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We have previously shown that 5-arylaminouracil derivatives can inhibit HIV-1, herpesviruses, mycobacteria, and other pathogens through various mechanisms. The purpose of this study was to evaluate the potential of 5-arylaminouracils and their derivatives against leukemia, neuroblastoma, and glial brain tumors. 5-Aminouracils with various substituents and their 5'-norcabocyclic and ribo derivatives were screened for cytotoxicity against two neuroblastoma cell lines (SH-SY5Y and IMR-32), K-562 lymphoblastic cells, HL-60 promyeoloblastic cells, and low-passage variants of well-differentiated glioblastoma multiforme (GBM5522 and GBM6138). Cytotoxicity assessment by the standard MTT test showed that most of the compounds lack significant toxicity towards the above cells. However, 5-(4-isopropylphenylamine)uracil and 5-(4-tert-butylphenylamine)uracil exhibited a dose-dependent toxic effect towards the GBM6138 cell line with half-maximal inhibitory concentrations (IC50) of 9 and 2.3 μМ, respectively. Antitumor activity was for the first time demonstrated for compounds of this type and can serve as a starting point for further research.

Targeted delivery of chemotherapeutic agents with aptamers is a very effective method increasing therapeutic index compared to non-targeted drugs., Objective: To study the effectiveness of in vitro therapeutic effect of covalently conjugated GR20 DNA aptamer with doxorubicin on glioblastoma cells compared to reference culture of human fibroblasts., Material and Methods: A Sus/fP2 cell culture was obtained from glioblastoma tissue sample to analyze the effectiveness of conjugate. A linear culture of human dermal fibroblasts (mesenchymal stem cells) DF1 was used as a control. To assess antiproliferative activity of covalently conjugated GR20 aptamer with doxorubicin, we used the MTS test. The Cell Index was measured using the xCelligence S16 cell analyzer assessing viability of cell cultures by recording changes in real time., Results: Human glioblastoma Sus/fP2 cells reduce own proliferative potential by 80% when exposed to doxorubicin (0.5 µM, 72 hours, MTS test), by 9% when exposed to GR20 aptamer (10 µM, 72 hours, MTS test) and by 26% when exposed to covalently conjugated DOX-GR20 (0.5 µM, 72 hours, MTS test). A long-term study of proliferative potential of Sus/fP2 cells on the xCelligence S16 analyzer revealed a significant decrease in the number of cells under the effect of doxorubicin and covalently conjugated DOX-GR20. Effectiveness of covalently conjugated DOX-GR20 is halved. GR20 aptamer at a concentration of 10 μM and its conjugate with doxorubicin DOX-GR20 at a concentration of 1 μM have no negative effect on cells of the control culture of DF1 fibroblasts, while doxorubicin is toxic for these cells. MTS test and xCelligence S16 cell analyzer found no decrease in metabolic activity of DF1 cells and their ability to proliferate., Conclusion: We established obvious antiproliferative effect of covalent conjugate DOX-GR20 on continuous human glioblastoma cell culture Sus/fP2 without toxic effect on the reference culture (dermal fibroblasts DF1).

Objective: Analysis of long-lived patients from the group of patients with glioblastomas after using photodynamic therapy in the structure of their complex treatment in order to assess the influence of various factors on their life expectancy., Material and Methods: In total, a single-center, retrospective categorical study analyzed the long-term results of treatment of 63 patients with glioblastoma in the structure of complex treatment including photodynamic therapy. Clinical factors (age, sex, number of cases, preoperative Karnofsky index, location and size of the tumor, radicality of the operation), histological (nuclear polymorphism, mitosis, vascular proliferation, necrosis), immunohistochemical (Ki-67, p53 index) molecular-genetic factors (expression of VEGF, MGMT, IDH, CD34 ), amount of radiation and chemotherapy were analyzed., Results: In the entire group of patients, there was a direct correlation of life expectancy with MGMT status, IDH status, the number of courses of chemotherapy, the age of the patient, and the severity of the first surgical intervention., Conclusion: Clinical features such as age at diagnosis and extent of surgical resection and amount of chemotherapy have predictive value in assessing their effect on life expectancy. Mutations in IDH and MGMT promoter methylation were the most important molecular factors determining long-term patient survival.

Objective: To analyze the influence of continued growth of glioblastoma between surgery and radiotherapy on subsequent survival., Material and Methods: Fractionation with a prescribed dose of 2 and 3 Gy was alternately applied using a pairwise modeling strategy in 140 patients with morphologically confirmed glioblastoma (grade 4). Early progression of disease between microsurgery and radiotherapy was diagnosed in 60 patients, and no tumor growth was noted in 80 patients., Results: The minimum period of early progression was 0.33 months, maximum - 4.27 months (median 1.1 (95.0% CI: 0.9-1.3)). The most significant predictors of early progression were resection quality ( p <0.0001), large residual tumor ( p =0.003) and no MGMT promoter methylation ( p =0.001). IDH1 status did not affect early progression. In residual tumor ≥1.2 cm 3 , the median period of early progression was 1.9 months ( n =70; 95% Cl: 1.3-2.5), <1.2 cm 3 - 3.5 months ( n =70; p =0.019). After resection of less than 76% of tumor, this value was 1.1 months ( n =28), ≥76% - 3.1 months ( n =112; p =0.006). Without tumor growth, the median overall survival was 33.41 months ( n =80; 95% Cl: 27.1-39.7), with early progression - 16.03 months ( n =60; 95% Cl: 13.5-18.6; p <0.0001). This predictor was significant for fractionation with a prescribed dose of 3 Gy ( p <0.0001) and standard radiotherapy (2 Gy; p =0.028). By December 2022, 26 out of 40 patients without early progression survived two years after treatment (3 Gy) (65%, median not reached). In case of fractionation with a prescribed dose of 2 Gy, 20 patients survived this period (50%, median reached)., Conclusion: Almost half of patients with newly diagnosed glioblastoma develop early progression between microsurgery and radiotherapy. Therefore, patients with and without early progression should be probably assigned to different prognostic groups regarding overall survival.

Chemotherapeutic agents containing targeted systems are a promising pathway to increase the effectiveness of glioblastoma treatment. Specific proteins characterized by increased expression on the surface of tumor cells are considered as possible targets. Integrin αvβ3 is one of such proteins on the cell surface. It effectively binds the cyclic Arg-Gly-Asp (cRGD) peptide. In this study, the cRGD peptide-modified doxorubicin (Dox) phospholipid composition was investigated. The particle size of this composition was 43.76±2.09 nm, the ζ-potential was 4.33±0.54 mV. Dox was almost completely incorporated into the nanoparticles (99.7±0.58%). The drug release increased in an acidic medium (at pH 5.0 of about 35±3.2%). The total accumulation and internalization of Dox used the composition of phospholipid nanoparticles with the targeted vector was 1.4-fold higher as compared to the free form. In the HeLa cell line (not expressing αvβ3 integrin) this effect was not observed. These results suggest the prospects of using the cyclic RGD peptide in the delivery of Dox to glioblastoma cells and the feasibility of further investigation of the mechanism of action of the entire composition as a whole.

Background: Doxorubicin is a well-known antitumor drug that is not employed for chemotherapy of brain tumors. Indeed, doxorubicin does not penetrate across the blood-brain barrier in therapeutic concentrations., Objective: To study the antitumor effect of doxorubicin combined with nitrosorbide on intracranial experimental glioblastoma 101/8 in rats., Material and Methods: Male Wistar rats ( n =86) with intracranial implanted glioblastoma 101/8 received doxorubicin (i.v. 1.5 mg/kg thrice) alone or in combination with nitrosorbide (i.v or orally, 0.5 mg/kg thrice) in 2, 5 and 8 days after implantation. Efficacy was assessed considering survival and brain tumor volume in 14 days after tumor implantation., Results: Combination of doxorubicin and nitrosorbide significantly increased survival (57% and 155%, respectively) and slowed down tumor growth (16±12 and 8±6 mm 3 , respectively) compared to doxorubicin alone. Effectiveness of nitrosorbide alone was trivial., Conclusion: Nitric oxide donor nitrosorbide considerably potentiated the antitumor effect of doxorubicin against intracranial 101/8 glioblastoma in rats.

Glioblastoma multiforme is characterized by persistent recurrent course despite surgical, radio- and chemotherapeutic treatment. The outcomes of superselective intra-arterial administration of bevacizumab with blood-brain barrier disruption in patients with recurrent glioblastoma have been published. The authors reported significant increase in overall survival (up to 2.5 years). We report treatment of recurrent glioblastoma in a young patient with progressive course of disease despite 4 previous neurosurgical interventions, radiotherapy and first-line chemotherapy. Superselective intra-arterial administration of bevacizumab with blood-brain barrier disruption made it possible to achieve clinical response and improve neurological status.

We report a patient with recurrent glioblastoma in eloquent brain area. Stereotactic fluorescence biospectroscopy and stereotactic photodynamic therapy of tumor in opercular area of the left frontal lobe under neurophysiological monitoring were carried out. Literature data on this issue were analyzed.

Studies carried out on samples of tumor and non-tumor tissue indicate that markers of radiosensitivity for predicting individual patient response to the planned radiation therapy may be the indicators of apoptosis and molecular profiles read from the DNA of patients. At present there is developed a technology for rapid and economical determining of indicators for the reasonable use of radiation therapy in the radiological practice in patients with breast cancer, bladder cancer and malignant glioblastomas by means of an evaluation of radiosensitivity of the DNA of blood.

Molecular chaperons can effectively activate innate and adaptive anti-tumor immune response. In the model of intracranial glioma C6 in Wistar rats we assessed immunomodulatory activity of recombinant protein Hsp70 in case of local, intratumoral injection. Single intratumoral infusion of chaperone had led to dramatic delay in tumor volume growth (on MRI of rat brain), which was accompanied by increase in survival rates. Incubation of rat spleenocytes with C6 cells elevated the levels of INF-gamma, that shows an immunologically specific T-cell response. With immunohistochemical assay we observed a marked infiltration of the tumor by T-lymphocytes and NK-cells. Thus, purified Hsp70 can efficiently induce innate and adaptive anti-tumor response and could be used as adjuvant in treatment of malignant brain tumors of central nervous system.

We developed a new method of accelerated chemoimmunoradiotherapy for cerebral glioblastoma and evaluated the immediate effects. A single focal dose of 3Gy was administered once a day 5 times a week until the total focal dose of 51 Gy was reached. Chemoradiotherapy was followed by a course of biotherapy with recombinant interleukine-2 (roncoleukine). On administering a total dose of 10 million units, a course of chemoimmunotherapeutic support was given after a 2-week break. Vincristine 1 mg was injected on day 1 and nitrosourea preparations (lomustine 160 mg or carmustine 100 mg) on day 2. Later on, the same regimen of roncoleukine was used. Our method was followed by longer survival as compared with standard treatment (control) and use of incomplete course chemoimmunotherapy.

Combined treatment of glyal and metastatic tumors of the brain allows prolongation of survival with the saved high physical and social level of the patients following the algorithm of the treatments: operative intervention with the minimal injury of the brain substance and preservation of all functionally important zones; chemotherapy with nitrosourea with the preferable bringing to the tumor zone; exposure to radiation.

The work deals with the results of study of the antineoplastic activity of a Soviet produced antineoplastic antibiotic reumycin in relation to 35 glial tumors of various degrees of malignancy in primary cultures and in heterotransplantation under the capsule of kidneys in mice. In tissue cultures 71.5% of gliomas were sensitive to reumycin, in the subcapsular test 75% of tumors proved to be reumycin sensitive with fluctuations of inhibited growth of heterotransplants within a range of 27-75%. Among the reumycin resistant tumors, the cultures of one of the glioblastomas showed stimulation of proliferation, which justifies the necessity for testing the individual sensitivity of the tumor to reumycin in each concrete patient.

The method of autoradiography for testing the efficacy of cytostatics with subsequent individually chosen chemotherapy is one of the components of rational therapy for neuro-oncological patients. Purposeful chemotherapy was applied in 17 cases with gliomas. Favourable results were recorded in 70.6% of them. Twelve patients received regular courses of treatment with one agent which inhibited DNA synthesis in vitro most potently (in 7 the therapeutic result was favourable), 5 patients were given course of polychemotherapy (favourable effect in 100%). Prolonged survival and a good remission allow autoradiography to be recommended as a method for the individual choice of antiblastic agents.

Individual sensitivity of 40 glial tumors (34 macroglial and 5 oligodendroglial tumors and 1 medulloblastoma) to 4 chemotherapeutical agents (fluorofur, 5-fluorouracil, methotrexate and sarcolysin) was studied in vitro on the basis of changes in the values of thymidine labelling index after 24-hour incubation of tumor-tissue fragments in a medium with the chemical agents. Each of the tumors studied possessed individual range of sensitivity to the chemotherapeutical agents distinguishing it from other tumors. None of the agents studied proved to more effective than others. The reaction of the tumor tissue to the effect of the chemotherapeutical agents did not depend on the proliferative activity of the tumor, while the degree of manifestation of the tumor reaction was often dependent on the concentration of the agents. An increase in the number of DNA-synthesizing cells in the tumor under the effect of the chemical agents was observed in rare cases.

The cytotoxic effect of antitumour antibiotics, such as dactinomycin, mithramycin, variamycin and olivomycin on the cells of the human brain tumours (multiform glyoblastoma, arachnoidendotelioma and astrocytoma) grown by the method of the primary plasmic culture was studied. Dactinomycin was superior to the antibiotics of the aureolic acid group in the rate and level of the cytotoxic effect on the tumour cells: 76 per cent of the above tumours were sensitive to dactinomycin, 56 per cent to mithramycin and 52 per cent to variamycin and olivomycin. Among the total number of the tumours sensitive to the drugs the number of the highly sensitive tumours amounted to 57.9 per cent for dactinomycin and 30.8--38.5 per cent for the antibiotics of the aureolic acid group. Definite differences in the efficiency of the antibiotics of the aureolic acid group with respect to different types of the brain tumours were observed.

Mongrel adult albino female rats with multiform glioblastoma transplanted to the right cerebellar hemisphere were given subcutaneous injections of 8 mg/kg of a serotonin-creatine sulphate solution beginning with the 3rd and to the 28th postoperative days. Rats with a tumor inoculated at the same periods and given injections of a physiological saline solution served as controls. The injection of serotonin leads to a significant increase in the survival of rats by 20% as compared to the survival of rats in the control group, but practically has no effect on the life span of sick animals. Consequently, serotonin either produces an antineoplastic effect in which case the animals do not contract the disease, or it has no effect on the tumor so that the animals die of the developing tumor. Study of the tryptophan content in the neoplasm and the 5-OIAA content in urine provides evidence of a disturbed serotonin synthesis and metabolism in these neoplasms.