Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system.
OBJECTIVE
Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated.


METHODS
Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg x kg(-1) body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED(50) +/- SE) were calculated from these curves.


RESULTS
Biodistribution studies indicated very low levels of boron (<3 microg x g(-1)) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 +/- 0.6 microg x g(-1)) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 +/- 2.6 microg x g(-1). Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation.


CONCLUSIONS
CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.
Normal Tissue Radiobiology Research Group, Research Institute, Churchill Hospital, Oxford OX3 7LJ, UK.
G M
GM
Morris
J A
JA
Coderre
J W
JW
Hopewell
P L
PL
Micca
M
M
Nawrocky
M
M
Miura
D000818:Animals; D001895:Boron; D016754:Boron Neutron Capture Therapy / Q000009:adverse effects / Q000379:methods*; D002490:Central Nervous System / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D009369:Neoplasms / Q000532:radiotherapy; D011166:Porphyrins / Q000737:chemistry*; D011833:Radiation Injuries, Experimental / Q000209:etiology; D011874:Radiometry; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000528:radiation effects; D013997:Time Factors
D011166:Porphyrins; D001895:Boron