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Hydroxylforms of p-Boronophenylalanine as Potential Boron Carriers on Boron Neutron Capture Therapy for Malignant Brain Tumors¹

Radiation Oncology Research Laboratory, Research Reactor Institute [M. T., K. O.] and Department of Neurosurgery, Graduate School of Medicine [Y. O., H. K.], Kyoto University, Kumatori-cho, Sennan-gun, Osaka 590-04; and Department of Chemistry, Graduate School of Science, Tohoku University [H. N., S. I., J. C., Y. Y.], Japan

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 10¹²nvt (n = 1), 1.33 x 10¹²nvt (n = 2), 3.37 x 10¹²nvt (n = 4), and 1.72 x 10¹²nvt (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 D_37-BPA to D_37-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.

¹ This study was supported by Grants-in-Aid for neurosurgical research (06454413) and cancer research (07274110) from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed. Phone: 81-724-52-8194; Fax: 81-724-52-8194; E-mail: rorl@rri.kyoto-u.ac.jp.

Received 2/ 2/96. Accepted 3/25/96.