ET-5 Biological effects of simultaneous use of multiple drugs in neutron capture therapy using rat brain tumor model

The world’s first clinical trial of boron neutron capture therapy (BNCT), which treats malignant brain tumors with a single dose of neutron irradiation using multiple boron drugs simultaneously, was performed at our institution, and its excellent results have stimulated BNCT research around the world. BNCT is a particle irradiation therapy that biologically targets cancer cells, and is expected to be a “new option for cancer treatment” because it can deliver a dose of radiation at the cellular level. In the case of BNCT using a combination of multiple drugs, a method to appropriately consider the biological effects of the combination in the dose calculation has not been established. At present, BNCT based on an accelerator-based irradiation system and a boron drug (BPA) based on essential amino acids has been approved by the regulatory approval for head and neck cancer and has shown good results in brain tumors. As basic research, we have continued to develop new boron drugs, which will be essential in the future, and have explored the interpretation of the biological effects of multiple boron drugs in combination and the optimal conditions required for drug development. The survival curve of BNCT in a rat brain tumor model showed that the effect of the new drug alone was comparable to that of BPA, and the effect of the combination was improved, but the effect of the combination did not match the prediction of the combined biological effect derived from each drug. However, it has been found that the effect of the combination does not match the prediction based on the combination of biological effects derived from each drug. In other words, even if the equivalent X-ray equivalent dose (Gy-Eq) is calculated, the combined effect of some drugs exceeds the prediction, while the combined effect of other drugs is poor.

The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model

Background: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine–amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model. Methods: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time. Results: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 μg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group. Conclusion: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT.

Use of a Luciferase-Expressing Orthotopic Rat Brain Tumor Model to Optimize a Targeted Irradiation Strategy for Efficacy Testing with Temozolomide

Glioblastoma multiforme (GBM) is a common and aggressive malignant brain cancer with a mean survival time of approximately 15 months after initial diagnosis. Currently, the standard-of-care (SOC) treatment for this disease consists of radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ). We sought to develop an orthotopic preclinical model of GBM and to optimize a protocol for non-invasive monitoring of tumor growth, allowing for determination of the efficacy of SOC therapy using a targeted RT strategy combined with TMZ. A strong correlation (r = 0.80) was observed between contrast-enhanced (CE)-CT-based volume quantification and bioluminescent (BLI)-integrated image intensity when monitoring tumor growth, allowing for BLI imaging as a substitute for CE-CT. An optimized parallel-opposed single-angle RT beam plan delivered on average 96% of the expected RT dose (20, 30 or 60 Gy) to the tumor. Normal tissue on the ipsilateral and contralateral sides of the brain were spared 84% and 99% of the expected dose, respectively. An increase in median survival time was demonstrated for all SOC regimens compared to untreated controls (average 5.2 days, p < 0.05), but treatment was not curative, suggesting the need for novel treatment options to increase therapeutic efficacy.

TB-03 THE SURVIVAL PROLONGATION EFFECT OF NOVEL BORON COMPOUND FOR BNCT USING RAT BRAIN TUMOR MODEL

INTRODUCTION Boron neutron capture therapy (BNCT) is form of tumor-cell selective particle irradiation. Although novel boron compounds have been developed, BPA (boronophenylalanine) and BSH (borocaptate sodium) are used in the clinical practice. The development of effective boron compounds is a major theme. We used Dodecaborate-containing BPA (AAL) which is combined the characteristics of both BPA and BSH. We have been conducting research on how the new compound for BNCT will affect rat brain tumor model. MATERIALS AND METHODS We evaluated the boron concentration of F98 glioma cells for BPA and AAL, and the biodistribution of these following BPA administrated intravenously (i.v.) or AAL administrated by convection-enhanced delivery (CED) in F98 glioma bearing rats. In BNCT study, the therapeutic effect was evaluated in terms of the survival time for all rats divided into six groups. RESULTS The uptake of boron showed almost the same value at all exposure times in high concentration. In biodistribution study, the AAL(CED) 6h after the termination group attained the highest boron concentrations of the tumor (59.9 ± 18.2 μg/g). In the BNCT study, the median survival time in the AAL(CED) group (31(29–35) days) was shorter than that in the BPA(i.v.) group(34(33–36) days). And the combination group of AAL(CED) and BPA(i.v.) gave the most significant prolongation of survival(38(36–40) days). DISCUSSION AAL(CED) and BPA(i.v.) combined group had a significant survival prolongation compared with the single-agent group. It is thought that AAL irradiated by thermal neutron had a cell-killing effect on cells in which BPA was not taken up. The combination uses of AAL (CED) provides additional BNCT effects. The mechanism by which AAL is incorporated has not been clarified, and further experiments including the influence on normal cells are in progress. CONCLUSION Dodecaborate-containing BPA (AAL) is a novel boron compound for BNCT that can be expected to prolong the survival time in combination with BPA.

Water Extract of Tamarix gallica L. as effective Agents against C6 and HeLa tumor cell lines

The aerial parts of Tamarix gallica L. taken from three different climatic stages in Algeria (Oum El Bouaghi: Semi-arid, ElTaref: Humid, and Ouargla: Arid) were extracted using boiling distilled water. The crude extracts were subjected to total phenolics and flavonoids quantifications in addition to anti-proliferative assessment against two tumor cell lines namely rat brain tumor (C6) and human cervix carcinoma (HeLa) using BrdU (bromo-deoxyuridine) ELISA(Enzyme-linked immune-sorbent assay) and xCELLigence assay. The total phenolics yield was found to range between 16.14 and 39.32 mg GAE (Gallic acid equivalent)/g of extract and a flavonoids yield ranging between 16.51 and 20.35 mg QE(quercetin equivalent)/g of extract. The various phenolics were identified using HPLC-TOF/MS to highlight hesperidin and rosmarinic Acid as major components. Moreover, the extracts exhibited different levels of antitumor potency against C6 and HeLa cell lines depending upon the climatic stage and the concentration. A good cytotoxic effect was recorded with the species collected from the humid region at 250 μg/mL. On the contrary, the other extracts revealed a weak activity for both tests.

Anti-proliferative activity of ethyl acetate extracts of Tamarix gallica L. grown at different climatic conditions in Algeria

The aerial parts of T. gallica collected from three different locations (arid, humid and semi-arid) were extracted using ethyl acetate. The crude extracts were subjected to phenolic appraisal and antiproliferative activity using ELISA and xCELLigence assays. The total phenolic and flavonoids were evaluated using appropriate techniques to give a yield of total phenolics ranging between 238.46 and 348.56 mg GAE (Gallic acid equivalent)/g dry weight extract. The flavonoids yield was found to vary from 36.6 to 103.14 mg QE (quercetin equivalent)/g dry weight extract. Moreover, the extracts were tested against rat brain tumor (C6) and human cervix carcinoma (HeLa) cell lines and displayed important differences in activity. These disparities highlighted the effect of climatic factors as quality determinants of secondary metabolites and therefore as a key control of the biological therapeutic effect.

Chemical constituents and antiproliferative effects of cultured Mougeotia nummuloides and Spirulina major against cancerous cell lines

In this study, the effect ofMougeotia nummuloidesandSpirulina majoron Vero cells (African green monkey kidney), C6 cells (rat brain tumor cells) and HeLa cells (human uterus carcinoma) was investigatedin vitro. The antiproliferative effect of the methanol extract ofM. nummuloidesandS. majorcompared with 5-fluorourasil (5-FU) and cisplatin was tested at various concentrations using the BrdU Cell Proliferation ELISA. BothM. nummuloidesandS. majorextracts significantly inhibited the proliferation of Vero, HeLa and C6 cancer cell lines with IC50and IC75values. TheM. nummuloidesextract exhibited higher activity than 5-FU and cisplatin on Vero and C6 cells at high concentrations. TheS. majorextract revealed better antifproliferative activity than standards against Vero cells at 500 μg/mL. The compounds of methanol extracts were determined by GC-MS after the silylation process. Trehalose, monostearin and 1-monopalmitin were detected as major products in theM. nummuloidesextract where as in theS. majorextract; monostearin, 1-monopalmitin and hexyl alcohol were the main constituents.