New biochemical mechanisms of the anticancer effect of Ukrain in the treatment of cancer of the urinary bladder.

The aim of this study was to elucidate the mechanisms of the anticancer effect of Ukrain by comparing the processes of formation of the pool of free amino acids and their derivatives in the blood plasma and tumor biopsy specimens and unchanged bladder tissue in 28 patients with T1N0M0 bladder cancer. The examination was carried out before and after Ukrain treatment (10 mg i.v./day, for 20 days), which was combined with systemic chemotherapy for bladder cancer. Twenty-eight patients served as controls and received systemic chemotherapy only. Compared with healthy donors, the blood plasma of patients with urinary bladder cancer showed decreased concentrations of thiol-containing free amino acids and glutamine (Gln) and increased levels of nonessential (glutamic acid, proline, alanine) and aromatic (phenylalanine) free amino acids. In contrast to conventional chemotherapy, treatment with Ukrain eliminated the blood plasma amino acid imbalance in patients with bladder cancer, concomitantly enriching the pool of free amino acids and their derivatives in unchanged urinary bladder tissue and decreasing concentrations of Gln and leucine (Leu), regulators of malignant cell proliferation and differentiation, by 30-50%. In this situation, the concentrations of Gln and Leu in tumor tissue and the surrounding healthy urinary bladder tissue correlated highly significantly and negatively (r = -0.95). In conclusion, Ukrain prevents active free amino acid transport into urinary bladder tumor tissue, inhibiting the activities of protein biosynthesis, gluconeogenesis and energy production. The combined decrease in Gln and Leu levels in urinary bladder tumor tissue is a specific sign of the antitumor effect of Ukrain and a mechanism of its cancerostatic action by controlling the processes of amino acid pool formation in the tumor.

Results of Ukrain monotherapy of prostate cancer.

This study included 15 patients with newly diagnosed prostate cancer with an average age of 71 years (62-85 years). The patients received Ukrain at a total dose of 100 mg (10 mg intravenously every second day, 10 injections altogether). After two to three injections of Ukrain, all the patients noted considerable subjective improvements in their state. Ukrain increased the amount of total T-lymphocytes, including "active" T-lymphocytes, decreased the content of T-suppressors and increased that of T helpers, correspondingly raising the T helper/T-suppressor ratio. Our results undoubtedly indicate the efficacy of Ukrain in the treatment of prostate cancer.

Comparison of the efficacy of different doses of Ukrain in the combined treatment of breast cancer.

The aim of this study was to compare the efficacy of different Ukrain doses in the combined treatment of 75 patients with breast cancer. The patients were divided into three groups: groups I and II (25 patients each) were treated with 50 mg and 100 mg of Ukrain, respectively, before surgery; group III (25 patients) served as control (without Ukrain treatment). Clinical observations, biochemical, hormonal and immunologic indices indicated that both doses of Ukrain had a similar beneficial effect on patient outcome and may be indicated in the presurgical treatment of patients with breast cancer.

Comparative evaluation of blood plasma and tumor tissue amino acid pool in radiation or neoadjuvant preoperative therapies of breast cancer with the antitumor drug Ukrain.

This study comparatively evaluated free amino acid pool formation in patients with T1-3N0-2M0 breast cancer treated with the drug Ukrain (25 patients, i.v. 100 mg/course) in combination with preoperative radiation or neoadjuvant therapies (25 subjects, total dose 20 Gy). All the patients underwent radical mastectomy. Preoperative radiation did not essentially change the range of the blood plasma parameters studied. However, we observed decreased concentrations of blood plasma ornithine and citrulline and a reduced content of aminobutyric acid, as compared with levels on admission, which may indicate an acceleration of detoxication processes in the liver. In comparison with healthy mammary gland tissue, the tumor tissue of the patients subjected to radiation therapy showed 1.5- to twofold increased concentrations of cysteate, taurine, aspartate, glutamate, proline, glycine, alanine, valine, tyrosine and histidine, which substantiates the idea of tumor tissue being a trap for numerous energy and plastic substrates and indicates active transport of the above compounds into the tumor. The application of Ukrain had virtually no influence on concentrations of the majority of blood plasma amino acids and derivatives: the total concentration of the compounds studied as well as the essential and nonessential amino acid pools remained unchanged. As compared with healthy breast tissue, the considerably increased levels of thiol-containing amino acids, such as methionine, cystine, cysteate and taurine, in the tumor tissue of patients receiving neoadjuvant therapy with Ukrain, indicates high activity of trans-sulfuration processes in this tissue. Simultaneously, in contrast to radiation therapy, Ukrain induced a marked dose-dependent increase in the concentration of proline in breast tumor tissue. The above changes were consistent with the results of the morphological study which confirmed the emergence of numerous foci of necrosis in the tumor and indicated activation of Ukrain-induced proteolytic and degradation processes in the tumor. The results obtained have led us to conclude that a mechanism of Ukrain's cancerostatic effect is to control the transport and reactions of intermediate amino acid metabolism as well as to activate proline biosynthesis in the tumor, causing enhanced development of connective tissue. It is suggested that an important practical conclusion from the present study is the lack of damaging effect of preoperative radiation therapy in the above regimen and the favorable (normalizing) action of Ukrain, at a course dose of 100 mg, on the amino acid pool formation in the organism of patients with breast cancer.

Clinical aspects of cancer treatment and new biochemical mechanisms of the drug Ukrain.

A random group of 50 patients in tumor stages T1-3N0-2M0 was selected from breast cancer patients and given Ukrain therapy by intravenous injection. Twenty-five patients received a total dose of 50 mg Ukrain (5 mg every second day, 10 injections altogether). Twenty-five patients received a total dose of 100 mg Ukrain (10 mg every second day, 10 injections altogether).

Ukrain: a novel antitumor drug.

A review of the recent literature on the new anticancer drug Ukrain is provided herein. We review Ukrain, a thiophosphate derivative of alkaloids from Chelidonium majus L., its capacity to exert selective cytotoxic and cytostatic effects on tumor cells, simultaneously acting as an immune response modifier, its good tolerance and lack of side effects even after long-term application, perspectives of the application of this drug in oncology.

Ukrain therapy of stage T1N0M0 bladder cancer patients.

The aim of the present study was to evaluate the efficacy of Ukrain as a new treatment modality in 28 patients with stage T1N0M0 bladder cancer. The tumor dimensions varied from 0.5 x 0.5 cm to 3 x 4 cm. The first group (nine patients) was treated with a total dose of 100 mg Ukrain, the second group (10 patients) received 200 mg Ukrain, and the third group (nine patients) was treated with 300 mg Ukrain. In all patients Ukrain was administered i.v. at a dose of 10 mg per day. In the patients from the second and third group each course of treatment, consisting of 10 injections, was followed by 14 days of no treatment. Ukrain, at a total dose from 100-300 mg as neoadjuvant therapy in patients with T1N0M0 bladder cancer, resulted in either complete or partial regression of tumors in 60.7 +/- 9.2% of cases. The best treatment regime included three courses of Ukrain at 2-week intervals.

Evaluation of the efficacy of Ukrain in the treatment of breast cancer: clinical and laboratory studies.

The aim of this study was to evaluate the efficacy of different doses of Ukrain in the treatment of 75 breast cancer patients. Patients were divided into three groups. Group I (25 patients) and group II (25 patients) were treated with 50 mg and 100 mg Ukrain, respectively, before surgery. The remaining 25 patients served as controls (no Ukrain treatment). Both clinical observations and laboratory parameters indicate that both doses of Ukrain tested had a similar beneficial effect on patient outcome and may be indicated for presurgical treatment of patients with breast cancer.

Influence of Ukrain on patients with surgically treated breast cancer (introductory remarks).

Studies were undertaken to evaluate the influence of Ukrain on the postoperative period in patients with breast cancer. The group under Ukrain medication was comprised of 10 patients in stage T1-3NO-1MO. The control group was comprised of 22 patients in the same clinical and laboratory staging as those treated with Ukrain in the first year of postoperative follow-up metastatic lymph nodes were observed in one patient from the control group. It is planned to enlarge the groups and to continue the observation up to the third year to obtain reliable and more statistically significant data.

Influence of Ukrain on breast cancer.

The influence of Ukrain on breast cancer was studied in ten women and monitored in each patient by clinical examination, mammography, ultrasonography, histopathology and immunofluorescence in the tissue material obtained after radical mastectomy performed ten days after discontinuation of the treatment. Observations accumulated during the study and analytical data support the view that Ukrain, by changing the antigenic expression of malignant cells, make them recognizable for the immune system which rejects them in a host-versus graft manner.

Influence of Ukrain on patients with surgically treated breast cancer. Part I. Clinical and laboratory parameters.

Studies were undertaken to evaluate the influence of Ukrain on clinical and laboratory parameters in ten patients with breast cancer treated with the drug in the preoperative phase. The control group was composed of eight patients of similar age and advancement of the disease who did not receive Ukrain before mastectomy. Data from the present studies indicate that the drug is distinctly helpful from the surgical viewpoint by increasing tumour hardness and enlargement of metastatic lymph nodes. Furthermore, treatment with it is fully safe, with no side effects or allergic reactions.

Influence of Ukrain on patients with surgically treated breast cancer. Part II. Hormonal profile.

The present study was undertaken to evaluate the influence of Ukrain on the hormonal status of ten patients with breast cancer, treated in the preoperative phase by Ukrain. A control group consisted of eight patients of similar age and advancement of the disease, who did not receive the drug before mastectomy. The data were compared to those obtained in ten healthy women of similar age. The results indicate that Ukrain only slightly influences the hormonal dynamics and its destructive mode of action on neoplastic tissue does not significantly affect hormonal activities.

Influence of Ukrain on patients with surgically treated breast cancer. Part III. The immune system.

The present study was undertaken to evaluate the influence of Ukrain on immune parameters in ten patients with breast cancer, treated with the drug in the preoperative phase. The control group consisted of eight patients of similar age and advancement of the disease, who did not receive Ukrain before mastectomy. The data were compared with the parameters obtained in 15 healthy blood donors. It was found that treatment with Ukrain distinctly regulates cellular and, slightly, humoral immunity, non-specific immunity and also complement activity.

Influence of Ukrain on patients with surgically treated breast cancer. Part IV. Electromicroscopic and cytochemical evaluation.

The present studies were undertaken to evaluate by light and by electron microscopy the influence of Ukrain on the morphology of breast cancer. The studies were carried out on material obtained from ten patients with breast cancer, treated preoperatively with Ukrain. Control material for the studies was obtained from patients of similar age and advancement of the disease, who did not receive Ukrain. The data obtained in the present studies indicate that Ukrain is responsible for severe changes in morphology of tumour cells. Histological examination by both light and electron microscopy revealed cells characteristic of those undergoing apoptosis. The stromal changes of the tumour were characterized by intensive proliferation of the connective tissue accompanied by an immune reaction expressed by mononuclear infiltrates.

Amino acids and their derivatives in blood plasma of patients with breast cancer treated with Ukrain. Part V.

The present study was undertaken to evaluate the influence of Ukrain on the free amino acids pool in blood plasma in ten patients with breast cancer, treated in the preoperative phase with the drug. The control group consisted of five patients of similar age and advancement of the disease, who did not receive Ukrain before mastectomy. The data obtained from these studies indicate that Ukrain positively influences the metabolism of amino acids and their derivatives. The most characteristic changes were increase of proline, taurine and glutamic acid.

Amino acids and their derivatives in tumour tissue from patients with breast cancer treated with Ukrain. Part VI.

The present study was undertaken to evaluate the influence of Ukrain on the amino acids pool and their derivatives in tumour tissue of ten patients with breast cancer, treated in the preoperative phase with Ukrain. The control group consisted of five patients of similar age and advancement of the disease, who did not receive Ukrain. The data obtained indicate that Ukrain influences cancerous tissue, as demonstrated at the level of amino acids. The most characteristic changes observed in cancerous tissue after treatment with Ukrain were increases in the levels of proline, taurine and glutamic acid.

Synergic influence of Ukrain and protoporphyrin amino acid conjugates on human malignant cell lines.

Simultaneous cytotoxicity of Ukrain and protoporphyrin amino-acid derivatives was tested on four malignant cell lines and the cytotoxic effect after laser irradiation was compared with cytotoxicity of Ukrain and protoporphyrin amino-acid derivatives applied on similar cell lines separately. It was found that Ukrain and protoporphyrin amino-acid derivatives act synergistically as cytotoxic substances on the malignant cell lines.

Potential therapeutic efficacy of Ukrain (NSC 631570) in AIDS patients with Kaposi's sarcoma.

In this study two case reports are presented of therapy with Ukrain, a semi-synthetic thiophosphoric acid compound of alkaloids isolated from Chelidonium majus L, for the treatment of AIDS patients with Kaposi's sarcoma. Ukrain was injected i.v. in the dose of 5 mg every other day for a total of 10 injections. During treatment the Kaposi's sarcoma lesions diminished in size, showed decolouration and no lesion appeared in the 30-day interval after the beginning of treatment. Both patients tolerated Ukrain well and showed an improved immunohaematological status: an increase in total leukocytes, T-lymphocytes and T-suppressor numbers. In one case T-helper lymphocytes were also increased. Future investigations are necessary for the evaluation of Ukrain efficacy in the treatment of this type of patients.

Ukrain both as an anti cancer and immunoregulatory agent.

Thirty six stage III cancer patients were treated with Ukrain, a semisynthetic drug derived from Chelidonium majus L. alkaloids conjugated with thiophosphoric acid. The drug was injected intravenously every second day in a dose of 10 mg per injection. Each patient received 300 mg of the drug (30 injections). The cytostatic effect of Ukrain was monitored clinically and by ultrasonography (USG) and computer tomography (CT), as well as by determination of CEA and CA-125 in the sera of patients with rectal and ovarian cancers, respectively. The influence of Ukrain on immune parameters was evaluated by monoclonal antibodies (MAb) to CD2, CD4, CD8 and CD22. The influence of Ukrain on immune parameters in cancer patients was matched with its effect on these parameters in 20 healthy volunteer controls. The results obtained indicate that Ukrain, in a concentration not cytostatic in normal cells, is cytostatic for malignant ones, and may suppress the growth of cancer. The compound also has immunoregulatory properties, regulating the T lymphocyte subsets.