boron and Melanoma

Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (

Topics: Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Head and Neck Neoplasms; Humans; Melanoma

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Glioblastoma; Humans; Isotopes; Melanoma; Neoplasms; Phenylalanine; Positron-Emission Tomography

In an investigation by the Swedish Cancer Society, an expert group described the present status, critical issues and future aspects and potentials for each of nine major areas of radiation therapy research. This report deals with radiation therapy using activation of stable nuclides.

Topics: Boron; Gadolinium; Glioma; Humans; Isotopes; Melanoma; Neoplasms; Neutron Capture Therapy

Topics: Adolescent; Animals; Boron; Boron Compounds; Cricetinae; Fatty Acids, Unsaturated; Gene Expression Regulation, Neoplastic; Hair Color; Humans; Infant, Newborn; Isotopes; Male; Melanins; Melanocytes; Melanoma; Melanoma, Experimental; Models, Biological; Monophenol Monooxygenase; Neoplasm Proteins; Neutrons; Phenylalanine; Pigmentation Disorders; Protein Processing, Post-Translational; Pyrones; Radiation-Sensitizing Agents; Skin Pigmentation; Subcellular Fractions; Swine

Topics: Animals; Antibodies, Monoclonal; Boron; Brain Neoplasms; Humans; Isotopes; Melanoma; Mice; Neutrons; Nuclear Reactors; Pharmaceutical Vehicles; Rats; Skin Neoplasms

Topics: Animals; Autoradiography; Bone Neoplasms; Boron; Brain; Brain Neoplasms; Carcinoma, Ehrlich Tumor; Glioma; Humans; Hyperthermia, Induced; Isotopes; Melanoma; Meningeal Neoplasms; Meningioma; Neutrons; Nuclear Reactors; Osteosarcoma; Radiotherapy Dosage; Sarcoma; Tomography, X-Ray Computed

A study of the (10)B-enriched p-boronophenylalanine-fructose complex ((10)BPA-F) infusion procedure in potential BNCT patients, including four melanoma of extremities and two high-grade gliomas (glioblastoma and ganglioglioma) was performed. T/B and S/B ratios for (10)B concentrations in tumor (T), blood (B) and skin (S) were determined. The T/B ratio for the glioblastoma was in the 1.8-3.4 range. The ganglioglioma did not show any significant boron uptake. For the nodular metastasic melanoma T/B values were between 1.5 and 2.6 (average 2.1+/-0.4), corresponding to the lower limit of the mean values reported for different melanoma categories. This result might suggest a lower boron uptake for nodular metastasic melanomas. S/B was 1.5+/-0.4. An open two-compartment pharmacokinetic model was applied to predict the boron concentration during the course and at the end of a BNCT irradiation.

Topics: Adult; Aged; Argentina; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Female; Fructose; Ganglioglioma; Glioblastoma; Humans; Male; Melanoma; Middle Aged

A Phase I/II protocol for treating cutaneuos melanomas with BNCT was designed in Argentina by the Comisión Nacional de Energía Atómica and the medical center Instituto Roffo. The first of a cohort of thirty planned patients was treated on October 9, 2003. This article depicts the protocol-based procedure and describes the first clinical case, treatment regime and planning, patient irradiation, retrospective dosimetric analysis and clinical outcome. Considering the low acute skin toxicity and the complete response in 21 of the 25 subcutaneous melanoma nodules treated, a second irradiation was performed in a different location of the extremity of the same patient. The corresponding clinical outcome is still under evaluation.

Topics: Argentina; Boron; Boron Compounds; Boron Neutron Capture Therapy; Clinical Protocols; Female; Fructose; Humans; Melanoma; Middle Aged; Radiotherapy Planning, Computer-Assisted; Skin Neoplasms; Treatment Outcome

Twenty-two patients with malignant melanoma were treated with boron neutron capture therapy (BNCT) using 10B-p-boronophenylalanine (BPA). The estimation of absorbed dose and optimization of treatment dose based on the pharmacokinetics of BPA in melanoma patients is described. The doses of gamma-rays were measured using small TLDs of Mg2SiO4 (Tb) and thermal neutron fluence was measured using gold foil and wire. The total absorbed dose to the tissue from BNCT was obtained by summing the primary and capture gamma-ray doses and the high LET radiation doses from 10B(n, alpha)7Li and 14N(n,p)14C reactions. The key point of the dose optimization is that the skin surrounding the tumour is always irradiated to 18 Gy-Eq, which is the maximum tolerable dose to the skin, regardless of the 10B-concentration in the tumor. The neutron fluence was optimized as follows. (1) The 10B concentration in the blood was measured 15-40 min after the start of neutron irradiation. (2) The 10B-concentration in the skin was estimated by multiplying the blood 10B value by a factor of 1.3. (3) The neutron fluence was calculated. Absorbed doses to the skin ranged from 15.7 to 37.1 Gy-Eq. Among the patients, 16 out of 22 patients exhibited tolerable skin damage. Although six patients showed skin damage that exceeded the tolerance level, three of them could be cured within a few months after BNCT and the remaining three developed severe skin damage requiring skin grafts. The absorbed doses to the tumor ranged from 15.7 to 68.5 Gy-Eq and the percentage of complete response was 73% (16/22). When BNCT is used in the treatment of malignant melanoma, based on the pharmacokinetics of BPA and radiobiological considerations, promising clinical results have been obtained, although many problems and issues remain to be solved.

Topics: Aged; Aged, 80 and over; Boron; Boron Neutron Capture Therapy; Dose-Response Relationship, Radiation; Female; Humans; Isotopes; Male; Melanoma; Middle Aged; Radiation Injuries; Radiometry; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Skin; Skin Neoplasms; Treatment Outcome

A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain.. Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250-350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions.. Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy.. We have demonstrated that BPA-f-mediated NCT can be precisely planned and delivered in a carefully controlled manner. Subsequent clinical trials of boron neutron capture therapy at Harvard and MIT will be initiated with a new high-intensity, high-quality epithermal neutron beam.

Topics: Adult; Aged; Boron; Brain; Brain Neoplasms; Female; Glioblastoma; Humans; Male; Melanoma; Middle Aged; Neutron Capture Therapy; Neutrons; Phantoms, Imaging; Radiometry; Radiotherapy Planning, Computer-Assisted; Tomography, X-Ray Computed

An open two-compartment model has been developed for predicting (10)B concentrations in blood after intravenous infusion of the l-p-boronophenylalanine-fructose complex (BPA-F) in humans and derived from studies of pharmacokinetics in 24 patients in the Harvard-MIT Phase I clinical trials of BNCT. The (10)B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of approximately 32 microg/g (for infusion of 350 mg/kg over 90 min) followed by a biphasic exponential clearance profile with half-lives of 0.34 +/- 0.12 and 9.0 +/- 2.7 h, due to redistribution and primarily renal elimination, respectively. The model rate constants k(1), k(2) and k(3) are 0.0227 +/- 0.0064, 0.0099 +/- 0.0027 and 0.0052 +/- 0.0016 min(-1), respectively, and the central compartment volume of distribution, V(1), is 0.235 +/- 0.042 kg/kg. The validity of this model was demonstrated by successfully predicting the average pharmacokinetic response for a cohort of patients who were administered BPA-F using an infusion schedule different from those used to derive the parameters of the model. Furthermore, the mean parameters of the model do not differ for cohorts of patients infused using different schedules.

Topics: Adult; Aged; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Female; Fructose; Glioblastoma; Humans; Infusions, Intravenous; Male; Melanoma; Middle Aged; Models, Biological; Phenylalanine; Skin Neoplasms

Topics: Boron; Clinical Trials as Topic; Gamma Rays; Humans; Isotopes; Melanoma; Neutrons; Radiotherapy; Radiotherapy Dosage; Skin Neoplasms

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Drug Delivery Systems; Fructose; Melanoma; Mice

Boron neutron capture therapy (BNCT) is a type of radiation therapy for eradicating tumor cells through a

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Death; Cell Line, Tumor; Cell Survival; Cobalt Radioisotopes; Computer Simulation; Dose-Response Relationship, Radiation; Gamma Rays; Humans; Isotopes; Melanoma; Models, Biological; Monte Carlo Method; Neutrons; Phenylalanine; Radiometry; Relative Biological Effectiveness; Time Factors

Our aim was to assess the long-term clinical outcome of boron neutron capture therapy (BNCT) using 10B-para-boronophenylalanine (BPA) as the boron delivery agent for cutaneous melanoma. Eight patients (eight lesions) were treated between October 2003 and April 2014. Their ages ranged from 48 to 86 years at the time of treatment. All of the targets were primary lesions and they were located on the sole or face. No patient had evidence of regional lymph node involvement, distant metastases or an active secondary cancer. The clinical stage was cT1-2N0M0 and performance scores were <2. BNCT was carried out at the Kyoto University Research Reactor (KUR). The patients were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin dose. Eight patients were evaluated and six showed a complete response (CR), while two patients had a partial response (PR). Of the two patients with a PR, one has remained a PR with brown spots persisting for 7.5 years following BNCT. The tumor in the other patient recurred after 6 years at the site of persisting brown macula. The overall control rate (CR + PR without recurrence) for the cohort was 88% (7/8). There have never been any adverse events >Grade 2 for the long follow-up period. Our results suggest that BNCT may be a promising treatment modality in the management of early stage cutaneous melanoma when wide local excision is not feasible.

Topics: Aged; Aged, 80 and over; Boron; Boron Neutron Capture Therapy; Female; Follow-Up Studies; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Recurrence, Local; Radiation Dosage; Radiometry; Radiotherapy Dosage; Skin Neoplasms; Treatment Outcome

Patients with the same histopathologic diagnosis of cutaneous melanoma treated with identical protocols of boron neutron capture therapy (BNCT) have shown different clinical outcomes. The objective of the present studies was to evaluate the biodistribution of boronophenilalanina ((10)BPA) for the potential application of BNCT for the treatment of melanoma on an individual basis.. The boronophenilalanine (BPA) uptake was evaluated in 3 human melanoma cell lines: MEL-J, A375, and M8. NIH nude mice were implanted with 4 10(6) MEL-J cells, and biodistribution studies of BPA (350 mg/kg intraperitoneally) were performed. Static infrared imaging using a specially modified infrared camera adapted to measure the body infrared radiance of small animals was used. Proliferation marker, Ki-67, and endothelial marker, CD31, were analyzed in tumor samples.. The in vitro studies demonstrated different patterns of BPA uptake for each analyzed cell line (P<.001 for MEL-J and A375 vs M8 cells). The in vivo studies showed a maximum average boron concentration of 25.9 ± 2.6 μg/g in tumor, with individual values ranging between 11.7 and 52.0 μg/g of (10)B 2 hours after the injection of BPA. Tumor temperature always decreased as the tumors increased in size, with values ranging between 37 °C and 23 °C. A significant correlation between tumor temperature and tumor-to-blood boron concentration ratio was found (R(2) = 0.7, rational function fit). The immunohistochemical studies revealed, in tumors with extensive areas of viability, a high number of positive cells for Ki-67, blood vessels of large diameter evidenced by the marker CD31, and a direct logistic correlation between proliferative status and boron concentration difference between tumor and blood (R(2) = 0.81, logistic function fit).. We propose that these methods could be suitable for designing new screening protocols applied before melanoma BNCT treatment for each individual patient and lesion.

Topics: Animals; Body Temperature; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Humans; Ki-67 Antigen; Melanoma; Melanoma, Cutaneous Malignant; Mice; Mice, Nude; Phenylalanine; Platelet Endothelial Cell Adhesion Molecule-1; Radioisotopes; Skin Neoplasms; Tissue Distribution; Tumor Burden

Neutron autoradiography is an imaging methodology that enables analysis of the spatial distribution of heavy ion emitters in a given material. In particular, it allows localization of (10)B in a tissue section put in contact with a nuclear track detector. Boron imaging is essential when considering boron neutron capture therapy as an option for treating cancerous tumors. A description of the autoradiography method is presented together with specific characteristics and technical details developed in our laboratory. We propose a new mounting technique to compare autoradiography images with the same section that gave rise to the latent tracks. The solid state nuclear track detector is polycarbonate, because it can be processed rapidly to obtain the autoradiographic results. It is a transparent material, which allows visualization of the sections mounted on it. Tissue can be removed easily and background is minimal.

Topics: Animals; Autoradiography; Boranes; Boron; Humans; Liver; Melanoma; Mice; Mice, Nude; Neoplasms, Experimental; Phenylalanine; Polycarboxylate Cement

Positron emission tomography (PET) has become a key imaging tool in clinical practice and biomedical research to quantify and study biochemical processes in vivo. Physiologically active compounds are tagged with positron emitters (e.g. (18)F, (11)C, (124)I) while maintaining their biological properties, and are administered intravenously in tracer amounts (10(-9)-10(-12)M quantities). The recent physical integration of PET and computed tomography (CT) in hybrid PET/CT scanners allows a combined anatomical and functional imaging: nowadays PET molecular imaging is emerging as powerful pharmacological tool in oncology, neurology and for treatment planning as guidance for radiation therapy. The in vivo pharmacokinetics of boron carrier for BNCT and the quantification of (10)B in living tissue were performed by PET in the late nineties using compartmental models based on PET data. Nowadays PET and PET/CT have been used to address the issue of pharmacokinetic, metabolism and accumulation of BPA in target tissue. The added value of the use of L-[(18)F]FBPA and PET/CT in BNCT is to provide key data on the tumour extraction of (10)B-BPA versus normal tissue and to predict the efficacy of the treatment based on a single-study patient analysis. Due to the complexity of a binary treatment like BNCT, the role of PET/CT is currently to design new criteria for patient enrolment in treatment protocols: the L-[(18)F]BPA/PET methodology could be considered as an important tool in newly designed clinical trials to better estimate the concentration ratio of BPA in the tumour as compared to neighbouring normal tissues. Based on these values for individual patients the decision could be made whether BNCT treatment could be advantageous due to a selective accumulation of BPA in an individual tumour. This approach, applicable in different tumour entities like melanoma, glioblastoma and head and neck malignancies, make this methodology as reliable prognostic and therapeutic indicator for patient undergoing BNCT.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Fluorine Radioisotopes; Humans; Isotopes; Lymphatic Metastasis; Melanoma; Models, Biological; Neoplasms; Phenylalanine; Positron-Emission Tomography; Prognosis; Radiation-Sensitizing Agents; Tomography, X-Ray Computed

The aim was to investigate and compare the influence of linear energy transfer (LET), dose and time on the induction of apoptosis in a human melanoma cell line exposed to accelerated light boron ((10)B) ions and photons. Cells were exposed in vitro to doses up to 6 Gy accelerated boron ions (40, 80, 125 and 160 eV nm(-1)) and up to 12 Gy photons (0.2 eV nm(-1)). The induction of apoptosis was measured up to 9 days after irradiation using morphological characterization of apoptotic cells and bodies. In parallel, measurements of cell-cycle distribution, monitored by DNA flow cytometry, and cell survival based on the clonogenic cell survival assay, were performed. In addition, the induction and repair of DNA double-strand breaks (DSB), using pulsed-field gel electrophoresis (PFGE) were studied. Accelerated boron ions induced a significant increase in apoptosis as compared with photons at all time points studied. At 1-5 h the percentage of radiation-induced apoptotic cells increased with both dose and LET. At the later time points (24-216 h) the apoptotic response was more complex and did not increase in a strictly LET-dependent manner. The early premitotic apoptotic cells disappeared at 24 h following exposure to the highest LET (160 eV nm(-1)). A postmitotic apoptotic response was seen after release of the dose-, time- and LET-dependent G2/M accumulations. The loss of clonogenic ability was dose- and LET-dependent and the fraction of un-rejoined DSB increased with increasing LET. Despite the LET-dependent clonogenic cell killing, it was not possible to measure quantitatively a LET-dependent apoptotic response. This was due to the different time course of appearance and disappearance of apoptotic cells.

Topics: Apoptosis; Boron; Cell Division; Cell Line, Tumor; Cell Survival; DNA Damage; DNA Repair; G2 Phase; Humans; Linear Energy Transfer; Melanoma

A new approach to determine the tumor-to-blood (10)B concentration ratio in boron neutron capture therapy (BNCT) is introduced. It is a statistical method, which uses maximum likelihood estimation on the clinical outcome of a BNCT treatment. Its performance is shown in a clinical case of cutaneous multiple nodular melanomas. The calculations involve a detailed dosimetry analysis, the determination of tumor control probabilities for the different nodules, the maximum likelihood estimation itself, and a parametric bootstrap to obtain confidence intervals for the tumor-to-blood ratio. The obtained ratio is 3.05 +/- 0.46 with a 95%-confidence interval. These results are consistent with those found in literature. Moreover, a single patient with multiple nodules proves enough to get statistically relevant results. The proposed method does not involve surgery and can be performed after a BNCT treatment without being invasive for the patient.

Topics: Boron; Boron Neutron Capture Therapy; Confidence Intervals; Humans; Isotopes; Likelihood Functions; Melanoma; Models, Biological; Radiotherapy Dosage

Boron neutron capture therapy (BNCT) is based on the ability of the non-radioactive isotope 10B to capture thermal neutrons and to disintegrate instantaneously. This reaction opens a way to selectively destroy tumour cells after specific uptake of 10B. In this paper, a method based on electron energy-loss spectroscopy is presented for detecting and quantifying boron in freeze-dried cryosections of human melanoma cells. A practical detection limit of around 6 mmol kg-1 in 0.1- micro m2 areas is estimated using specimens prepared from standard boron solutions. Preliminary results of boron mapping in the spectrum-imaging acquisition mode reveal boron penetration and probably spot-like accumulation within melanoma cells when exposed to culture medium containing sodium borocaptate.

Topics: Boron; Boron Neutron Capture Therapy; Cryoultramicrotomy; Humans; Melanoma; Specimen Handling; Subcellular Fractions; Tumor Cells, Cultured

The present work reports on the genotoxicity of the boron neutron capture (BNC) reaction in human metastatic melanoma cells (A2058) assessed by the cytokinesis block micronucleus assay (CBMN) using p-borono-L-phenylalanine (BPA) as the boron delivery agent. Different concentrations of BPA (0.48, 1.2 and 2.4 mM) and different fluences of thermal neutrons were studied. Substantial genotoxic potential of alpha and lithium particles generated inside or near the malignant cell by the BNC reaction was observed in a dose-response manner as measured by the frequency of micronucleated binucleated melanoma cells and by the number of micronuclei (MN) per binucleated cell. The distribution of the number of MN per micronucleated binucleated cell was also studied. The BNC reaction clearly modifies this distribution, increasing the frequency of micronucleated cells with 2 and, especially, > or =3 MN and conversely decreasing the frequency of micronucleated cells with 1 MN. A decrease in cell proliferation was also observed which correlated with MN formation. A discrete genotoxic and anti-proliferative contribution from both thermal neutron irradiation and BPA was observed and should be considered secondary. Additionally, V79 Chinese hamster cells (chromosomal aberrations assay) and human lymphocytes (CBMN assay) incubated with different concentrations of BPA alone did not show any evidence of genotoxicity. The presented results reinforce the usefulness of the CBMN assay as an alternative method for assessment of the deleterious effects induced by high LET radiation produced by the BNC reaction in human melanoma cells.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Division; Cell Line; Cells, Cultured; Cricetinae; Drug Carriers; Fast Neutrons; Humans; Isotopes; Melanoma; Micronucleus Tests; Phenylalanine; Radiation-Sensitizing Agents; Tumor Cells, Cultured

Longitudinal and transverse relaxation rates for the 11B resonances in sodium borocaptate (BSH) at varying concentrations were measured in undiluted horse serum in a 4.7 Tesla field. The results could be fit by a model that assumes fast exchange of the BSH molecule between a free and a bound state, using values of 0.77+/-0.7 MHz for the 11B quadrupole coupling constant and (6.3+/-0.9) x 10(-9) s for the rotational correlation time in the bound state. These results were used as a basis for assessing the requirements and limitations of quantitative determination of BSH concentrations in vivo, using 11B NMR. Surface coil 11B NMR spectroscopy was performed on a total of 14 mice injected with BSH. Some of the animals (n=9) had implanted M2R melanoma tumors grown to various sizes in the rear thigh, in which case the surface coil was placed against the tumor, whereas for the other animals (without tumor), the coil was placed against the rear thigh muscle. NMR spectra were acquired under fully relaxed conditions. The spectra were quantitated by peak integration; apparent absolute BSH concentrations were derived by comparison with spectra from a phantom with known BSH concentration, using extrapolation of the time-domain data to zero preacquisition delay. The results indicate significantly higher 11B BSH signal intensities in tumors, compared with muscle tissue, whereas the uptake and clearance kinetics were similar.

Topics: Algorithms; Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Injections, Intraperitoneal; Injections, Intravenous; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Melanoma; Metabolic Clearance Rate; Mice; Mice, Nude; Muscle, Skeletal; Neoplasm Transplantation; Phantoms, Imaging; Soft Tissue Neoplasms; Sulfhydryl Compounds; Thigh; Time Factors; Tumor Cells, Cultured

Detection and diagnosis of human malignant melanoma by Positron Emission Tomography (PET) using 18F-10B-L-BPA, a specific melanogenesis-seeking compound synthesized for use in Boron Neutron Capture Therapy for malignant melanoma (NCT), has been developed. This resulted in a novel, highly effective methodology for the selective three dimensional imaging of metastatic malignant melanomas, and for accurate determination of 10B concentration in the tumor and surrounding tissue, providing almost all diagnostic information necessary for complete non-invasive radiation dose planning in the treatment of malignant melanoma both for NCT as well as other therapeutic modalities.

Topics: Boron; Boron Compounds; Brain; Brain Neoplasms; Fluorine Radioisotopes; Humans; Isotopes; Lymphatic Metastasis; Melanoma; Phenylalanine; Tomography, Emission-Computed

The lipid core of human plasma low-density lipoprotein (LDL) was extracted using hexane and the LDL reconstituted with the addition of n-octyl-carborane. Biodistribution studies of the boronated LDL were performed in BALB/c mice bearing subcutaneous Harding-Passey melanoma xenografts. When diet supplementation with coconut oil and cholesterol for 21 days and regular dosing with hydrocortisone for 7 days before the studies was used to down-regulate the liver LDL receptors and the adrenal receptors, respectively, the tumour-blood boron concentration ratio of 5:1 was achieved.

Topics: Adrenal Glands; Animals; Boron; Boron Neutron Capture Therapy; Cholesterol, Dietary; Coconut Oil; Down-Regulation; Drug Carriers; Half-Life; Humans; Lipoproteins, LDL; Liver; Male; Melanoma; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Plant Oils; Receptors, LDL; Skin; Tissue Distribution; Transplantation, Heterologous

Basic investigation into the nature of melanin monomer and polymer synthesis in pigment cells has revealed many of the new underlying factors involved in its regulation and control by three melanogenesis-related genes, tyrosinase, TRP-1 and TRP-2, and other non-tyrosinase glycoproteins. Pigment cells can undergo clinically and biologically recognizable progressive multi-step carcinogenesis. Generally parallel to this progressive cancerization is accentuated melanogenesis. Using this accentuated melanogenesis to develop a specific diagnosis and cure for melanoma (Mm) has long been a challenge. However, until recently, no success was achieved. As an example, attempting to utilize the fact that dopa accumulates as a melanin substrate within Mm cells, hybrid compounds of dopa and cytotoxic drugs were developed. However, these compounds were found to have severe systemic side effects and were therefore unusable. Another newer Mm treatment involves high energy radiation such as fast neutrons. But this is quite non-selective, killing both the target cancer and the normal surrounding tissue. Since 1972, I have developed the idea of coupling the high energy releasing system of thermal neutron irradiation with the non-toxic 10B-dopa analogue, 10B1-L-p-boronophenylalanine (10B1-L-BPA). Thermal neutrons are essentially harmless, but, after specific absorption by 10B, release high LET alpha-particles and 7Li-atoms with an energy of 2.33 MeV up to a distance of 14 mu, the diameter of Mm cells, thus selectively killing them without damaging surrounding normal tissue. After the synthesis of 10B1-L-BPA, exhaustive in vitro and in vivo radiological studies on its enhanced killing effect were done to develop optimal Mm Boron Neutron Capture Therapy (NCT).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Animals; Boron; Cricetinae; Female; Humans; Isotopes; Melanins; Melanocytes; Melanoma; Neutron Capture Therapy; Skin Neoplasms; Tomography, Emission-Computed; Treatment Outcome

We have developed neutron-capture therapy (NCT) for cutaneous malignant melanoma using a melanoma-seeking 10B-dopa, analogue, 10B1-para-boronophenylalanine (10B1-BPA). In order to explore the feasibility of applying NCT further to ocular melanoma, we investigated the boron concentrations in ocular melanomas and normal ocular tissues by 10B1-BPA administration to three patients, because success of NCT depends mainly upon selective boron accumulation in melanoma. In the first and second ocular melanoma patients, to whom 10B1-BPA fructose complex (total dose of 10B1-BPA: 170 mg/kg body weight) was administered orally in two divided doses, the boron concentrations in blood, vitreous body, sclera and retina choroidea were lower than that in melanoma examined. In the third conjunctival melanoma patient, to whom 10B1-BPA fructose complex (dose of 10B1-BPA: 85 mg/kg body weight) was administered by intravenous drip infusion, the average boron concentration in four melanoma samples was 17.7 ppm, which was estimated to be within the range necessary for melanoma eradication by thermal neutron irradiation. Boron uptake by lens, vitreous body, retina choroidea and sclera was much lower than that by melanoma. It was suggested that such a superficial ocular melanoma as iris melanoma can be destroyed by NCT, although vision may be affected--mainly due to cataract formation.

Topics: Boron; Boron Compounds; Clinical Trials as Topic; Eye Neoplasms; Humans; Isotopes; Mass Spectrometry; Melanoma; Neutron Capture Therapy; Phenylalanine; Radiation-Sensitizing Agents

To improve the effectiveness of boron neutron capture therapy, the possibility of stimulating boron uptake was investigated in an experimental model. B16F1 mouse melanoma cells were exposed to boronophenylalanine (BPA). The intracellular boron concentration followed Michaelis-Menten kinetics in the early incubation phase. In the late phase, cellular boron concentration was linearly related to the BPA concentration in the culture medium. Incubation with L-tyrosine before exposure to BPA (preloading) increased the intracellular boron concentration by a factor of three. It is concluded that in B16F1 cells BPA is transported by L and presumably ASC (alanine, serine, and cysteine) transport systems, and that boron uptake can be effectively stimulated by L-tyrosine preloading.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Melanoma; Mice; Phenylalanine; Radiation-Sensitizing Agents; Time Factors; Tumor Cells, Cultured; Tyrosine

To study the biodistribution of p-Boronophenylalanine in patients undergoing surgery for intracranial tumors or metastatic melanoma.. D,L-p-Boronophenylalanine was administered as boronophenylalanine.fructose in an intravenous bolus 1-4 h before the operation. Blood samples were collected for 24 h from the time of administration of the compound, and the blood boron elimination parameters were determined. For the glioma patients tumor samples were obtained and skin, dura, periosteum, and surrounding brain samples were collected whenever possible. For the metastatic melanoma patients tumor, fat, skin, and muscle were collected. Determination of the boron content was performed using inductively coupled plasma-atomic emission spectrometry. Twelve melanoma patients and six glioma patients participated in the study. The melanoma patients included four cases of cutaneous metastatic melanoma, six cases of metastatic melanoma to the lymph nodes and two cases of cerebral metastasis.. The results for the metastatic melanoma patients are encouraging with an average tumor:blood boron concentration ratio and standard deviation of about 4.4 +/- 3.2 and a maximum value of 10 for the cerebral metastasis. The glioma patients involved high grade glioma for which the tumor:blood ratio was 2.2 +/- 1.2.. The tumor:blood ratios for melanoma fulfil requirements for epithermal boron neutron capture therapy for cerebral melanoma metastases, whereas those for high grade glioma do not.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Glioma; Humans; Melanoma; Phenylalanine; Radiation-Sensitizing Agents

A rat brain tumor model has been developed utilizing nude rats and the human melanoma cell line MRA 27. For pharmacokinetic and tissue distribution studies, 2 10(5) MRA 27 cells were implanted intracerebrally (i.c.), and 30 days later, 120 mg of 10B-enriched L-boronophenylalanine were injected i.p. into nude rats. 10B concentrations in the tumor, blood, and normal brain were 23.7, 9.4, and 8.4 micrograms/g, respectively, 6 h following administration. For therapy experiments, tumor bearing rats were irradiated at the Brookhaven Medical Research Reactor 30 days following implantation. The median survival time was 44 days for untreated rats, 76 days for those receiving a physical dose of 2.7 Gy, and 93 days for those receiving 3.6 Gy. Animals receiving both 10B-L-boronophenylalanine and physical doses of 1.8, 2.7, or 3.6 Gy (total tumor physical doses of 5.0, 7.5, or 10.1 Gy) had median survival times of 170, 182, and 262 days, respectively. Forty % of rats that received the highest tumor dose (10.1 Gy) survived > 300 days. In a replicate experiment 21% of animals that had received L-boronophenylalanine and irradiation (total tumor physical dose of 10.1 Gy) were alive 220 days after therapy. In a parallel study, animals that were irradiated with gamma photons from a 137Cs source with 12 Gy or 2.0 Gy 9 delivered to the head had median survival times of 86 and 79 days, respectively, compared to 47 days for untreated animals. Our results indicate that boron neutron capture therapy is effective against i.c. melanoma in a rodent model and suggest that large animal studies are warranted to further assess its efficacy.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain; Brain Neoplasms; Cell Survival; Humans; Male; Melanoma; Middle Aged; Phenylalanine; Radiation-Sensitizing Agents; Radiotherapy Dosage; Rats; Rats, Nude; Tissue Distribution

The role of Neutron Capture Therapy for the treatment of uncontrollable, localised tumours is examined. Several boron carrier biochemicals are already in use for the selective accumulation of boron in cancer cells, and therapeutic boron concentrations have been achieved in glioblastoma and melanoma in animal models and in patients. Local control of glioblastoma and subcutaneous melanoma has been reported after thermal neutron irradiation. Different neutron beam requirements apply for the treatment of these cancers, in the former case a thermal beam is adequate but a more penetrating epithermal beam is needed for the treatment of deep-seated tumours. A thermal facility for small animal irradiations is available in Australia, and the development of a patient thermal/epithermal facility is under active consideration.

Topics: Boron; Boron Compounds; Brain Neoplasms; Glioblastoma; Humans; Isotopes; Melanoma; Neutrons; Skin Neoplasms

10B1-para-boronophenylalanine (10B1-BPA), one of our boronated dopa analogues developed for thermal neutron capture therapy, has been found to have a selective affinity for malignant melanoma. We have established a method of 'in situ' detection of subcutaneous melanoma lesions, using this melanoma-seeking 10B-labeled compound. In this study, we applied an 'in situ' 10B microanalysis system via detection of the prompt gamma-ray from the 10B(n, alpha)7Li reaction triggered by irradiating the 10B-containing target with pure thermal neutrons, called prompt gamma-ray spectrometry, to hamsters bearing Greene's melanoma in subcutis and to a human patient whose occipital subcutaneous tumor was suspected of being a metastatic melanoma. In the hamsters, the time-dependent 10B dynamics showed increased 10B accumulation in melanoma, after 10B1-BPA administration, in contrast to that in non-melanoma normal skin. In the human patient, after subcutaneous injection of 10B1-BPA into perilesional sites 4 cm distant from the tumor margin, the average 10B concentration in the tumor was determined to be 24 ppm (microgram/g), in contrast to 3 ppm in skin covering the tumor and 1.1 ppm in blood, indicative of selectively high 10B1-BPA uptake by the tumor.

Topics: Aged; Animals; Boron; Boron Compounds; Cricetinae; Disease Models, Animal; Female; Humans; Isotopes; Male; Melanoma; Mesocricetus; Phenylalanine; Skin Neoplasms; Spectrometry, Gamma; Time Factors

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Boron; Boron Compounds; Brain Neoplasms; Glioblastoma; Humans; Immunotoxins; Isotopes; Melanoma; Mice; Neoplasms; Neutrons; Phenylalanine; Radiation Dosage

Topics: Boron; Carcinoma, Squamous Cell; Cell Survival; Culture Media; Fast Neutrons; Head and Neck Neoplasms; Humans; Isotopes; Melanoma; Neutrons; Particle Accelerators; Radiotherapy Dosage; Tumor Cells, Cultured

Topics: Animals; Boron; Boron Compounds; Brain; Brain Neoplasms; Dogs; Glioma; Humans; Isotopes; Melanoma; Methods; Mice; Neutrons

Topics: Aged; Aged, 80 and over; Boron; Foot Diseases; Humans; Isotopes; Male; Melanoma; Neutrons; Radiotherapy Dosage; Scalp; Skin Neoplasms

Biodistribution of two compounds presently considered for use in neutron capture therapy has been studied in mice carrying a transplantable Harding-Passey melanoma. A method is described by which quantitative assessment can be made of the boron distribution in whole-body sections of such animals. An alpha-particle-sensitive film is placed in close contact with a freeze-dried section of an animal and exposed to neutrons. The tracks visible after etching are analyzed optoelectronically in fields of 0.6 X 0.6 mm2 and compared to standards of boron homogeneously distributed in liver homogenates. The dynamic range of this method is about two orders of magnitude in concentration, with a lower detection limit of 0.1 to 0.01 ppm 10B, depending on the rate of induction of spurious tracks by fast neutrons present in the neutron beam chosen. In a transplantable Harding-Passey melanoma in mice, it was found that the sulfhydryl boron hydride Na2B12H11SH presently used for therapy of glioblastoma clears blood, muscle, and brain very rapidly. Its accumulation in tumors was persistent for more than three days. A higher tumor accumulation was observed with its disulfide, which has been suggested for neutron capture therapy. For both compounds, a marked heterogeneity of boron distribution within one tumor was found.

Topics: Animals; Autoradiography; Boron; Melanoma; Methods; Mice; Neoplasm Transplantation; Neutrons; Radiography; Tissue Distribution

Topics: Animals; Boranes; Boron; Brain; Disulfides; Female; Melanoma; Mice; Mice, Inbred BALB C; Neutrons; Pharmaceutical Vehicles; Sulfhydryl Compounds

Topics: Animals; Boron; Isotopes; Kinetics; Melanoma; Mice; Neutrons

The kinetics of DNA-synthesizing cells and melanocytes in the peripheral and central zones of transplantable B-16 mouse melanoma was studied by the cytometry and autoradiography methods at varying time after single administration of mercaptoundecahydrododecaborate saturated by 10B, a drug used for neutron capture therapy of malignant tumors. The drug was shown to induce proliferation and differentiation on the 1st day after injection (on the 8th day after transplantation). In the next 2 days proliferation did not change and differentiation was inhibited. The stimulation of proliferation and differentiation was more noticeable on tumor periphery, differentiation inhibition in tumor center.

Topics: Animals; Borohydrides; Boron; Cell Division; Isotopes; Male; Melanoma; Mice; Mice, Inbred C57BL; Sulfhydryl Compounds

Topics: Animals; Boron; Cricetinae; Liver; Magnetic Resonance Spectroscopy; Melanoma; Spectrophotometry

Topics: Animals; Boron; Boron Compounds; Cricetinae; Isotopes; Melanoma; Neoplasms, Experimental; Neutrons; Phenylalanine; Skin; Skin Neoplasms; Spectrometry, Gamma

Topics: Alpha Particles; Animals; Boron; Cell Line; Cell Survival; Chlorpromazine; Dose-Response Relationship, Radiation; Evaluation Studies as Topic; Fast Neutrons; Gamma Rays; Melanins; Melanoma; Mice; Neoplasms, Experimental; Radiotherapy; Skin Neoplasms

Topics: Adolescent; Adult; Astrocytoma; Boron; Brain Neoplasms; Female; Frontal Lobe; Glioblastoma; Humans; Male; Melanoma; Middle Aged; Neutrons; Occipital Lobe; Parietal Lobe; Radiation Injuries; Radioisotopes; Radiotherapy Dosage; Spinal Cord; Temporal Lobe

Topics: Animals; Boron; Cricetinae; Eye Neoplasms; Melanoma; Neoplasm Transplantation; Neoplasms, Experimental; Rabbits; Radioisotopes