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Biomedical subjects

S B Kahl

Publications and source records attributed to S B Kahl.

At least 19 recordsLinked to original sources
PubMed2004

Boron neutron capture therapy for undifferentiated thyroid carcinoma: preliminary results with the combined use of BPA and BOPP.

We have shown the selective uptake of borophenylalanine (BPA) by undifferentiated human thyroid cancer (UTC) ARO cells both in vitro and in vivo. Moreover, a 50% histologic cure of mice bearing the tumor was observed when the complete boron neutron capture therapy was applied. More recently we have analyzed the biodistribution of BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) and showed that when BOPP was injected 5 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs. 20 ppm with BPA alone). Five days post the i.p BOPP injection and 1h after BPA the ratios were: tumor/blood 3.75; tumor/distal skin 2. Other important ratios were tumor/thyroid 6.65 and tumor/lung 3.8. The present studies were performed in mice transplanted with ARO cells and injected with BOPP and BPA. Only in mice treated with the neutron beam and injected with the boronated compounds we observed a 100% control of tumor growth. Two groups of mice received different total absorbed doses: 3.00 and 6.01 Gy, but no further improvement in the outcome was found compared to the previous results using BPA alone (4.3 Gy).

Animals↗
PubMed2001

Phase I and pharmacokinetic study of photodynamic therapy for high-grade gliomas using a novel boronated porphyrin.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of a novel boronated porphyrin (BOPP) for photodynamic therapy (PDT) of intracranial tumors. PATIENTS AND METHODS: BOPP was administered alone in increasing doses (0.25, 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg) preoperatively in patients with intracranial tumors undergoing postresection PDT until dose-limiting toxicity (DLT) was observed. RESULTS: Twenty-nine assessable patients with intracranial tumors received BOPP intravenously 24 hours before surgery. The recommended dose was 4 mg/kg. Dose escalation was limited by thrombocytopenia. The most common nonhematologic toxicity was skin photosensitivity. Pharmacokinetic parameters showed increased area under the plasma concentration-time curve and maximum concentration with increased dose. Tumor BOPP concentrations also increased with increased dose. CONCLUSION: BOPP at a dose of 4 mg/kg was well tolerated. DLT was thrombocytopenia, and photosensitivity was the only other toxicity of note. The efficacy of PDT using BOPP requires further exploration.

Adult↗
PubMed2000

Plasma pharmacokinetics and tissue biodistribution of boron following administration of a boronated porphyrin in dogs.

This study was undertaken to determine the plasma pharmacokinetics and tissue biodistribution of boron in dogs following the administration of a boronated porphyrin (BOPP) compound, a potential sensitizing agent for binary therapies of cancer. An intravenous dose of 35 mg/kg of BOPP was administered to a total of sixteen dogs and plasma samples obtained at multiple time points for up to 28 days after administration. Groups of four dogs each were studied for 25, 79, 240, and 672 h. At the end of each study period, subjects were sacrificed and tissue samples obtained. Boron concentrations were determined for all tissue and plasma samples, and pharmacokinetic parameters were determined using mixed effects modeling. Plasma boron levels displayed triexponential kinetics with a long terminal half-life and small volume of distribution. Liver, lymph node, adrenal, and kidney tissues accumulated the highest levels of boron, with very low levels associated with most tissues of the head. We conclude that BOPP has pharmacokinetic and tissue distribution properties that suggest that it may be a suitable compound for use as a sensitizing agent in binary therapy of cancer.

Animals↗
PubMed1999

Boronated protoporphyrin (BOPP): localization in lysosomes of the human glioma cell line SF-767 with uptake modulated by lipoprotein levels.

PURPOSE: Boronated protoporphyrin (BOPP) is a candidate for use in both boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) of glioblastoma multiforme (GBM). Our objectives are to identify factors that influence the uptake and retention of BOPP in vitro and to determine BOPP distribution in a human glioma cell line in vitro. This information will aid the development of compounds and treatment strategies that increase the effectiveness of BNCT therapy for GBM. METHODS AND MATERIALS: The amount, distribution pattern, and site of internalization of BOPP were assessed using fluorescence microscopy. Living human glioma (SF-767) cells were imaged after a 24-h exposure to BOPP (20-135.6 microg/ml, normal serum). Dose-dependent uptake of BOPP was determined using both fluorescence microscopy of individual living cells and inductively-coupled plasma-atomic emission spectroscopy (ICP-AES) analysis of cell pellets. Lysosome- or mitochondria-specific fluorescent probes were used to identify the cellular compartment containing BOPP. Two human fibroblast cell lines, AG-1522 (LDL receptor-positive) and GM019-15C (LDL receptor-deficient), were used to investigate LDL receptor-dependent BOPP uptake. The dependence of BOPP uptake on lipoproteins in the media was determined by exposing each of the three cell types to BOPP in medium containing either normal (NS) or lipoprotein deficient serum (LPDS). RESULTS: BOPP accumulated in the lysosomes of human glioma cells in vitro, and not in the mitochondria, as reported for C6 rat glioma cells in vitro. BOPP uptake was concentration-dependent and was also dependent on the amount of lipoproteins in the medium. Over the range of incubation concentrations studied and at the single exposure duration time point investigated (24 h), all cells retained a similar amount of BOPP. At the lowest incubation concentration (20 microg/ml, NS), the amount of boron retained was near 10(9) atoms per cell (15 microg B/g cells). Lysosomes containing high concentrations of BOPP were randomly distributed throughout the cytoplasm; however, larger lysosomes containing BOPP were concentrated around the cell nucleus. Little or no BOPP accumulated in the cell nucleus. At incubation concentrations of 20 and 40 microg/ml (24-h time point), BOPP uptake in SF-767 cells was reduced in LPDS compared with NS (66% reduction). A similar result was observed for normal human fibroblasts (AG-1522 cells, 40 microg/ml, 24 h). At 40 microg/ml, in both NS and LPDS at 24 h, BOPP accumulation in LDL receptor-deficient human fibroblasts (GM019-15C cells) was reduced relative to AG-1522 cells. BOPP accumulation in GM019-15C cells (40 microg/ml, 24 h) was not affected by serum lipoprotein levels. CONCLUSION: In cell culture, BOPP is taken up by human glioma cells via the LDL pathway and is compartmentalized into cellular lysosomes. Knowledge of this mechanism of BOPP uptake and retention will be important in attempts to modify toxicity and efficacy of this drug.

Antineoplastic Agents↗
PubMed1999

Biopharmaceutics of boronated radiosensitizers: liposomal formulation of MnBOPP (manganese chelate of 2,4-(alpha, beta-dihydroxyethyl) deuterioporphyrin IX) and comparative toxicity in mice.

Binary treatment modalities such as photodynamic therapy (PDT) and neutron capture therapy (NCT) combine low-toxicity electromagnetic irradiation with an appropriate radiation sensitizer to enhance selectivity for tumor targets. The porphyrin derivative tetrakiscarborane carboxylate ester of 2,4-(alpha, beta-dihydroxyethyl) deuterioporphyrin IX (BOPP) shows tumor-selective uptake and is active in both treatment modalities. BOPP also chelates paramagnetic ions such as Mn(2+), and therefore its tissue accumulation and selectivity can be detected noninvasively by using magnetic resonance imaging. However, local and systemic toxicity appears elevated for the Mn(2+) chelate (MnBOPP), but is poorly characterized. Here we have developed a liposomal formulation of MnBOPP and compared its toxicity with that of MnBOPP administered to mice in saline. The optimal liposome composition and maximal capacity to accommodate MnBOPP were investigated by differential scanning calorimetry and by encapsulation efficiency. MnBOPP was encapsulated quantitatively at up to 12 mol % (drug:lipid) in liposomes of varying composition, and remained incorporated during extended dialysis. Phase separation of drug- and lipid-rich domains was observed above 12% drug. MnBOPP in buffered saline was lethal to animals at 90 micromol/kg, and caused severe necrosis at the injection site at dose levels of 60 micromol/kg or greater. In contrast, MnBOPP formulated in liposomes was well tolerated at the highest tested dose of 135 micromol/kg, with the elimination of local toxicity.

Animals↗
PubMed1999

Toxicology of a boronated porphyrin in dogs.

Among the most important characteristics of any therapeutic agent are efficacy and an acceptable toxicity. Prior to human use, toxicity studies are performed in both small and large animal models. Our laboratory has developed a new binary therapy agent, a boronated porphyrin (BOPP), with excellent potential efficacy. The purpose of this study is to examine the toxicology of this compound in dogs. Sixteen dogs were given 35 mg/kg of BOPP intravenously and evaluated for up to 28 days following administration. Clinical and pathologic responses were measured. BOPP was clinically well tolerated with some cases of weight loss, vomiting and mild photosensitivity. Adverse effects were limited primarily to thrombosis at the administration site in several subjects and three cases of mild, possibly transient, liver injury. Clinical pathologic tests found reversible changes in white blood cell counts and platelets, with neither change being clinically significant. The low toxicity associated with BOPP as shown in this study provides valuable evidence supporting the use of BOPP in binary therapy.

Animals↗
PubMed1996

Mitochondria are the functional intracellular target for a photosensitizing boronated porphyrin.

A photosensitizing boron-containing porphyrin derivative denoted BOPP, which is selectively localised into mitochondria, has been tested on Namalwa cells, in each of two genetic configurations: rho+ cells containing normal mtDNA and mitochondrial respiratory functions, or rho0 cells lacking mtDNA and devoid of mitochondrial oxidative phosphorylation. After short-term cellular uptake for 18 h, BOPP (30 micrograms/ml) was not cytotoxic, but did show marked phototoxicity in Namalwa rho+ cells, concomitant with substantial reduction of mitochondrial respiratory activity. After long-term (3 days or more) exposure to BOPP without light, growth of Namalwa rho+ cells was inhibited at concentrations significantly above 30 micrograms/ml. At such concentrations BOPP was shown to have direct inhibitory effects on mitochondrial azide-sensitive respiration of p+ cells. By contrast, BOPP showed neither cytotoxic nor phototoxic effects in rho0 cells. These results indicate functional mitochondria to be a major cellular target in vivo after BOPP uptake and photoactivation.

Boron Compounds↗
PubMed1996

Photophysics and intracellular distribution of a boronated porphyrin phototherapeutic agent.

The absorption and emission spectra, fluorescence quantum yields and lifetimes and triplet state properties of a boronated porphyrin, the tetrakiscarborane carboxylate ester of 2,4-(alpha, beta-dihydroxyethyl) deuteroporphyrin IX (BOPP), have been determined. This compound is an alternative photodynamic therapy (PDT) agent that exhibits highly selective tumor localization, with the potential to be used in conjunction with boron neutron capture therapy. The photophysical characteristics of BOPP are similar to other porphyrins and it exhibits marked aggregation and acid-base speciation under typical physiological conditions. In particular, protonation of the porphyrin imino (-N=) nitrogens occurs in the pH 5-7 region and influences the photophysical properties. Time-resolved confocal fluorescence imaging of the intracellular distribution of BOPP in C6 glioma cells indicates distinct subcellular localization and heterogeneity of emission. The results are interpreted and discussed in terms of the possible mechanisms for cellular uptake and localization.

Boron Compounds↗
PubMed1996

The biological effects of Auger electrons compared to alpha-particles and Li ions.

The present study reports the results of V-79 Chinese hamster cell survival studies in which Auger electron emission was stimulated in gadolinium (Gd) after thermal neutron capture. When a porphyrin that had previously been labeled with boron (10BOPP) was also labeled with Gd (Gd-10BOPP), the cells were incubated with Gd-10BOPP to assess the compound's ability to physiologically transport the Gd into the cell, and localize the Gd atoms in or near the cell's critical target, presumably the DNA. It was anticipated that Auger electron emission, stimulated during the 157Gd (n, gamma)158Gd interaction, would impart additional high LET damage to that observed from the alpha-particle and Li ion during the 10B(n, alpha) 7Li reaction. Following irradiation with thermal neutrons from the Brookhaven Medical Research Reactor, the effectiveness of the Auger electrons was determined by comparing the response of cells incubated with 10BOPP, where damage was imparted by the boron neutron capture (BNC) products, to that from Gd-10BOPP, with equal concentration of 10B in both solutions. An Auger effectiveness factor of approximately 2 was found for the Gd-10BOPP cells. The Auger effectiveness observed with Gd strongly suggested that the 10BOPP molecule physiologically transported the Gd3+ ion intracellularly where it probably bound to DNA. Others have reported that Gd3+ does, in fact, complex with DNA. While depositing less energy per interaction than the high LET BNC reaction by-products, Auger electron ionization was more effective.

Animals↗
PubMed1995

Selective tumor kill of cerebral glioma by photodynamic therapy using a boronated porphyrin photosensitizer.

The prognosis for patients with the high-grade cerebral glioma glioblastoma multiforme is poor. The median survival for primary tumors is < 12 months, with most recurring at the site of the original tumor, indicating that a more aggressive local therapy is required to eradicate the unresectable "nests" of tumor cells invading into adjacent brain. Two adjuvant therapies with the potential to destroy these cells are porphyrin-sensitized photodynamic therapy (PDT) and boron-sensitized boron neutron capture therapy (BNCT). The ability of a boronated porphyrin, 2,4-(alpha, beta-dihydroxyethyl) deuteroporphyrin IX tetrakiscarborane carboxylate ester (BOPP), to act as a photosensitizing agent was investigated in vitro with the C6 rat glioma cell line and in vivo with C6 cells grown as an intracerebral tumor after implantation into Wistar rats. These studies determined the doses of BOPP and light required to achieve maximal cell kill in vitro and selective tumor kill in vivo. The data show that BOPP is more dose effective in vivo by a factor of 10 than the current clinically used photosensitizer hematoporphyrin derivative and suggest that BOPP may have potential as a dual PDT/BNCT sensitizer.

Animals↗
PubMed1995

A comparative study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model.

Boron neutron capture therapy is a treatment modality for cancer that depends on the specific uptake of boron by the tumor cells. The infiltrative growth of malignant gliomas requires that boron reach and accumulate in migrating cells outside the margin of the tumor; thus, it is important that the biodistribution of new boron compounds is also studied in the surrounding healthy brain tissue. This study is undertaken in the present work, in which the biodistribution and pharmacokinetics of sulfhydryl boron hydride (BSH) and boronated porphyrin (BOPP) in the RG2 rat glioma model are investigated. This model mimics the characteristics of human glioma with cells migrating into the surrounding brain. The animals were infused intravenously with either BSH (25 micrograms or 175 micrograms of boron per gram of body weight) or BOPP (12 micrograms of boron per gram body weight). For the low dose of BSH, the maximum tumor-boron content was 8 ppm at approximately 9 hours after the infusion with a tumor-to-blood ratio of 0.6. At the higher dose, the corresponding figures were 15 ppm after 12 hours with a tumor-to-blood ratio of 0.5. For BOPP, a tumor-boron concentration of 81 ppm was achieved 24 hours after the infusion and sustained in that range for at least 72 hours. The tumor-to-blood ratio at 24 hours was slightly above 6, but continued to increase as the blood was cleared. These results indicate that both compounds are spread into the normal brain tissue following the same pathways as the migrating tumor cells and in this way can be taken up even in distant tumor cell foci.

Animals↗
PubMed1994

Enhanced therapeutic effect on murine melanoma and angiosarcoma cells by boron neutron capture therapy using a boronated metalloporphyrin.

We have already achieved successful treatment of several human patients with malignant melanoma by boron neutron capture therapy (BNCT) using 10B1-paraboronophenylalanine (10B1-BPA). In this communication we used a new compound, a manganese boronated protoporphyrin (Mn-10BOPP), and compared it to 10B1-BPA.HCl with respect to uptake in murine melanoma and angiosarcoma cells as well as to their respective cell killing effects using BNCT. Mn-10BOPP was found to be 3 to 10 times more effectively taken up by melanoma cells and angiosarcoma cells than 10B1-BPA.HCl when the content of 10B was measured by the new method, inductively coupled plasma-mass spectrometry (ICP-MS). In addition, melanoma cells and angiosarcoma cells preincubated with Mn-10BOPP were 15 to 20 times more efficiently killed by BNCT than cells preincubated with 10B1-BPA.HCl. These results suggest that Mn-10BOPP is a suitable compound for BNCT of not only malignant melanoma but also angiosarcoma.

Animals↗
PubMed1992

Selective tumor uptake of a boronated porphyrin in an animal model of cerebral glioma.

The prognosis for patients with high-grade cerebral glioma is poor. Most treatment failures are due to local recurrence of tumor, indicating that a more aggressive local therapy could be beneficial. Adjuvant treatments such as porphyrin-sensitized photodynamic therapy (PDT) or boron neutron capture therapy (BNCT) have the potential to control local recurrence. The selective tumor uptake of a boronated porphyrin was studied in CBA mice bearing an implanted intracerebral glioma. Biopsy samples of tumor, normal brain, and blood were analyzed by a fluorometric assay following intraperitoneal and intravenous administration of boronated protoporphyrin (BOPP). This compound was selectively localized to tumor at ratios as high as 400:1 relative to normal brain. Confocal laser scanning microscopy of glioma cells in vitro and in vivo showed that BOPP was localized within mitochondria and excluded from the nucleus of these cells. This discrete subcellular localization was confirmed by density gradient ultracentrifugation after homogenization of mouse tumor biopsies. The selective discrete localization of these compounds within the tumor suggests that this compound may be used as a dual PDT/BNCT sensitizer.

Animals↗
PubMed1991

Biological efficacy of boronated low-density lipoprotein for boron neutron capture therapy as measured in cell culture.

Low-density lipoproteins (LDLs) are known to be internalized by the cell through receptor-mediated mechanisms. There is evidence that LDLs may be taken up avidly by tumor cells to provide cholesterol for the synthesis of cell membranes. Thus, the possibility exists that LDLs may provide an ideal vehicle for the transport of boron to tumor cells for boron neutron capture therapy. A boronated analogue of LDL has recently been synthesized for possible application in boron neutron capture therapy. The analogue was tested in cell culture for uptake and biological efficacy in the thermal neutron beam at the Brookhaven Medical Research Reactor. It was found that boron concentrations 10 times higher than that required in tumors for boron neutron capture therapy were easily obtained and that the amount of uptake was consistent with a receptor-mediated binding mechanism. The measured intracellular concentration of approximately 240 micrograms 10B/g cells is significantly higher than that obtained with any other boron compound previously evaluated for possible clinical application.

Animals↗
PubMed1990

In vitro determination of uptake, retention, distribution, biological efficacy, and toxicity of boronated compounds for neutron capture therapy: a comparison of porphyrins with sulfhydryl boron hydrides.

A major problem remaining in the evaluation of boronated compounds for neutron capture therapy (NCT) is the need to know the intra- or extracellular microdistribution of boron. This is a consequence of the short range of the 10B(n,alpha)7Li reaction products (approximately 10 microns), such that biological efficacy is dependent upon intracellular distribution. In particular, if boron location is predominantly extracellular, a significant reduction in efficacy would be expected. The in vitro procedure described here was developed mainly to provide information regarding the intra- and extracellular location and concentration of boron. However, use of the technique also allows the measurement of compound uptake and retention (binding) and the determination of biological efficacy by the evaluation of survival curves obtained following irradiation with thermal neutrons. Comparison is made to results obtained with boric acid (H3(10)BO3) and to results calculated for various boron distributions. Concomitantly, an indication of compound toxicity can be obtained from the plating efficiency of unirradiated control cells. Currently, most investigators utilize in vivo systems for testing and evaluating boron uptake from various carrier molecules. Given the large number of boron compounds being synthesized and needing evaluation as to their usefulness for NCT, the in vitro technique described here is simple and advantageous for initial compound screening. In addition to sparing animal lives, it is both time and cost effective and utilizes much smaller quantities of test compound than are required for an in vivo assay. A boronated porphyrin (BOPP) evaluated by the above procedure shows an uptake and retention approximately 20 times that of sulfhydryl boron hydride monomer (BSH); the latter compound is currently being used clinically for NCT in Japan and is anticipated for use in clinical trials in the United States. If the advantages demonstrated by BOPP in these in vitro studies are validated in animal experiments, BOPP should be considered for clinical application.

Animals↗
PubMed1990

Uptake of a nido-carboranylporphyrin by human glioma xenografts in athymic nude mice and by syngeneic ovarian carcinomas in immunocompetent mice.

A tetraphenylporphyrin bearing four dicarbollide ([B9C2H11]-) cages linked to the o-phenyl ring positions by anilide bonds, known as boronated tetraphenylporphyrin (BTPP), has been synthesized in excellent yield from tetra-(o-aminophenyl) porphyrin and carborane carbonyl chloride followed by base-assisted cage opening and ion exchange to give the highly water-soluble potassium salt. Preliminary studies showed that BTPP accumulates in liver and in a syngeneic ovarian carcinoma, but not in normal brain parenchyma, of mice infused with BTPP subcutaneously for 6 or 7 days via surgically implanted osmotic minipumps. In this study, the uptake of boron was measured in human gliomas xenografted subcutaneously to athymic nude mice in which BTPP was infused intraperitoneally or subcutaneously or both for 3 or 7 days by using similar minipumps. Immunocompetent mice bearing a syngeneic ovarian carcinoma were similarly infused to provide comparative data. Bulk concentrations of boron up to 18 micrograms/g of glioma and up to 45 micrograms/g of carcinoma were observed when up to 102 micrograms/g of tissue was present in the liver after 7 days of BTPP infusion. Glioma boron concentrations were increased by approximately 80% on the average (up to 33 micrograms/g) when correspondingly greater amounts of BTPP were infused in only 3 days. Cell counts and chemical tests on blood samples from individual mice indicate that BTPP causes moderate hepatotoxicity and thrombocytopenia. This hepatohematic toxicity syndrome should be taken into account if BTPP or a similar agent is used for boron neutron-capture therapy (BNCT) of human malignancies.

Animals↗