Reaction products from the 10B(n, alpha)7 Li reaction have a range of about 10 microns in tissue and are known to have a high bilogical effectiveness. Localization of B-10 in tumor permits selective irradiation of cancer cells within the neutron radiation field. The overall aim is to exploit the full potential of neutron capture therapy (NCT) by utilizing boronated compounds which show selective phsiological localization in tumors, and an epithermal neutron beam which allows improved tissue penetration and a reduced surface tissue exposure compared to conventional neutron beams. A boronated analog of phenylalanine will be tested in a murine melanoma model. It is known that melanotic melanomas actively metabolize aromatic amino acids for use as precursors in the synthesis of the pigment melanin. In preliminary experiments, the injection of melanoma-bearing mice with p-boronophenylalanine (BPA) resulted in a selective accumulation of boron in the tumor which reached maximum values about 6 hours post-injection. The concentration of boron in tumor is within the range needed for effective NCT (15-30 micrograms 10B/gram). The ratio of boron in tumor to that in blood and muscle is about 5-10 and 5 respectively. Using these conditions we have been able to obtain tumor growth control following neutron irradiation at the Medical Research Reactor. These results support the assumption that BPA is transported into the melanoma cells via the aromatic amino acid transport systems. Reasoning from this biochemical model and drawing on the extensive literature of aromatic amino acid transport and metabolism, studies are proposed which are intended to optimize the selective boron loading of melanoma cells while keeping the normal tissue boron content suitable for NCT. Specific aspects addressed are: (1) the carrying capacity of the transport system; (2) inhibitors of BPA transport; (3) the metabolic fate of the boron atom; and (4) alternative routes for delivering BPA or inhibitors of melanin biosynthesis into melanoma cells. Although the ultimate goal is therapy of cancer in human beings, clinical treatment is not part of this research plan. This work, however, should establish the feasibility of NCT in an experimental melanoma and, by extension of the underlying principles, radiation inactivation of other types of tumors based on physiological localization of boron-containing metabolites.
|Coderre, J A; Joel, D D; Micca, P L et al. (1992) Control of intracerebral gliosarcomas in rats by boron neutron capture therapy with p-boronophenylalanine. Radiat Res 129:290-6|
|Coderre, J A; Slatkin, D N; Micca, P L et al. (1991) Boron neutron capture therapy of a murine melanoma with p-boronophenylalanine: dose-response analysis using a morbidity index. Radiat Res 128:177-85|
|Coderre, J A; Glass, J D; Fairchild, R G et al. (1990) Selective delivery of boron by the melanin precursor analogue p-boronophenylalanine to tumors other than melanoma. Cancer Res 50:138-41|
|Coderre, J A; Glass, J D; Packer, S et al. (1990) Experimental boron neutron capture therapy for melanoma: systemic delivery of boron to melanotic and amelanotic melanoma. Pigment Cell Res 3:310-8|
|Coderre, J A; Kalef-Ezra, J A; Fairchild, R G et al. (1988) Boron neutron capture therapy of a murine melanoma. Cancer Res 48:6313-6|