Boron Neutron Capture Therapy of Glioblastoma Multiforme Using the p-Boronophenylalanine-Fructose Complex and Epithermal Neutrons
The amino acid analog p-boronophenylalanine (BPA) has been under investigation at Brookhaven National Laboratory (BNL) as a neutron capture agent for BNCT of glioblastoma multiforme (GBM) for the past six years. BPA, delivered orally, is effective in BNCT of the intracerebral 9L rat gliosarcoma1. Histologic examination of the brains of long-term BNCT survivors showed scar tissue replacing the tumor with no serious damage to the contiguous normal brain2. A series of 17 patients undergoing surgical removal of tumor (GBM or melanoma) received BPA orally as the free amino acid. Favorable tumor/blood boron concentration ratios were obtained but the absolute amount of boron in the tumor would have been insufficient for BNCT3. BPA can be solubilized at neutral pH by complexation with fructose4. BPA-fructose (BPA-F) is administered intravenously (iv) for thermal neutron-based BNCT of melanoma in Japans. Intraperitoneal (ip) injection of the soluble BPA-F complex produces much higher tumor boron concentrations in the rat intracerebral 9L gliosarcoma than were previously possible using oral administration of BPA. Higher boron concentrations have allowed higher radiation doses to be delivered to the tumor while maintaining the dose to the normal brain vascular endothelium below the threshold of tolerance. This resulted in long-term survival of over 90% of BNCT-treated rats6. Surviving rats show no obvious neurologic deficit. We have measured the relative biological effectiveness (RBE) of the various high-linear energy transfer (LET) components of the total BNCT dose in both tumor and normal tissues. Our data indicate a therapeutic ratio (tumor dose/normal tissue dose) in excess of 5:1 (Coderre et al., these proceedings). A biodistribution study of iv BPA-F in patients with high-grade gliomas is reported elsewhere in these proceedings (Bergland et al.,these proceedings).
KeywordsGlioblastoma Multiforme Boron Concentration Biodistribution Study Boron Neutron Capture Therapy Relative Biological Effective
Unable to display preview. Download preview PDF.
- 3.J.A. Coderre, A Phase I biodistribution study of p-boronophenylalanine, in: `Boron Neutron Capture Therapy: Towards Clinical Trials of Glioma with BNCT,“ R. Moss and D. Gabel. eds., Plenum Press, New York, 1992, pp. I1 I - 121.Google Scholar
- 4.K. Yoshino, A. Suzuki, Y. Mori, H. Kanihana, C. Honda, Y. Mishima, T. Kobayashi, K. Kanda, Improvement of solubility of pboronophenylalanine by complex formation with monosaccharides, Strahlentherapie und Oncologie 165: 127–129, 1989.Google Scholar
- 5.Y. Mishima, M. Ichihashi, C. Honda, M. Shiono, T. Nakagawa, H. Obara,.1. Shirakawa, J. Hiratsuka, K. Kanda, T. Kobayashi, T. Nozaki, O. Aizawa, T. Sato, H. Karashima, K. Yoshino, and H. Fukuda, Advances in the control of cutaneous primary and metastatic melanoma by thermal neutron capture therapy, in: “Progress in Neutron Capture Therapy for Cancer,” B.J. Allen, D.E. Moore. and B.V. Harrington, eds., Plenum Press, New York, 1992, pp. 577–583.CrossRefGoogle Scholar
- 8.LaHann, T.R., Lu, D.R., Daniell, G., Sills, C., Kraft, S.L., Gavin, P.R., and Bauer, W.F. Bioavailability of intravenous formulations ofp-boronophenylalanine in dog and rat. In: Soloway, A.; Barth, R.; Carpenter, D., eds. Advances in Neutron Capture Therapy. New York: Plenum Press; 513–517; 1993.CrossRefGoogle Scholar
- 9.J.A. Coderre, M.S. Makar, P.L. Micca, M.M. Nawrocky, H.B. Liu, D.D. Joel, D.N. Slatkin, and H.I. Amols, Derivations of relative biological effectiveness for the high-LET radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo. Int..1. Radial. Oncol. Biol. Phys. 27: 1121–1129, 1993.CrossRefGoogle Scholar
- 12.H. Fukuda, J. Hiratsuka, C. Honda, T. Kobayashi, K. Yoshino, H. Karashima, J. Takahashi, Y. Abe, K. Kanda, M. Ichihashi, and Y. Mishima, Boron neutron capture therapy of malignant melanoma using 10Bparaboronophenylalanine with special reference to evaluation of radiation dose and damage to the skin, Radiat. Res. 138: 435–442, 1994.PubMedCrossRefGoogle Scholar