Biomedical subjects

J A Coderre

Publications and source records attributed to J A Coderre.

At least 19 recordsLinked to original sources

PubMed2005

Porphyrin-mediated boron neutron capture therapy: a preclinical evaluation of the response of the oral mucosa.

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].

Animals↗

PubMed2004

The effect of dexamethasone on the uptake of p-boronophenylalanine in the rat brain and intracranial 9L gliosarcoma.

The steroid dexamethasone sodium phosphate (DEX) is routinely used to treat edema in brain tumor patients. The objective of the present study was to evaluate the effects of DEX on the uptake of boronophenylalanine (BPA) using the rat 9L gliosarcoma tumor model and surrounding brain tissue. Two steroid dosage protocols were used. The high-dose DEX protocol involved five 3mg/kg intraperitoneal injections at 47, 35, 23, 11 and 1 h prior to the administration of the BPA for a total dose of 15 mg DEX/kg rat. The low-dose DEX administration protocol involved two doses of 1.5mg/kg at 17 h and 1h prior to BPA injection for a total dose of 3mg DEX/kg rat. The control animals received no pretreatment, prior to the administration of BPA. Seventeen days after tumor implantation, rats were injected i.p. with 0.014 ml/g body weight BPA solution (1200 mg BPA/kg; approximately 59 mg (10)B/kg). In all groups, rats were euthanized at 3h after BPA injection. Administration of the steroid had an effect on tumor weight, which decreased to approximately 78% (p > 0.05) of the control weight in the low-dose DEX group, and approximately 48% (p < 0.001) of the control weight in the high-dose DEX group. At 3 h after the administration of BPA, the concentration of boron in tumor was comparable (p > 0.1) in the control and high-dose DEX groups. The lowest mean value (73.8+/-1.6 microg/g) was obtained in the low-dose DEX group. This was significantly lower (p > 0.02) than the tumor boron contents in the high-dose DEX and control groups, which were 81.1+/-1.9 and 79.9+/-1.7 microg/g, respectively. Tumor:blood boron partition ratios for the control, low- and high-dose DEX groups were 2.3, 2.3 and 2.5, respectively. Boron concentrations were also measured in the normal brain and in the zone of brain adjacent to the tumor exhibiting edema. Although treatment with DEX had no appreciable effect on boron uptake in the normal brain of the rat, after the administration of BPA, it did impact on the boron levels in the zone of peritumoral edema. After the high-dose DEX administration protocol, boron levels in the zone of edema were reduced by approximately 14% (p < 0.02). This finding suggests that BPA targeting of tumor cells in the peritumoral zone could be compromised by DEX. These cells appear to play a critical role in tumor recurrence after BNCT or conventional radiotherapy.

Animals↗

PubMed2004

Tolerance of normal human brain to boron neutron capture therapy.

Data from the Harvard-MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1cm(3)) dose and average whole-brain dose show a steep dose-response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED(50)+/-SE) were 6.2+/-1.0 Gy(w) for average whole-brain dose and 14.1+/-1.8 Gy(w) for peak brain dose.

Boron Compounds↗

PubMed2004

Effects of boron neutron capture irradiation on the normal lung of rats.

The whole lung of rats was irradiated with X-rays, thermal neutrons, or thermal neutrons in the presence of p-boronophenylalanine (BPA). A >/= 20% increase in breathing rate, in the period 40-80 days after irradiation, was indicative of radiation-induced pneumonitis. The ED(50) (+/-SE) for a >/= 20% increase in breathing rate, relative to age-matched controls, was 11.6 +/- 0.13 Gy for X-rays and 9.6 +/- 0.08 Gy for neutrons only. This indicated a thermal neutron beam RBE of 1.2 and an RBE of 2.2 for the high-LET components of the dose, assuming a dose reduction factor of 1.0 for gamma rays. Preliminary data indicate the compound biological effectiveness factor for BPA in the lung is approximately 1.5.

Animals↗

PubMed2003

Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system.

PURPOSE: 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. MATERIALS AND 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.

Animals↗

PubMed2002

The combination of X-ray-mediated radiosurgery and gene-mediated immunoprophylaxis for advanced intracerebral gliosarcomas in rats.

Rats with advanced, imminently lethal, approximately 4 mm diameter, left-sided intracerebral 9L gliosarcoma (9LGS), a well characterized malignant tumor with some similarities to human high-grade astrocytomas, were used as a therapy model 14 days post-implantation of 10(4) cells. Such tumor-bearing rats die within two weeks (median, 6 days) thereafter if untreated. However, if these tumors are exposed on day 14 to 12-25 Gy of an electron-equilibrated 6 MV photon beam (radiosurgery), survival is extended about 5-6 fold to a median of 34 days, but long-term survival (> 1 year) is increased only to approximately 18%. Multiple subcutaneous inoculations of radiation-disabled 9LGS cells post-radiosurgery (immunoprophylaxis) extended lifespan and long-term (> 1 year) survival minimally (median, 37 days; 25%, respectively). In sharp contrast, radiosurgery followed by multiple subcutaneous inoculations of radiation-disabled 9LGS cells that had been transfected with granulocyte macrophage colony stimulating factor (GMCSF), a cytokine with demonstrated immune-enhancing properties (i.e. gene-mediated immunoprophylaxis, GMIMPR) increased long-term survival to approximately 67%. To our knowledge, these results are the first to show that the combination of photon radiosurgery and GMIMPR is effective for an advanced, imminently lethal brain tumor in a mammal. These data raise the possibility that GMIMPR following radiation therapy might prove effective for the treatment of some human malignant gliomas.

Animals↗

PubMed2002

Boron microquantification in oral muscosa and skin following administration of a neutron capture therapy agent.

Clinical trials of boron neutron capture therapy (BNCT) for intracranial tumours using boronophenylalanine-fructose undertaken at Harvard-MIT and Brookhaven National Laboratory have observed acute normal tissue reactions in the skin and oral mucosa. Because the range of the 10B(n, alpha)7Li reaction products is very short, 10-14 microns combined, knowledge of the 10B microdistribution in tissue is critical for understanding the microdosimetry and radiobiology of BNCT. This paper reports measurements of the microdistribution of 10B in an animal model, rat skin and tongue, using high resolution quantitative autoradiography (HRQAR), a neutron-induced etched track autoradiographic technique. The steep spatial gradient and high absolute value relative to blood of the 10B concentration observed in some strata of the rat tongue epithelium and skin are important for properly evaluating the radiobiology and the biological effectiveness factors for normal tissue reactions such as oral mucositis, which are generally assessed using the blood boron concentration rather than the tissue boron concentration.

Animals↗

PubMed2002

Long-term infusions of p-boronophenylalanine for boron neutron capture therapy: evaluation using rat brain tumor and spinal cord models.

Rat 9L gliosarcoma cells infiltrating the normal brain have been shown previously to accumulate only approximately 30% as much boron as the intact tumor after administration of the boronated amino acid p-boronophenylalanine (BPA). Long-term i.v. infusions of BPA were shown previously to increase the boron content of these infiltrating tumor cells significantly. Experiments to determine whether this improved BPA distribution into infiltrating tumor cells after a long-term i.v. infusion improves tumor control after BNCT in this brain tumor model and whether it has any deleterious effects in the response of the rat spinal cord to BNCT are the subjects of the present report. BPA was administered in a fructose solution at a dose of 650 mg BPA/kg by single i.p. injection or by i.v. infusion for 2 h or 6 h, at 330 mg BPA/kg h(-1). At 1 h after the end of either the 2-h or the 6-h infusion, the CNS:blood (10)B partition ratio was 0.9:1. At 3 h after the single i.p. injection, the ratio was 0.6:1. After spinal cord irradiations, the ED(50) for myeloparesis was 14.7 +/- 0.4 Gy after i.p. administration of BPA and 12.9 +/- 0.3 Gy in rats irradiated after a 6-h i.v. infusion of BPA; these values were significantly different (P < 0.001). After irradiation with 100 kVp X rays, the ED(50) was 18.6 +/- 0.1 Gy. The boron compound biological effectiveness (CBE) factors calculated for the boron neutron capture dose component were 1.2 +/- 0.1 for the i.p. BPA administration protocol and 1.5 +/- 0.1 after irradiation using the 6-h i.v. BPA infusion protocol (P < 0.05). In the rat 9L gliosarcoma brain tumor model, the blood boron concentrations at 1 h after the end of the 2-h infusion (330 mg BPA/kg h(-1); n = 15) or after the 6-h infusion (190 mg BPA/kg h(-1); n = 13) were 18.9 +/- 2.2 microg 10B/g and 20.7 +/- 1.8 microg 10B/g, respectively. The irradiation times were adjusted individually, based on the preirradiation blood sample, to deliver a predicted 50% tumor control dose of 8.2 Gy ( approximately 30 photon-equivalent Gy) to all tumors. In the present study, the long-term survival was approximately 50% and was not significantly different between the 2-h and the 6-h infusion groups. The mode of BPA administration and the time between administration and irradiation influence the 10B partition ratio between the CNS and the blood, which in turn influences the measured CBE factor. These findings underline the need for clinical biodistribution studies to be carried out to establish 10B partition ratios as a key component in the evaluation of modified administration protocols involving BPA.

Animals↗

PubMed2001

Quantitative imaging and microlocalization of boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy: relevance to neutron capture therapy.

Boron neutron capture therapy (BNCT) is dependent on the selective accumulation of boron-10 in tumor cells relative to the contiguous normal cells. Ion microscopy was used to evaluate the microdistribution of boron-10 from p-boronophenylalanine (BPA) in the 9L rat gliosarcoma and the F98 rat glioma brain tumor models. Four routes of BPA administration were used: i.p. injection, intracarotid (i.c.) injection [with and without blood-brain barrier disruption (BBB-D)], and continuous timed i.v. infusions. i.p. injection of BPA in the 9L gliosarcoma resulted in a tumor-to-brain (T:Br) boron-10 concentration ratio of 3.7:1 when measured at the tumor-normal brain interface. In the F98 glioma, i.c injection of BPA resulted in a T:Br ratio of 2.9:1, and this increased to 5.4:1 when BBB-D was performed. The increased tumor boron uptake would potentially enhance the therapeutic ratio of BNCT by >25%. At present, ion microscopy is the only technique to provide a direct measurement of the T:Br boron-10 concentration ratio for tumor cells infiltrating normal brain. In the 9L gliosarcoma, this ratio was 2.9:1 after i.p. administration. In the F98 glioma, i.c injection resulted in a ratio of 2.2:1, and this increased to 3.0:1 after BBB-D. Ion microscopy revealed a consistent pattern of boron-10 microdistribution for both rat brain tumor models. The boron-10 concentration in the main tumor mass (MTM) was approximately twice that of the infiltrating tumor cells. One hour after a 2-h i.v. infusion of BPA in rats with the 9L gliosarcoma, tumor boron-10 concentrations were 2.7 times higher than that of infiltrating tumor cells [83 +/- 23 microg/g tissue versus 31 +/- 12 microg/g tissue (mean +/- SD)]. Continuous 3- and 6-h i.v. infusions of BPA in the 9L gliosarcoma resulted in similar high boron-10 concentrations in the MTM. The boron-10 concentration in infiltrating tumor cells was two times lower than the MTM after a 3-h infusion. After 6 h, the boron-10 concentration in infiltrating tumor cells had increased nearly 90% relative to the 2- and 3-h infusions. A 24-h i.v. infusion resulted in similar boron-10 levels between the MTM and the infiltrating tumor cells. Boron concentrations in the normal brain were similar for all four infusion times (approximately 20 microg/g tissue). These results are important for BNCT, because clinical protocols using a 2-h infusion have been performed with the assumption that infiltrating tumor cells contain equivalent amounts of boron-10 as the MTM. The results reported here suggest that this is not the case and that a 6-h or longer infusion of BPA may be necessary to raise boron-10 levels in infiltrating tumor cells to that in the MTM.

Animals↗

PubMed2001

Biodistribution of copper carboranyltetraphenylporphyrins in rodents bearing an isogeneic or human neoplasm.

The biodistributions of carborane-containing copper porphyrins, CuTCP and CuTCPH, have been studied previously in mice bearing subcutaneously implanted mammary carcinomas. We now report biodistributions of those porphyrins in Fischer 344 rats bearing intracranial and/or multiple subcutaneous isogeneic 9L gliosarcomas (9LGS). The porphyrin was given either by i.v. infusion or by multiple i.p. injections. When 190 mg CuTCPH/kg body weight was given to the rats by i.v. infusion, median tissue boron concentrations (microg/g) 3 days after the end of infusion were: 64 in subcutaneous tumor, 13 in intracranial tumor, 1 in blood and 3 in brain. When 450 mg CuTCPH/kg body weight was given to the rats by serial i.p. injections, the median concentrations (microg B/g) 4 days after the last injection were: 117 in subcutaneous tumor, 50 in intracranial tumor, 4 in blood, and 4 in brain. CuTCPH biodistribution was also studied in xenografts of the human malignant gliomas U87 and U373, and of the murine EMT-6 mammary carcinoma and the rat 9LGS, each grown subcutaneously in mice with severe combined immunodeficiency (SCIDs). In SCIDs, median boron concentrations (microg/g) 2 days after the last s.c. injection of a total of 190 mg CuTCPH/kg body weight were: 251 in U373, 33 in U87, <0.6 in blood and <0.5 in brain. Because there were such high boron levels in the U373, and because xenografted U373 is similar to spontaneous intracerebral human glioblastoma multiforme (GBM) microscopically, CuTCPH could prove useful as a boron carrier for boron neutron-capture therapy (BNCT) of GBM and of other human malignant gliomas.

Animals↗

PubMed2001

Boron neutron capture therapy: effects of split dose and overall treatment time.

New clinical protocols are being developed that will entail the administration of considerably higher doses of the boron delivery agent boronophenylalanine (BPA) than those in current clinical use. Fractionation (2 or 4 fractions) of BPA mediated boron neutron capture therapy (BNCT) is also under consideration at some clinical centres. Given the considerably higher infusion volumes that will be entailed in the delivery of BPA in the new high dosage protocols, there will be a requirement to extend the gap between fractions to 2 or more days. In order to assess the effects of a 2 fraction protocol on the therapeutic efficacy of BPA mediated BNCT, a series of split dose irradiations (two equal fractions) were undertaken using the rat intracranially implanted 9L gliosarcoma model. A single dose exposure to BPA mediated BNCT of 3.0 Gy resulted in long term survival levels of 50%. Survival levels increased to 71% and 77% with a 3 and 5 day gap between dose fractions (two equal fractions), respectively, using the same total dose. A further increase in the time interval between dose fractions to 7 days resulted in a reduction in survival to 36%. However, there was no significant difference between the single dose and the 3, 5 and 7 day survival data (P > 0.1) The difference between the 5 and 7 day split dose survival data was of border-line significance (P = 0.05). It is anticipated that mucositis, could become a potential problem in future BNCT clinical protocols involving higher doses, larger field sizes or multiple fields. The potential sparing of the oral mucosa, due to repopulation during the interval between the two fractions, was investigated using a series of split dose BPA mediated BNC irradiations. The ventral surface of the rat tongue was utilised as a model for oral mucosa. The ED50 (50% incidence) values for the ulceration end point were 3.0+/-0.1, 3.2+/-0.1, 3.0+/-0.1 and 3.6+/-0.1 Gy, for 3, 5, 7 and 9 day splits between doses, respectively. It is evident from this data that there were no significant changes in the ED50 (p < 0.001) until the 9 day dose split, when the ED50 value was 20% higher than the ED50 value after a 7 day split. It was concluded that the two fraction BNCT protocol, with dose splits of up to 5 days, did not diminish the therapeutic response of the rat 9L gliosarcoma, when compared with a single dose BNCT protocol. Tolerance of the oral mucosa to BNC irradiation was not increased until there was a 9 day gap between fractions. However, the beneficial effects of dose sparing at this time interval between doses, would probably be counteracted by a reduction in the therapeutic effectiveness of the BNCT modality, due to repopulation of tumour clonogens between doses.

Alanine↗

PubMed2001

Boron neutron capture therapy of a murine mammary carcinoma using a lipophilic carboranyltetraphenylporphyrin.

The first control of a malignant tumor in vivo by porphyrin- mediated boron neutron capture therapy (BNCT) is described. In mice bearing implanted EMT-6 mammary carcinomas, boron uptake using a single injection of either p-boronophenylalanine (BPA) or mercaptoundecahydrododecaborane (BSH) was compared with either a single injection or multiple injections of the carboranylporphyrin CuTCPH. The BSH and BPA doses used were comparable to the highest doses of these compounds previously administered in a single injection to rodents. For BNCT, boron concentrations averaged 85 microg (10)B/g in the tumor and 4 microg (10)B/g in blood 2 days after the last of six injections (over 32 h) that delivered a total of 190 microg CuTCPH/g body weight. During a single 15, 20, 25 or 30 MW-min exposure to the thermalized neutron beam of the Brookhaven Medical Research Reactor, a tumor received average absorbed doses of approximately 39, 52, 66 or 79 Gy, respectively. A long-term (>200 days) tumor control rate of 71% was achieved at a dose of 66 Gy with minimal damage to the leg. Equivalent long-term tumor control by a single exposure to 42 Gy X rays was achieved, but with greater damage to the irradiated leg.

Animals↗

PubMed2000

Models for estimation of the (10)B concentration after BPA-fructose complex infusion in patients during epithermal neutron irradiation in BNCT.

PURPOSE: To create simple and reliable models for clinical practice for estimating the blood (10)B time-concentration curve after p-boronophenylalanine fructose complex (BPA-F) infusion in patients during neutron irradiation in boron neutron capture therapy (BNCT). METHODS AND MATERIALS: BPA-F (290 mg BPA/kg body weight) was infused i.v. during two hours to 10 glioblastoma multiforme patients. Blood samples were collected during and after the infusion. Compartmental models and bi-exponential function fit were constructed based on the (10)B blood time-concentration curve. The constructed models were tested with data from six additional patients who received various amounts of infused BPA-F and data from one patient who received a one-hour infusion of 170 mg BPA/kg body weight. RESULTS: The resulting open two-compartment model and bi-exponential function estimate the clearance of (10)B after 290 mg BPA/kg body weight infusion from the blood with satisfactory accuracy during the first irradiation field (1 ppm, i.e., 7%). The accuracy of the two models in predicting the clearance of (10)B during the second irradiation field are for two-compartment model 1.0 ppm (8%) and 0.2 ppm (2%) for bi-exponential function. The models predict the average blood (10)B concentration with an increasing accuracy as more data points are available during the treatment. CONCLUSION: By combining the two models, a robust and practical modeling tool is created for the estimation of the (10)B concentration in blood after BPA-F infusion.

Boron↗

PubMed2000

Determination of the MRI contrast agent concentration time course in vivo following bolus injection: effect of equilibrium transcytolemmal water exchange.

For bolus-tracking studies, it is commonly assumed that CR concentration bears a linear relationship with the measured (usually longitudinal) (1)H(2)O relaxation rate constant, R*(1) identical with(T(1) *)(-1). This requires that equilibrium transcytolemmal water exchange be in the fast exchange limit (FXL). However, though systems remain in fast exchange, the FXL will not usually obtain. Here, the consequences are considered: 1) the measurement of R(1) * itself can be affected, 2) the resultant non-linear [CR]-dependence causes significant error by assuming FXL, 3) the thermodynamic [CR] (based on the space in which CR is actually distributed) can be determined, 4) transcytolemmal water permeability may be estimated, and 5) the pharmacokinetic parameters can be factored. For a 30-sec, 0.17 mmol/kg dose of GdDTPA(2-), the FXL assumption underestimates the [CR] maximum in rat thigh muscle by a factor of almost two. Similar results are obtained for a rat brain GS-9L gliosarcoma tumor model.

Animals↗

PubMed2000

The combination of boron neutron-capture therapy and immunoprophylaxis for advanced intracerebral gliosarcomas in rats.

Glioblastoma multiforme (GBM) is the most common primary human brain tumor. About 7000 new cases are diagnosed yearly in the USA and GBM is almost invariably fatal within a few years after it is diagnosed. Despite current neurosurgical and radiotherapeutic tumor cytoreduction methods, in most cases occult foci of tumor cells infiltrate surrounding brain tissues and cause recurrent disease. Therefore the combination of neurosurgical and radiotherapeutic debulking methods with therapies to inhibit occult GBM cells should improve prognosis. In this study we have combined boron neutron-capture therapy (BNCT), a novel binary radiotherapeutic treatment modality that selectively irradiates tumor tissue and largely spares normal brain tissue, with immunoprophylaxis, a form of active immunization initiated soon after BNCT treatment, to treat advanced, clinically relevantly-sized brain tumors in rats. Using a malignant rat glioma model of high immunogenicity, the 9L gliosarcoma, we have shown that about half of the rats that would have died after receiving BNCT debulking alone, survived after receiving BNCT plus immunoprophylaxis. Further, most of the surviving rats display immunological-based resistance to recurrent 9LGS growth six months or more after treatment. To our knowledge this study represents the first time BNCT and immunoprophylaxis have been combined to treat advanced brain tumors in rats.

Animals↗

PubMed2000

Tolerance of the normal canine brain to epithermal neutron irradiation in the presence of p-boronophenylalanine.

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950 mg of 10B-enriched BPA/kg as its fructose complex. The 5 x 10 cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose-volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1 cm3 of brain at the depth of maximum thermal neutron flux) ranged from 7.6 Gy (photon-equivalent dose: 11.8 Gy-Eq) to 11.6 Gy (17.5 Gy-Eq). The average dose to the brain ranged from 3.0 Gy (4.5 Gy-Eq) to 8.1 Gy (11.9 Gy-Eq) and to the left hemisphere, 6.6 Gy (10.1 Gy-Eq) to 10.0 Gy (15.0 Gy-Eq). Maximum tolerated 'threshold' doses were 6.7 Gy (9.8 Gy-Eq) to the whole brain and 8.2 Gy (12.3 Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5 Gy (14.3 Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.

Animals↗

PubMed2000

Long-term immunological memory in the resistance of rats to transplanted intracerebral 9L gliosarcoma (9LGS) following subcutaneous immunization with 9LGS cells.

Glioblastoma multiforme (GBM) is the most common primary human brain tumor. About 7000 new cases are diagnosed yearly in the USA. Despite current neurosurgical and postoperative radiotherapeutic tumor cytoreduction methods, in most cases occult foci of tumor cells infiltrate surrounding edematous brain tissues and cause recurrent disease within one year. GBM is almost invariably fatal within a few years after it is diagnosed. Our goal is to achieve long-term control of GBM by combining immunoprophylaxis with a radiation-based technique, such as boron neutron-capture therapy (BNCT), potentially capable of specifically targeting the infiltrating tumor cells while sparing the surrounding normal brain tissue. It has long been known that the subcutaneous (sc) injection of irradiated cells or untreated cultured cells (and the removal of the resulting tumors) derived from the well characterized, highly immunogenic 9L gliosarcoma (9LGS) rat model into young isogenic rats can prevent tumor growth after subsequent sc or intracranial (ic) injection of untreated, otherwise lethal 9LGS cells. In this study we have confirmed, quantified and extended those findings to study the efficacy of such immunological memory in normal aging rats and in aging rats previously treated for ic 9LGS tumors by BNCT. (1) The sc injection of 5,000,000 untreated 9LGS cells and the surgical removal of the resulting tumors (method A) protected 80% of normal young rats from an ic challenge with 10,000 untreated 9LGS cells, and a single sc injection of 5,000,000 lethally X-irradiated 9LGS cells (method B) protected 66% of them, but multiple sc injections with a crude particulate fraction prepared from 9LGS cells were not protective. Protection is long-lasting since contralateral ic rechallenge of six-month survivors with an injection of 10,000 viable 9LGS cells resulted in 100% survival. (2) Normal one-year-old rats were only slightly less protected than were normal young rats, approximately 70% rather than approximately 80% (method A) and approximately 60% rather than approximately 66% (method B). (3) BNCT treatment alone resulted in partial immunological protection, as 30% of one-year post-BNCT survivors of ic 9LGS tumors prevailed after contralateral ic rechallenge with 10,000 viable 9LGS cells. Moreover a single sc immunization with 5,000,000 untreated 9LGS cells prior to ic rechallenge boosted survival from 30% to 100%. The relevance of these observations to strategies of preclinical experimentation for immunoprophylaxis of malignant gliomas is discussed.

Animals↗

PubMed2000

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy.

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,alpha)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 +/- 0.02. This compares with a previously published CBE factor for BPA of 4.87 +/- 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT.

Animals↗