificial outflow of bile) without further treatment in February 1996, was sent home. Since March 1996, we began to administer her NSC631570. The general condition of the patient is simply wonderful. (...) In some patients, I saw a definitely positive impact on the course of the disease in the progressive stage"
Dr. Omar Abu-Dayeh informed: "In my observations, I noticed that the preparation NSC631570 is really a significant help and a positive application to other types of treatment. Along with remissions, that we achieved, it should be noted that during and after treatment, patients feel well, and the quality of their life is significantly improved."
Dr. Grazyna Nowicki: "In my practice I applied NSC631570for seven years. Most of the 15 patients who were treated personally by me, were recognized as incurably ill (...). First, it should be noted that after thefirst injections with the preparation in all these patients, an unexpected subjective and objective improvement of both physical and mental state was achieved, which I can not call the effect of placebo effect. They have improved sleep and appetite, facilitated pain, in connection with which in many cases, no strong analgesics were needed."
Phase I Clinical Study
The phase I clinical study was performed on 19 healthy volunteers on the out-patient basis. Beside general clinical condition, following parameters were evaluated: blood count, clinical chemistry, immune values, electrolytes, microelements, neopterin. NSC 631570 was administered intramuscularly or intravenously daily, on the alternate days or every third day at a daily dose of from 5 up to 50 mg for 7-40 days. In a special case, the medicine was administered during three years at a total dose of 3500 mg divided into several therapy courses. No significant changes in clinical status were revealed at the examination. In the case of intramuscular administration, volunteers reported local pain, sometimes sleepiness, increased thirst and polyuria. In some cases, a light non-significant increase of the body temperature and minor blood pressure decrease were observed. The authors concluded NSC 631570 at single doses of 5, 10, 20 and 50 mg were well tolerated, also at prolonged administration. (11)
The Dose Finding Study (Phase II)
To find out the correct dosage for NSC 631570 a phase II clinical study was performed on 70 end stage cancer patients. NSC 631570 was administered intramuscularly or intravenously daily, on the alternate days, every third, every forth, or every fifth day. Single doses were 2.5, 5, 10, 15, 20, or 25 mg in ascending order (from 2.5 up to 25 mg), descending from 25 mg to 2.5 mg, or 5, 10, 15, 20 or 25 mg constantly. The duration of a therapy courses was 10-90 days. Breaks between courses varied from seven days up to three months. In all cases the therapy with NSC 631579 was well tolerated. In some patients the analgesics dosage could be reduced. The quality of life improved in the most cases. Subjective as well as objective symptoms and signs were observed like headache, dizziness, thirst, sweating, polyuria, fever (with the body temperature increase of 1-2 °C), and pain at the tumor and/or metastases area. Increased temperature at the tumor area was observed also. Temporary tumor swelling, increased heart beat rate and minor blood pressure decrease were observed as well. The intensity of such concomitants correlated with the response to the therapy. After full remission these concomitants were not anymore observed (31; 28).
In healthy volunteers, such concomitant events are observed not so extensively or not observed at all. It can be suggested they are triggered by the tumor degradation products. The intensity of these concomitants can be decreased with the detoxification measures.
Phase III Clinical Trials
NSC631570 can cause the full regression of the
main tumor and also of metastases. In the treatment of advanced tumors NSC631570 can improve the quality of life and prolong survival. Many clinical studies have proved this, such as those of the work groups led by Prof. Beger in Germany and of Prof. Zemskov in Ukraine with pancreatic cancer (17; 64; 18; 19; 20; 21; 61), as well as groups led by Prof. Susak and Prof. Bon-dar in Ukraine with colon cancer (45, 62, 63, 5). Neoadjuvant (before surgery) use of NSC631570 can induce encapsulation of tumors as revealed the studies by the researchers of Grodno Medical University (Grodno, Belarus) in breast cancer (49; 8; 53; 50; 51; 52, 55, 58; 59; 34).
In an open study total 203 advanced cancer patients were treated with NSC 631570 and partially with local hyperthermia (37.4%) after all conventional treatment modalities had failed and the disease progressed or relapsed. Full remission was achieved in 41 cases (20.2%), partial remission - in 122 cases (60.1%). Sem-inoma and prostate cancer responded especially well with remission rate of more than 75% (1; 2.).
Pancreatic carcinoma
In a controlled randomized study by Prof. H. Be-ger et al. in the Ulm University Hospital, Germany, the therapy with NSC 631570 and Gemcitabine doubled the survival rate in the patients with inoperable advanced pancreatic cancer (17). The longest survival was 19 months in the group treated with gemcitabine alone, 26 months in the combined group, and in the NSC 631570 alone group two patients were alive after 28 months. NSC 631570 was well tolerated. The study authors consider further evaluation of NSC 631570 as justified whereas the quality of life of the patients improved (18).
Adjuvant therapy in pancreas cancer: comparison of three studies
Patients were further observed after the conclusion of the study and it was noted that NSC631570 was well tolerated and could be administered without problem to all patients. NSC631570 brought about a significant increase in survival time in comparison to therapy with gemcitabine alone. Combination therapy with gemcitabine and NSC631570 showed no advantage over mon-otherapy with UKRAIN. The longest survival in the gemcitabine group was 19 months, 21 months in the Gemcitabine+NSC631570 group, and in the NSC631570 group a patient was still alive after 28 months. The authors concluded: 'As a result of this study we highly recommend the treatment of patients suffering from advanced pancreatic cancer with NSC631570 (19)
2007 the results of another clinical study by the same research team were published. This time the efficacy of the adjuvant therapy with NSC 631570 has been demonstrated in the patients with advanced pancreatic cancer after surgery. The patients were treated with a combination of NSC 631570 and Gemcitabine.
The median survival was 33.8 months and the 5-year survival rate was 23.3% which is clearly better than results reported in the earlier studies without NSC 631570, with the median survival of 20.1 months and the 5-year survival rate was 21% (https://www.neim.org/doi/full/10.1056/NEJMoa0322 95). Moreover, NSC 631570 at therapeutic dose range has only minimal adverse effects, improves the quality of life of patients and can be administered also on outpatient basis. All these features distinguish this drug favorable compared to the standard cytostatic agents.
Author Year Number of patients
Therapy Relapse free survival Median survival
Neoptolemos
2001 238 5-FU/FS
k. A. 19,7 Mo.
Kurosaki
2004 16
Gemcitabine 16,8 Mo. 20,4 Mo.
Gansauge
2007 30
NSC 631570/ Gemcitabine 26 Mo. 37,6 Mo.
Again, this publication supports the efficacy (and safety) of the use of NSC631570 as it demonstrates a considerable prolongation of survival compared to what is known from other clinical studies (21).
Other researcher confirmed the efficacy of NSC 631570 in pancreatic carcinoma (20; 24; 26), while the partial remission rate was as high as 85.7% in one study (3). The longest survival in palliative therapy was more than six years (64; 18).
Histological changes caused by the treatment with NSC 631570 in the pancreatic tumor and in the surrounding tissue were profoundly studied. NSC 631570 has been revealed to bring about the fibrotic and sclerotic transformation of the tumor. Perivascular sclerosis has also occurred (46).
Colorectal cancer
In a controlled randomized clinical study by the National Medical University (Kyiv, Ukraine) colon cancer patients were treated with NSC 631570 or with 5-fuorouracil and x-ray therapy. The survival rate after 21 months was 78.6% in the NSC 631570 group and
33.3% in the group treated with 5-FU and radiotherapy (45).
Within a randomized study in the Donezk Regional Cancer Center (Ukraine) rectal cancer patients received either high-dose radiotherapy and 5-FU before surgery, or the therapy with NSC 631570: one course before surgery (10 mg every second day up to 60 mg) and another course afterwards (up to 40 mg). During following 14 months, relapses occurred in six patients (25%) from the combined group and in 2 patients (8.3%) in the NSC 631570 group. Two year relapse rate was 33.3% (8 patients) in the combined group and 16.7% (4 patients) in the NSC 631570 group (112). Now, 11 years after this publication 18 from 24 patients (75%) in the NSC 631570 group are still alive.
Prostate cancer
The efficacy of NSC 631570 in prostate cancer has been confirmed in a controlled clinical study. In the study patients, all standard treatment modalities had been exhausted. The cancer relapsed and/or progressed and no therapy protocol was available. The patients
were treated with NSC 631570 and partially with local patients (22%). Only in 4 patients (5%) the therapy did
hyperthermia. Following results were achieved: full re- not affect the course of the disease (4).
mission in 54 patients (73%), partial remission in 16 __
Total number of patients Full remission Partial remission Disease progression
74 54 16 4
100% 73% 22% 5%
The good efficacy of NSC 631570 in prostate cancer has been confirmed in another study (57).
Breast cancer
In a controlled clinical study conducted at the University Grodno (Grodno, Belarus), after the therapy with NSC 631570 the hardening of the tumor, a slight increase in the tumor size (5-10%) and proliferation of connective tissues were observed. The tumors appeared harder and slightly enlarged after NSC 631570 therapy, and were easier to detect by ultrasound or radiological examination. Metastatic lymph nodes were also hardened and sclerotic (fibrous). Tumors and metastatic lymph nodes were clearly demarcated from healthy tissue and therefore easier to remove. Based on the results of this study the scientists from Grodno recommended the use of NSC 631570, at the higher dosage, in all breast cancer operations (7, 49, 8, 53, 55).
In a series of articles the researchers have studied the effect of NSC 631570 on various parameters in breast cancer patients (58, 59, 34, 60). Best results were achieved with higher dosage of NSC 631570. Almost every patient noted the improvement of the general well-being, sleep and appetite. During the surgery, the tumors as well as involved lymph nodes were presented sclerotic and well demarcated from the surrounding tissue. This alleviated the surgical removal of the tumor considerably (59). In the tumor tissue, increased concentration of the amino acid proline was revealed indicating augmented production of connective tissue that demarcates the tumor from surrounding tissue (34). NSC 631570 improved also the amino acid balance of patients (60).
Bladder cancer
In a study NSC 631570 caused full remission in three patients for six months (56, 54).
Biochemical evaluation revealed NSC 631570 had favorably affected the amino acid metabolism (33).
Malignant melanoma
The first publication on the using NSC 631570 in malignant melanoma describes the full remission in a patient with metastases to the lung (42).
A long lasting remission (more than 10 years without recurrence) has been observed in a patient with malignant nodular melanoma after the treatment with NSC 631570. At the beginning of the NSC 631570 therapy liver metastases were present and melanin was excreted with urine (22).
The effects of NSC 631570 alone and in combination with the pathogen associated molecules (PAM) on the cell cycle and apoptotic induction were compared in two melanoma cell lines MM-4 and MM-4M2 with different metastatic properties (cell division rate, hem-atogenous metastazing, sensitivity to the TNF-induced apoptosis).
Apoptosis induction and cell viability were analyzed using trypan blue exclusion test, morphological
criteria, DNA gel electrophoresis, and flow cytometry. Cell cycle distribution of tumor cells was estimated by flow cytometry. The therapy with NSC 631570 induced apoptosis in both melanoma cell lines in a dose-dependant matter. The cell line with higher metastatic potential was more sensitive to NSC 631570. In the cell line with low metastatic potential, combined use of NSC 631570 and PAM induced apoptosis more effectively (39).
Brain tumors
NSC 631570 has been successfully used in the treatment of brain tumors (43;
44). In a review on the clinical studies with NSC 631570 performed so far the researchers from the Universities of Exeter & Plymouth suggested this agent to have potential as an anticancer drug (12).
Malignant gynecologic tumors
Earlier, there was a report on the successful using NSC 631570 in the treatment of ovarian cancer (29). Also in the tests of National Cancer Institute (Bethesda, Maryland, USA) NSC 631570 was toxic against all ovarian cancer cell lines tested (32) Other authors reported on good results in the therapy of cervical cancer (38, 25).
Autofluorescence of NSC 631570 in the tumor area
The selective effect of NSC 631570 on cancer cells has been confirmed due to its autofluorescence under UV light (36). First time this feature of NSC 631570 was presented 1983 at 13th International Congress of Chemotherapy in Vienna. It has been confirmed in this work NSC 631570 to selectively accumulate in cancer cells. The accumulation of NSC 631570 in cancer cells correlates with the efficacy of the drug. With the elimination of the preparation from the body the intensity of the fluorescence decreases also (35).
At this congress, the first reports on the successful using NSC 631570 in the treatment of the end-stage cancer patients were presented, where all standard therapy modalities had failed. Though poor prognosis, NSC 631570 brought about full remission in a part of the patients and some of those are still alive.
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