NEUTRON-CAPTURE THERAPY OF THE 9L RAT GLIOSARCOMA USING THE P-BORONOPHENYLALANINE-FRUCTOSE COMPLEX

Purpose: Intraperitoneal(IP) injection of the solubilized fructose com plex of L-p-boronophenylalanine (BPA-F) produced higher boron concentr ations in a rat brain tumor model than was possible using intragastric (IG) administration of L-p-boronophenylalanine (BPA). The effectivene ss of IP BPA-F was compared to IG BPA in boron neutron capture therapy irradiations of the 9L rat brain tumor model. Methods and Materials: The time course of boron accumulation in tumor and normal tissues was determined in male F344 rats bearing either SC or intracerebral 9L gli osarcomas following a single IP injection of BPA-F. On day 14 after in oculation of intracranial tumors, rats were irradiated with single dos es of either: 250 kVp X rays; the thermal neutron beam of the Brookhav en Medical Research Reactor following IG administration of BPA; or the rmal neutrons following IP injection of BPA-F. Magnetic resonance imag ing was used to visualize the tumor scars and to assess damage to the normal brain in long-term survivors. Results: 4 h after IP injection o f 1200 mg/kg of BPA-F the boron concentrations in tumor, blood, and no rmal brain were 89.6 +/- 7.6, 27.7 +/- 2.8 and 17.5 +/- 1.5 mu g B-10/ g, respectively. Two IG doses of BPA (750 mg/kg each, 3 h apart) produ ced 39 +/- 5, 12 +/- 1 and 10 +/- 1 mu g(10)B/g in tumor, blood and br ain, respectively at 5 h after the second dose. Three groups of rats w ere treated with thermal neutrons: one following IC BPA and two groups following IP BPA-F. The total physical absorbed doses to the tumor in the three BNCT groups were 15.5 Gy (IG BPA, n = 12), 17.0 Gy (IP BPA- F, n = 8), and 31.5 Gy (IP BPA-F, n = 8), respectively. The median sur vival of the untreated controls was 22 days. The median survival of th e rats treated with 22.5 Gy of 250 kVp X rays (n = 23) was 35 days wit h 20% long-term survivors. Fifty percent of the rats in the IG BPA + t hermal neutrons group survived over 1 year. All rats in both groups th at received IP BPA-F + thermal neutrons have survived over 8 months. M agnetic resonance imaging of the brains of the long-term boron neutron capture therapy survivors showed a scar at the site of tumor implanta tion in all animals. In the IP BPA-F high-dose group one rat showed ev idence of edema and one rat showed a fluid-filled cyst replacing the t umor. Conclusion: The use of IP BPA-F has significantly improved long- term survival compared to IG BPA. The high percentage of long-term tum or control (100%, n = 16) in the intracerebral rat 9L gliosarcoma brai n tumor model, together with little or no damage to the surrounding no rmal brain in the majority of surviving animals, demonstrate the subst antial therapeutic gain produced by boron neutron capture therapy.