Simultaneous Determination of Docetaxel and Celecoxib in Porous Microparticles and Rat Plasma by Liquid-Liquid Extraction and HPLC with UV Detection: in vitro and in vivo Validation and Application.

PURPOSE: A simple, rapid, sensitive, and reliable HPLC method with UV detection was developed and validated for simultaneous quantitation of docetaxel and celecoxib and paclitaxel for dissolution characterization and pharmacokinetic studies. METHODS: The HPLC assay was performed isocratically on a reversed-phase C18 µ-Bondapack column using a mobile phase of acetonitrile:water (45:55, v/v) at a flow rate of 1.2 mL/min, and the analytes were detected at 230 nm. Paclitaxel was used as an internal standard for analysis of plasma samples following simple liquid-liquid extraction with n-hexane:isoamyl alcohol (97:3). The method was validated for specificity, linearity, sensitivity, precision, accuracy, robustness, and in vitro-in vivo application. RESULTS: The retention times for docetaxel, paclitaxel, and celecoxib were 10.94, 12.4, and 16.81 min, respectively. The standard curves covering 0.1-1 µg/mL and 0.05-4 µg/mL were linear using dissolution medium and rat plasma, respectively. The limit of quantitation of the method was 50 ng/mL using 100 µL of rat plasma sample and injection of 50 µL of the residue. Within- and between-day precision and accuracy did not exceed 16.86% and 12.10%, respectively. This validated method was successfully used to quantify docetaxel and celecoxib simultaneously in the release study of docetaxel- celecoxib -loaded porous microparticles and pharmacokinetics studies. The methods were found to be simple, specific, precise, accurate, and reproducible. In this study, paclitaxel was used as the internal standard while dexamethasone, flutamide, and budesonide proved suitable alternative as an internal standard. CONCLUSION: Since docetaxel and celecoxib could be co-administered for the treatment of a wide range of cancers such as non-small cell lung carcinoma, the developed method is particularly advantageous for routine therapeutic drug monitoring and pharmacokinetic studies of these drugs.

A LC-MS/MS method for therapeutic drug monitoring of sorafenib, regorafenib and their active metabolites in patients with hepatocellular carcinoma.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sorafenib (SORA), its N-oxide active metabolite and of regorafenib (REGO) and its two active metabolites regorafenib N-oxide and N-desmethyl regorafenib N-oxide in hepatocellular carcinoma patients' plasma. A proper analytes' separation was obtained with Synergi Fusion RP column (4 µm, 80 Å, 50 × 2.0 mm) using a gradient elution of 10 mM ammonium acetate with 0.1% formic acid (mobile phase A) and methanol:isopropanol (90:10, v/v, mobile phase B) containing 0.1% formic acid. The analysis was then performed by electrospray ionization in negative mode coupled with a triple quadrupole mass spectrometry, API 4000QT, monitoring two transitions for each analyte, one for the quantification and the other for confirmation. The method could be easily applied to the clinical practice thanks to the short run (7 min), the low amount of patient plasma necessary for the analysis (5 µL) and the fast sample processing based on protein precipitation. The method was therefore fully validated according to FDA and EMA guidelines. The linearity was assessed (R2≥0.998) over the concentration ranges of 50-8000 ng/mL for SORA and REGO, and 30-4000 ng/mL for their metabolites, that appropriately cover the therapeutic plasma concentrations. The presented method also showed adequate results in terms of intra- and inter-day accuracy and precision (CV ≤ 7.2% and accuracy between 89.4% and 108.8%), recovery (≥85.5%), sensitivity, analytes stability under various conditions and the absence of the matrix effect. Once the validation was successfully completed, the method was applied to perform the Cmin quantification of SORA, REGO and their metabolites in 54 plasma samples collected from patients enrolled in a clinical study ongoing at the National Cancer Institute of Aviano.

[Determination of thallium in the urine with colloidal palladium as the matrix modifier by graphite furnace atomic absorption Spectrometry].

Objective: To instruct a method of determining thallium in the urine by graphite furnace atomic absorption spectrometry(GF-AAS) with colloidal palladium as the matrix modifier. Methods: Urine samples were first diluted and then determined by GF-AAS with colloidal palladium while using thermal sample injection. Results: The optimum volume of colloidal palladium was 6 µl and the best ashing temperature was 600-800 ℃ while the atomization temperature was 1700-1900 ℃ . This method showed a good linearity relationship when the concentration between 0.33 and 50.0 µg/L while the correlation coefficient of standard curve line was 0.9992, and the detection limit was 0.33 µg/L and the recovery rate was between 92.7% and 102.3% with the intra-day precision in the range of 2.55% to 3.66% and the inter-day precision in the range of 1.77% to 3.85%. Conclusion: This method has the advantages of low detect limit, high sensitivity and good precision, and it can be used in the biological monitoring and emergency detecting of workers exposed to thallium.

Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments.

Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations. Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood.

Development and validation of a LC-FL method for the simultaneous determination of doxorubicin and celecoxib in nanoparticulate fixed dose combination (NanoFDC).

An isocratic reversed phase HPLC method for the simultaneous determination of doxorubicine (DOX) and celecoxib (CXB) out of a nanoparticulate fixed dose combination (NanoFDC) was developed and validated. Linearity of the results was demonstrated from 1-11 µg/mL for both components. Lower limits of detection were determined as 7 ng/mL for DOX and 13 ng/mL for CXB. Total run time was approximately 15 min.

Microfluidic-Enabled Print-to-Screen Platform for High-Throughput Screening of Combinatorial Chemotherapy.

Since the 1960s, combination chemotherapy has been widely utilized as a standard method to treat cancer. However, because of the potentially enormous number of drug candidates and combinations, conventional identification methods of the effective drug combinations are usually associated with significantly high operational costs, low throughput screening, laborious and time-consuming procedures, and ethical concerns. In this paper, we present a low-cost, high-efficiency microfluidic print-to-screen (P2S) platform, which integrates combinatorial screening with biomolecular printing for high-throughput screening of anticancer drug combinations. This P2S platform provides several distinct advantages and features, including automatic combinatorial printing, high-throughput parallel drug screening, modular disposable cartridge, and biocompatibility, which can potentially speed up the entire discovery cycle of potent drug combinations. Microfluidic impact printing utilizing plug-and-play microfluidic cartridges is experimentally characterized with controllable droplet volume and accurate positioning. Furthermore, the combinatorial print-to-screen assay is demonstrated in a proof-of-concept biological experiment which can identify the positive hits among the entire drug combination library in a parallel and rapid manner. Overall, this microfluidic print-to-screen platform offers a simple, low-cost, high-efficiency solution for high-throughput large-scale combinatorial screening and can be applicable for various emerging applications in drug cocktail discovery.

Direct drug cocktail analyses using microscale vortex-assisted electroporation.

Combination therapy has become one of the leading approaches for treating complex diseases because it coadministers clinically proven drugs to concurrently target multiple signaling pathways of diseased cells. Identification of synergic drug combinations at their respective effective doses without unwanted accumulative side effects is the key to success for such therapy. In this work, we demonstrate the feasibility of the vortex-assisted microfluidic electroporation system for direct drug cocktail analyses where drug substances were individually delivered into cytosols in a sequential and dosage-controlled manner. Through quantitative analyses, the synergic combinational dosage ratios of the chemotherapeutic drug and the anticancer flavonoid were identified. When integrated with high-throughput label-free rare cell purification techniques, the presented system has the potential for development of personalized medicines as the system would be capable of comprehensively assessing drug combinations directly on patients' cellular samples.

[Stability study of oxaliplatin and doxorubicin for intraperitoneal administration with hyperthermia]. / Estudio de estabilidad de oxaliplatino y doxorrubicina para su administración intraperitoneal con hipertermia.

OBJECTIVE: To evaluate the in vitro physicochemical stability of oxaliplatin and doxorubicin when the in vivo hyperthermic intraperitoneal conditions are reproduced. METHODS: Three solutions were prepared, A (oxaliplatin 200 mg/L), B(doxorubicin 15 mg/L) and C (oxaliplatin 200 mg/L with doxorubicin 15mg/L) in glucose 5%. The three solutions were subjected to the maximum temperature reached in vivo (49° C) for two hours. Physical stability was focused on visual control of particles or precipitates in solutions, discharge of gases, odor and color. Samples were taken every 15 minutes and the chemical stability was evaluated by determining the concentration of oxaliplatin and doxorubicin remaining in the samples. Oxaliplatin concentrations were determined by atomic absorption graphite chamber while doxorubicin was determined by high performance liquid chromatography.The chemical stability criteria selected was the one described by the American Pharmacopoeia, which sets a permissible variation range between the 90-110% of the initial concentration. RESULTS: During the assay there was no appearance of particles, precipitates in the samples, discharge of gases, nor colour changes in the solutions. The samples showed a remaining concentration of oxaliplatin and doxorubicin within the 90-110% limit. The stability of the samples that follow to two cycles of freeze-thaw after hyperthermia was also found within the specified limits. CONCLUSION: A, B and c solutions in 5% glucose, are physically and chemically stable at 49° C for two hours. Under these conditions, these solutions could be used with guarantees of stability in patients with peritoneal carcinomatosis subsidiary of intraperitoneal hyperthermic chemotherapy based in these antineoplastic agents.

Objetivo: Determinar in vitro la estabilidad físico-química de oxaliplatino ydoxorrubicina en las condiciones de hipertermia utilizadas in vivo duranteel tratamiento de pacientes con carcinomatosis peritoneal, tras cirugía citorreductora.Métodos: Se prepararon tres disoluciones: A (oxaliplatino 200 mg/L), B(doxorrubicina 15 mg/L) y C (oxaliplatino 200 mg/L + doxorrubicina 15 mg/L)en glucosa al 5%. Las tres disoluciones se sometieron a la temperaturamáxima alcanzada in vivo (49º C) durante dos horas. La estabilidad física secentró en el control visual de partículas y/o precipitados en las disoluciones,el desprendimiento de gases, olor y color. Para controlar la estabilidad química,se extrajeron muestras cada 15 minutos desde el inicio del estudio yse determinó la concentración remanente de oxaliplatino y doxorrubicina enlas mismas. Las concentraciones de oxaliplatino se determinaron por absorciónatómica con cámara de grafito mientras que doxorrubicina se determinómediante cromatografía líquida de alta resolución. Como criterio deestabilidad química se seleccionó el establecido en la Farmacopea Americanaque establece un margen de variación permitido entre el 90-110% de laconcentración inicial.Resultados: Durante el tiempo de ensayo, no se observó la aparición departículas o precipitados, ni el desprendimiento de gases o cambios decolor en las disoluciones. Las muestras analizadas presentaron una concentraciónremanente de oxaliplatino y doxorrubicina dentro del límite de 90-110%. La estabilidad de las muestras sometidas a dos ciclos de congelación-descongelación tras la hipertermia también se encontró dentro de loslímites especificados.Conclusiones: Las disoluciones A, B y C en glucosa al 5%, son establesfísica y químicamente a 49º C, durante dos horas. En estas condiciones,podrían ser utilizadas con garantías de estabilidad en pacientes con carcinomatosisperitoneal subsidiarios de recibir quimioterapia intraperitonealcon hipertermia basada en estos agentes antineoplásicos.

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma.

BACKGROUND: The outcome of patients with systemic diffuse large B-cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high-risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high-dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R-CHOP) chemotherapy to decrease CNS recurrence in high-risk patients. METHODS: A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression-free survival, and overall survival were calculated. RESULTS: Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m(2) with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow-up of 33 months, there were only 2 CNS recurrences (3%) in this high-risk population. The 3-year progression-free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients. CONCLUSIONS: Intravenous methotrexate can be safely administered concurrently with R-CHOP and is associated with a low risk of CNS recurrence in high-risk patients.

Simultaneous determination of nilotinib, imatinib and its main metabolite (CGP-74588) in human plasma by ultra-violet high performance liquid chromatography.

We describe a high performance liquid chromatography (HPLC) method that separates two of the currently licenced tyrosine kinase inhibitors (TKIs); nilotinib (AMN107, Tasigna) and imatinib (STI571, Glivec), together with its main metabolite, CGP-74588, from human plasma. After solid phase extraction the drug mix was separated through a Gemini C6-phenyl column (150 mm x 4.6mm, i.d.; 5 microm) (Phenomenex), UK) under isocratic mobile phase conditions of methanol:50mM ammonium acetate (pH 8) (65:35, v/v) with ultra-violet (UV) detection at 260 nm wavelength. For all compounds the intra-day coefficient of variation and bias were <3% and <5% respectively; and inter-day were <4% and <9%. This simple and novel method may be used to quantify levels of TKIs when used alone or in combination with drug treatments for clinical samples.

Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells.

Despite the crucial roles dendritic cells (DC) play in host immunity against cancer, the pharmacologic effects of many chemotherapeutic agents have remained mostly unknown. We recently developed a DC biosensor clone by engineering the stable murine DC line XS106 to express the yellow fluorescent protein (YFP) gene under the control of interleukin (IL)-1beta promoter. In this study, the resulting XS106 pIL1-YFP DC clone was used to screen 54 anticancer drugs. Each drug was tested at five concentrations (0.1-10 micromol/L) for its effects on YFP expression, cell viability, and granulocyte macrophage colony-stimulating factor-dependent growth. Our unbiased systematic screening unveiled a striking heterogeneity among the tested anticancer drugs in their effects on the three functional variables. Interestingly, 15 drugs induced significant YFP expression at subcytotoxic concentrations and were thus categorized as "DC-stimulatory" anticancer drugs. These drugs were subsequently found to induce at least one of the characteristic maturational changes in mouse bone marrow-derived DCs. For example, vinblastine, a prototypic drug of this class, induced the production of IL-1beta, IL-6, and IL-12, increased surface expression of CD40, CD80, CD86, and MHC class II, and augmented T cell-stimulatory capacity of DCs. Not only do these results illustrate the differential pharmacologic effects of commonly used chemotherapeutic agents on DCs, they may also provide a conceptual framework for rationale-based selection and combination of anticancer drugs for clinical application.

Simultaneous determination of decitabine and vorinostat (Suberoylanalide hydroxamic acid, SAHA) by liquid chromatography tandem mass spectrometry for clinical studies.

A reverse-phase high-performance liquid chromatography method with electrospray ionization and detection by tandem mass spectrometry is described for the simultaneous quantitative determination of decitabine (5-aza-2'-deoxycytidine) and vorinostat (Suberoylanalide hydroxamic acid, SAHA) in human plasma. The method involves a simple acetonitrile precipitation step and centrifugation followed by injection of the supernatant onto a C18 150mmx2.1mm I.D., 3microm HPLC column at 36 degrees C. Separation of decitabine, SAHA and their respective internal standards was achieved with a gradient elution and detection was via the mass spectrometer operated in selected reaction monitoring mode. The method was within the defined validation parameters for linearity, repeatability, reproducibility and stability. The limit of detection was determined as 1.0 and 0.125ngml(-1) and lower limits of quantitation were 10 and 1ngml(-1) for decitabine and SAHA, respectively. Effects of sample preparation on stability were also evaluated in human plasma. For clinical sample handling tetrahydrouridine, an inhibitor of cytidine deaminase was found to help prevent decitabine degradation. The method is currently being used in clinical pharmacokinetic studies for the evaluation of decitabine and SAHA combination therapies.

Phenoxodiol-Topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects.

OBJECTIVE: We previously showed that Phenoxodiol is able to sensitize epithelial ovarian cancer cells to Paclitaxel, Carboplatin, Gemcitabine, and Docetaxel. The aim of this study was to determine the value of Phenoxodiol-Topotecan coadministration. METHODS: Nine epithelial ovarian cancer cell lines isolated from ascites or ovarian tissue were treated with increasing concentrations of Topotecan (5-500 ng/ml) with or without Phenoxodiol pretreatment (10 microg/ml) for 24 h and cell viability was measured using CellTiter 96 AQueous One Solution Cell Proliferation Assay. The effect of Phenoxodiol-Topotecan combination therapy in vivo was determined using the topotecan resistant A2780 mouse xenograft model. RESULTS: In vitro, pretreatment with Phenoxodiol lowers the topotecan IC50 from >500 ng/ml to 2.5-100 ng/ml in five out of nine cell lines tested. RESULTS from animal experiments confirmed the advantage of Phenoxodiol-Topotecan combination therapy over monotherapy controls. Median tumour kinetics from animals receiving Phenoxodiol-Topotecan in combination was significantly slower compared to those animals receiving the respective monotherapies. In addition, co-administration with Phenoxodiol reversed Topotecan-induced myelosuppression. CONCLUSION: Phenoxodiol-Topotecan combination therapy allows the administration of both agents at lower doses while retaining significant anti-tumor activity compared to monotherapy. These findings suggest that the Phenoxodiol-Topotecan combination may represent an alternative treatment modality for the management of ovarian cancer and justifies further investigation in the clinical setting.

Effect of a copper gradient on plant community structure.

Vegetation data including plant cover, biomass, species richness, and vegetation height was sampled on a copper-contaminated field with total copper contents varying from 50 to almost 3,000 mg/kg soil. The field was covered by early succession grassland dominated by Agrostis stolonifera. Plant cover, biomass, species richness, and vegetation height generally decreased with increasing copper content, although the highest biomass was reached at intermediate copper concentrations. Multivariate statistical analyses showed that plant community composition was significantly correlated with soil copper concentration and that community composition at soil copper concentrations above 200 mg/kg differed significantly from community composition at lower copper levels. Comparison of single-species (Black Bindweed, Fallopia convolvulus) performance at the field site and in laboratory tests involving field soil and spiked soil indicates that the laboratory tests conventionally applied for risk assessment purposes do not overestimate copper effects. Interaction between copper and other stressors operating only in the field probably balance the higher bioavailability in spiked soil.

Novel reagents for the sensitive spectrophotometric determination of flutamide, an anticancer drug in pharmaceutical preparations.

Simple and sensitive spectrophotometric methods for the determination of flutamide (FLA) in either pure form or in its pharmaceutical preparations are described. The first method is based on the diazotisation of reduced FLA, followed by coupling with alcoholic iminodibenzyl (IDB) in acid medium to give a purple coloured product having a lambda(max) of 570 nm. In the second method, the diazotisation of reduced FLA followed by coupling with 4-amino-5-hydroxy-2,7-naphthalenedisulphonic acid monosodium salt (AHND) in a buffer medium of pH 12, gives a red coloured product having a lambda(max) of 520 nm. Common excipients used as additives in pharmaceutical preparations do not interfere in the proposed methods. Both the methods are highly reproducible and have been applied to a wide variety of pharmaceutical preparations and the results compare favourably with the reported method.

Development of obesity and neurochemical backing in aurothioglucose-treated mice.

To clarify the neurochemical backing of aurothioglucose (ATG)-induced obesity in mice, we investigated lesion sites, hypothalamic neurotransmitters and c-Fos-like immunoreactivity (Fos-IR). At day 2 after ATG, tissue loss or cells death was observed in several parts of the ventral area of the ventromedial hypothalamic nucleus (VMH), and the dorsal area of arcuate nucleus and in the nucleus of the solitary tract (NTS). However, the greater part of the VMH was retained. Body weight began to increase in week 1. Hypothalamic serotonin (5-HT) and the metabolites were increased at day 2. The contents of acetylcholine, norepinephrine and dopamine in the hypothalamus showed no significant change. In week 1, the area shown tissue loss was compacted and plugged up. In the control group, most obvious c-Fos-like immunoreactive region was paraventricular nucleus (PVN). At day 2, Fos-IR was observed around destroyed regions in the hypothalamus and NTS, but few Fos-IR was found in the other regions including PVN. The Fos-IR around destroyed regions diminished after week 1. In week 3, Fos-IR in the PVN increased. These results suggest that the development of ATG-induced obesity cannot be attributed to solely VMH destruction. The restoration processes of the neuronal dysfunction involving PVN seem to play an important role in the development of obesity. NTS lesion and 5-HT system might contribute to decrease in food intake for several days after ATG.

All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60 human leukemia cells in spite of decreased cellular ara-CTP accumulation.

BACKGROUND: Accumulation of the cytosine arabinoside (ara-C) metabolite ara-C-triphosphate (ara-CTP) in leukemic blast cells is considered to be the main determinant of ara-C cytotoxicity in vitro and in vivo. Retinoids such as all-trans-retinoic acid (ATRA) have been shown to increase the sensitivity of acute myelogenous leukemic (AML) blast cells to ara-C. To investigate the mechanism of this sensitisation, the hypothesis was tested that ATRA augments cellular ara-CTP levels in human-derived myelogenous leukemia HL-60 cells. MATERIALS AND METHODS: The effect of ATRA and 13-cis-retinoic acid on ara-CTP accumulation and ara-C-induced apoptosis was studied. Ara-CTP levels were measured by high-performance liquid chromatography (HPLC), cytotoxicity by the tetrazolium (MTT) assay, and apoptosis by occurrence of DNA fragmentation (gel electrophoresis), cell shrinkage and DNA loss (flow cytometry). RESULTS: Pretreatment of HL-60 cells with ATRA (0.01-1 microM) caused a significant decrease in intracellular ara-CTP levels; e.g., incubation for 72 hours with ATRA 1 microM prior to one hour ara-C 10 microM reduced ara-CTP levels to 41% +/- 4% of control. Similar results were obtained after preincubation with 13-cis-retinoic acid. In spite of decreased ara-CTP levels, the cytotoxicity of the combination was supraadditive and ATRA augmented ara-C-induced apoptosis. CONCLUSION: At therapeutically relevant concentrations ATRA increased ara-C cytotoxicity and ara-C induced apoptosis but this augmentation is not the corollary of elevated ara-CTP levels. The feasibility of ara-C treatment optimisation via strategies other than those involving elevation of ara-CTP levels should be investigated further.

Photodynamic therapy using Photofrin in combination with buthionine sulfoximine (BSO) to treat 9L gliosarcoma in rat brain.

BACKGROUND AND OBJECTIVE: The reactive oxygen mechanisms associated with cell damage after photodynamic therapy (PDT) may be exploited to enhance tumor destruction. Pharmacological reduction of glutathione (GSH), an inhibitor of reactive oxygen species, can be induced by administration of buthionine sulfoximine (BSO). STUDY DESIGN/MATERIALS AND METHODS: BSO was administered in combination with Photofrin as the photosensitizer in order to promote PDT induced cell damage. Photofrin (12.5 mg/kg) or Photofrin with BSO (440 mg/kg) were administered to male Fischer rats (n = 27) containing an intracerebral 9L gliosarcoma or to non tumored rats. Brain tumor or non tumored brain was treated with an optical (632 nm) irradiance of 140 J/cm2. Animals were sacrificed 24 h after PDT and the volume of tissue necrosis was measured. Brain Photofrin concentration was measured in tumor and in non tumor bearing animals administered either Photofrin or Photofrin with BSO. GSH was measured by high pressure liquid chromatography in tumor and homologous non tumor tissue in animals administered BSO or control solution. RESULTS: The volume of tumor necrosis was significantly greater in animals administered Photofrin and BSO than in animals administered only Photofrin. No differences were detected in non tumored tissue damage between groups. No differences in Photofrin concentration were detected in tumored or nontumored animals between animals administered Photofrin and animals administered Photofrin and BSO. BSO administration preferentially and significantly reduced GSH in tumor compared to non tumor tissue. CONCLUSIONS: Our data suggest that BSO administration preferentially augments tumor destruction without compromising non tumored tissue.