ABSTRACT
A method for the preparation of 11α-hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α-mesyloxy group of the methyl esters of 3α-acetate-12α-mesylate and 3α,7α-diacetate-12α-mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting â³11 -3α-acetoxy and â³11 -3α,7α-diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α-hydroxylation of the â³11 -3α,24-diol and â³11 -3α,7α,24-triol intermediates with B2 H6 /tetrahydrofuran (THF); and (4) selective oxidation at C-24 of the resulting 3α,11α,24-triol and 3α,7α,11α,24-tetrol to the corresponding C-24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α-dihydroxy-5ß-cholan-24-oic acid and 3α,7α,11α-trihydroxy-5ß-cholan-24-oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.
Subject(s)
Bile Acids and Salts/chemical synthesis , Biological Products/chemical synthesis , Chenodeoxycholic Acid/chemistry , Lithocholic Acid/chemistry , Bile Acids and Salts/chemistry , Biological Products/chemistry , Molecular Conformation , StereoisomerismABSTRACT
The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ(9(11))-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ(9(11))-enes using m-chloroperbenzoic acid catalyzed by 4,4'-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9α-hydroxylation of the Δ(9(11))-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The (1)H- and (13)C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5ß-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids.
Subject(s)
Biological Products/chemical synthesis , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/chemical synthesis , Lithocholic Acid/analogs & derivatives , Lithocholic Acid/chemical synthesis , Biological Products/chemistry , Chenodeoxycholic Acid/chemistry , Lithocholic Acid/chemistry , Molecular ConformationABSTRACT
OBJECTIVE: Since 2002-2007, we applied boron neutron capture therapy (BNCT) to >50 cases of malignant gliomas (MGs) with epithermal neutron irradiations. Recently, we showed the early radiographical improvement of malignant glioma patients by our modified BNCT, with simultaneous use of BPA (borono-phenylalanine) and BSH (sodium borocaptate). In this time, we focused on the survival benefit from BNCT for the newly diagnosed glioblastoma patients. METHODS: BNCT group including 21 newly histological confirmed glioblastoma patients treated with surgical removal followed by BNCT in Osaka Medical College during 2002-2006 period. Ten patients were treated with BNCT only, and in the other 11 patients, 20-30 Gy fractionated external beam X-ray irradiation therapy (XRT) was performed after BNCT. No chemotherapy was administered until tumor progression was observed. RESULTS: Treatments were well tolerated. Any kind of acute systemic or local severe toxicity were not demonstrated. Mean over all survival of the patients treated by BNCT was 20.7 and the median was 15.6 months with 2-years survival of 25%. Stratification by RPA criteria showed 6, 6, 8 and 1 patients, respectively, in classes III-VI. Three patients out of six in class III and one out of eight in class V are alive at the end point of this study. All the patients in classes IV and VI died. Median survival time for the BNCT group compared to the RTOG database was as follows: 20.6 months vs. 17.9 months for class III; 16.9 months vs. 11.1 months for class IV; 13.2 months vs. 8.9 months for class V. CONCLUSION: The RTOG RPA prognostic criteria were helpful in establishing which class of glioma patients could potentially benefit from BNCT. BNCT showed a survival benefit in all of the RPA classes of the RTOG database not only for the good prognosis group.
Subject(s)
Boron Neutron Capture Therapy/methods , Brain Neoplasms/radiotherapy , Glioblastoma/radiotherapy , Borohydrides/therapeutic use , Boron Compounds/therapeutic use , Brain Neoplasms/mortality , Brain Neoplasms/surgery , Clinical Protocols , Combined Modality Therapy , Glioblastoma/mortality , Glioblastoma/surgery , Humans , Japan/epidemiology , Phenylalanine/analogs & derivatives , Phenylalanine/therapeutic use , Prognosis , Radiation-Sensitizing Agents/therapeutic use , Sulfhydryl Compounds/therapeutic use , Survival RateABSTRACT
We evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.
Subject(s)
Boron Neutron Capture Therapy/methods , Brain Neoplasms/radiotherapy , Glioblastoma/radiotherapy , Adolescent , Adult , Aged , Brain Neoplasms/diagnosis , Combined Modality Therapy , Female , Glioblastoma/diagnosis , Humans , Male , Middle Aged , Survival Rate , Treatment Outcome , Young AdultABSTRACT
OBJECT: Boron neutron capture therapy (BNCT) requires selective delivery of a high concentration of boron-10 ((10)B) to tumor tissue. To improve a drug delivery in BNCT, we devised transferrin-conjugated polyethylene-glycol liposome encapsulating sodium borocaptate (TF-PEG-BSH). METHODS: (10)B concentrations of U87Delta human glioma cells from three boron delivery systems (BDS) (bare BSH, PEG-BSH, and TF-PEG-BSH) were analyzed in vitro by use of inductively coupled plasma-atomic emission spectrometry (ICP-AES). A colony-forming assay (CFA) was performed using this cell line with the three BDS and neutron irradiation. Subcellular localization of BSH in tumor cells was analyzed in vitro by immunocytochemistry using monoclonal antibodies raised for BSH. Brain tumor models were made and the (10)B concentrations of the tumor, blood, and normal brain from each BDS were analyzed in vivo by use of ICP-AES. The tumor-to-blood and the tumor-to-normal brain ratios were evaluated. BNCT for the brain tumor models was performed and survival was analyzed. RESULTS: In CFA, TF-PEG-BSH showed the most prominent effects by neutron irradiation among the three BDS. TF-PEG-BSH showed highly selective and highly efficient (10)B delivery in tumor tissue. The survival rate in the treatment experiment was best in the TF-PEG-BSH group. Immunocytochemically, TF-PEG-BSH delivered BSH efficiently not only into the cytoplasm but also into the nucleus. CONCLUSION: TF-PEG-BSH is a potent BDS for BNCT not only in terms of delivering a high concentration of (10)B into tumor tissue, but also the selective delivery of (10)B into the tumor cells.
Subject(s)
Borohydrides/administration & dosage , Boron Neutron Capture Therapy/methods , Brain Neoplasms/radiotherapy , Drug Delivery Systems , Glioma/radiotherapy , Sulfhydryl Compounds/administration & dosage , Animals , Borohydrides/pharmacokinetics , Humans , Liposomes/administration & dosage , Male , Mice , Mice, Nude , Polyethylene Glycols/administration & dosage , Spectrophotometry, Atomic , Sulfhydryl Compounds/pharmacokinetics , Tissue Distribution , Transferrin/administration & dosageABSTRACT
OBJECTIVE: Malignant meningiomas, similar to glioblastomas, are difficult tumors to control. We tried to control malignant tumors related to meningiomas by boron neutron capture therapy (BNCT). METHODS: Since June 2005, we applied BNCT with 13 rounds of neutron irradiation to seven cases of malignant tumors related to meningiomas. Three were anaplastic meningiomas, two were papillary meningiomas, one was an atypical meningioma, and one was a sarcoma transformed from a meningioma with cervical lymph node metastasis. All patients had previously undergone repetitive surgeries and radiotherapy. Follow-up images were available for six patients with an observation period between 7 and 13 months. We applied 18F-boronophenylalanine (BPA)-positron emission tomography (PET) before BNCT in six of the seven patients. One patient underwent methionine-PET instead of 18F-BPA-PET. RESULTS: Five of the six patients who underwent BPA-PET analysis showed good BPA uptake, with a greater than 2.7 tumor-to-healthy brain ratio. The atypical meningioma case showed a tumor-to-healthy brain ratio of 2.0. The original tumor sizes were between 13.6 and 109 ml. Two of the three anaplastic meningiomas showed a complete response, and all six patients available for follow-up imaging showed radiographic improvements. Clinical symptoms before BNCT, such as hemiparesis and facial pain, were improved after BNCT in all but one patient. In this patient, a huge atypical meningioma arose from the falcotentorial junction and extended to the bilateral occipital lobes and brainstem; visual problems worsened after repetitive BNCT, with an increase in peritumoral edema. CONCLUSION: Malignant meningiomas seem to be good candidates for BNCT.