title: Hydroxylforms of p-boronophenylalanine as potential boron carriers on boron neutron capture therapy for malignant brain tumors.
abstract: Hydroxylforms of boronophenylalanine (BPA) were synthesized by conjugation with a cascade of polyols to decrease the BPA uptake of normal parenchyma without affecting uptake into the tumor. We determined their tumor cell killing effect on boron neutron capture therapy (BNCT) against BPA using the human glioma cell line T98G. The thermal neutron doses yielding the D37 (dose used to inhibit 63% colony formation) values of dl-p-BPA(OH)n were 1.45 x 10(12)nvt (n = 1), 1.33 x 10(12)nvt (n = 2), 3.37 x 10(12)nvt (n = 4), and 1.72 x 10(12)nvt (n = 0). The relative tumor cell killing effect on BNCT of dl-p-BPA(OH)n against dl-p-BPA, which was defined as the ratio of D37-BPA to D37-BPA(OH)n, was 1.18 (n = 1) 1.29 (n = 2), and 0.51 (n = 4). The tumor:normal brain ratio of dl-p-BPA(OH)n in 9L rat brain tumor models was improved 1.2- (n = 1) and 1.4-fold (n = 2) against that of dl-p-BPA without a decrease of its uptake into the tumor. The water solubility of BPA(OH)n increased against BPA, and the toxicity represented as the IC50 value of dl-p-BPA(OH)2 was nearly one half that of dl-p-BPA, being established in our previous works. Hydroxylforms of BPA, especially dl-p-BPA(OH)2, might be more suitable boron carriers of BNCT to malignant brain tumors since the radiation injury to the normal parenchyma surrounding the tumor is reduced.
authors.affiliation: Radiation Oncology Research Laboratory, Kyoto University, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takagaki
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: Y
authors.initials: Y
authors.lastname: Oda
authors.forename: H
authors.initials: H
authors.lastname: Kikuchi
authors.forename: H
authors.initials: H
authors.lastname: Nemoto
authors.forename: S
authors.initials: S
authors.lastname: Iwamoto
authors.forename: J
authors.initials: J
authors.lastname: Cai
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; D010649:Phenylalanine; C033685:4-boronophenylalanine