title: Porphyrin-mediated boron neutron capture therapy: a preclinical evaluation of the response of the oral mucosa.
abstract: Preclinical studies are in progress to determine the potential of boron neutron capture therapy (BNCT) for the treatment of carcinomas of the head and neck. Recently, it has been demonstrated that various boronated porphyrins can target a variety of tumor types. Of the porphyrins evaluated so far, copper tetracarboranylphenyl porphyrin (CuTCPH) is potentially a strong candidate for clinical use. In the present investigation, the response of the oral mucosa to CuTCPH-mediated boron neutron capture (BNC) irradiation was assessed using the ventral surface of the tongue of adult male Fischer 344 rats, a standard rodent model. CuTCPH was administered by intravenous infusion, at a dose of 200 mg/kg body weight, over a 48-h period. Three days after the end of the administration of CuTCPH, biodistribution studies indicated very low levels of boron (<2 microg/g) in the blood. Levels of boron in tongue tissue were 39.0 +/- 3.8 microg/g at this time. This was the time selected for irradiation with single doses of thermal neutrons from the Brookhaven Medical Research Reactor. The estimated level of boron-10 in the oral mucosa was used in the calculation of the physical radiation doses from the 10B(n,alpha)7Li reaction. This differs from the approach using the present generation of clinical boron carriers, where boron levels in blood at the time of irradiation are used for this calculation. Dose-response curves for the incidence of mucosal ulceration were fitted using probit analysis, and the doses required to produce a 50% incidence of the effect (ED50 +/- SE) were calculated. Analysis of the dose-effect data for CuTCPH-mediated BNC irradiation, compared with those for X rays and thermal neutrons alone, gave a compound biological effectiveness (CBE) factor of approximately 0.04. This very low CBE factor would suggest that there was relatively low accumulation of boron in the key target epithelial stem cells of the oral mucosa. As a consequence, with low levels of boron (<2 microg/g) in the blood, the response of the oral mucosa to CuTCPH-mediated BNCT will be governed primarily by the radiation effects of the thermal neutron beam and not from the boron neutron capture reaction [10B(n,alpha)7Li].
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Morris
authors.forename: J A
authors.initials: JA
authors.lastname: Coderre
authors.forename: P L
authors.initials: PL
authors.lastname: Micca
authors.forename: M M
authors.initials: MM
authors.lastname: Nawrocky
authors.forename: J W
authors.initials: JW
authors.lastname: Hopewell
authors.forename: M
authors.initials: M
authors.lastname: Miura
mesh_terms: D000818:Animals; D001822:Body Burden; D016754:Boron Neutron Capture Therapy / Q000009:adverse effects* / Q000379:methods; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D005260:Female; D007928:Lethal Dose 50; D008665:Metalloporphyrins / Q000009:adverse effects / Q000627:therapeutic use*; D009061:Mouth Mucosa / Q000473:pathology* / Q000528:radiation effects*; D019226:Oral Ulcer / Q000209:etiology* / Q000473:pathology*; D011832:Radiation Injuries / Q000209:etiology* / Q000473:pathology*; D011879:Radiotherapy Dosage; D051381:Rats; D011916:Rats, Inbred F344; D012062:Relative Biological Effectiveness; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D008665:Metalloporphyrins; C491007:copper tetracarboranyltetraphenylporphyrin