Cost-effectiveness of lung volume reduction coil treatment in patients with severe emphysema: results from the 2-year follow-up crossover REVOLENS study (REVOLENS-2 study).

BACKGROUND: The REVOLENS study compared lung volume reduction coil treatment to usual care in patients with severe emphysema at 1 year, resulting in improved quality-adjusted life-year (QALY) and higher costs. Durability of the coil treatment benefit and its cost-effectiveness at 2 years are now assessed. METHODS: After one year, the REVOLENS trial's usual care group patients received coil treatment (second-line coil treatment group). Costs and QALYs were assessed in both arms at 2 years and an incremental cost-effectiveness ratio in cost per QALY gained was calculated. The uncertainty of the results was estimated by probabilistic bootstrapping. RESULTS: The average cost of coil treatment in both groups was estimated at €24,356. The average total cost at 2 years was €9655 higher in the first-line coil treatment group (p = 0.07) and the difference in QALY between the two groups was 0.127 (p = 0.12) in favor of first-line coil treatment group. The 2-year incremental cost-effectiveness ratio (ICER) was €75,978 / QALY. The scatter plot of the probabilistic bootstrapping had 92% of the replications in the top right-hand quadrant. CONCLUSION: First-line coil treatment was more expensive but also more effective than second-line coil treatment at 2 years, with a 2-year ICER of €75,978 / QALY. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01822795 .

Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial.

IMPORTANCE: Therapeutic options for severe emphysema are limited. Lung volume reduction using nitinol coils is a bronchoscopic intervention inducing regional parenchymal volume reduction and restoring lung recoil. OBJECTIVE: To evaluate the efficacy, safety, cost, and cost-effectiveness of nitinol coils in treatment of severe emphysema. DESIGN, SETTING, AND PARTICIPANTS: Multicenter 1:1 randomized superiority trial comparing coils with usual care at 10 university hospitals in France. Enrollment of patients with emphysema occurred from March to October 2013, with 12-month follow-up (last follow-up, December 2014). INTERVENTIONS: Patients randomized to usual care (n = 50) received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen; those randomized to bilateral coil treatment (n = 50) received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures. MAIN OUTCOMES AND MEASURES: The primary outcome was improvement of at least 54 m in the 6-minute walk test at 6 months (1-sided hypothesis test). Secondary outcomes included changes at 6 and 12 months in the 6-minute walk test, lung function, quality of life as assessed by St George's Respiratory Questionnaire (range, 0-100; 0 being the best and 100 being the worst quality of life; minimal clinically important difference, ≥4), morbidity, mortality, total cost, and cost-effectiveness. RESULTS: Among 100 patients, 71 men and 29 women (mean age, 62 years) were included. At 6 months, improvement of at least 54 m was observed in 18 patients (36%) in the coil group and 9 patients (18%) in the usual care group, for a between-group difference of 18% (1-sided 95% CI, 4% to ∞; P = .03). Mean between-group differences at 6 and 12 months in the coil and usual care groups were +0.09 L (95% CI, 0.05 L to ∞) (P = .001) and +0.08 L (95% CI, 0.03 L to ∞) (P = .002) for forced expiratory volume in the first second, +21 m (95% CI, -4 m to ∞) (P = .06) and +21 m (95% CI, -5 m to ∞) (P = .12) for 6-minute walk distance, and -13.4 points (95% CI, -8 points to ∞) and -10.6 points (95% CI, -5.8 points to ∞) for St George's Respiratory Questionnaire (1-sided P < .001 for both). Within 12 months, 4 deaths occurred in the coil group and 3 in the usual care group. The mean total 1-year per-patient cost difference between groups was $47,908 (95% CI, $47,879-$48,073) (P < .001); the incremental cost-effectiveness ratio was $782,598 per additional quality-adjusted life-year. CONCLUSIONS AND RELEVANCE: In this preliminary study of patients with severe emphysema followed up for 6 months, bronchoscopic treatment with nitinol coils compared with usual care resulted in improved exercise capacity with high short-term costs. Further investigation is needed to assess durability of benefit and long-term cost implications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01822795.

Extracellular NAADP affords cardioprotection against ischemia and reperfusion injury and involves the P2Y11-like receptor.

BACKGROUND AND PURPOSE: Extracellular nucleotides may play important regulatory roles within the cardiovascular system and notably in cardioprotection. We aimed to look for a possible pharmacological preconditioning effect of extracellular NAADP ([NAADP]e) against ischemia/reperfusion injury. [NAADP]e has been recently reported to be a full agonist of the P2Y11 receptor. Therefore, we characterized the involvement of the P2Y11-like receptor in mediating ischemic/reperfusion tolerance induced by [NAADP]e. EXPERIMENTAL APPROACH: The cardioprotective effects of [NAADP]e were evaluated in a model of ischemia/reperfusion carried out on Langendorff perfused rat hearts. This model was also instrumented with a microdialysis probe. Furthermore, using isolated cardiomyocytes, we assessed cAMP, inositol phosphate accumulation and prosurvival protein kinases activation induced by [NAADP]e pretreatement. RESULTS: Pretreatment with 1µM [NAADP]e induced cardioprotective effects with regards to functional recovery, necrosis and arrhythmogenesis (p<0.05). These effects were completely suppressed with NF157, an antagonist of the P2Y11 receptor. Moreover, global ischemia induced a time-dependent increase in interstitial concentration of adenosine, NAADP and UTP. In cardiomyocyte cultures, NF157 suppressed cAMP and inositol phosphate accumulation induced by [NAADP]e. [NAADP]e induced phosphorylation of ERK 1/2, AKT and its downstream target GSK-3ß (p<0.05). These activations were also suppressed by NF157. CONCLUSIONS: Evidence suggests that NAADP signalling at the P2Y11-like receptor affords significant cardioprotection against ischemia/reperfusion injury. Besides adenosine and UTP, microdialysis study supports a potential endogenous role of [NAADP]e.

Association between proton pump inhibitors and severe hematological toxicity in patients receiving pemetrexed-based anticancer treatment: The prospective IPPEM study.

OBJECTIVE: Pemetrexed is associated with hematological toxicity. Drug-drug interactions (DDIs) between methotrexate and proton pump inhibitors (PPIs) induce a higher risk of hematological toxicity due to the inhibition of methotrexate excretion by PPIs. As pemetrexed and methotrexate are both excreted by human organic anion transporter 3 (hOAT3), this study investigates the hypothetical DDI between pemetrexed and PPIs in lung cancer patients. The primary objective was the occurrence of severe (grade ≥ 3) hematological toxicity. The secondary objectives were to describe the type of hematological toxicity and associated clinical consequences (NCT03537833). MATERIALS AND METHODS: PPI consumption was collected for each patient receiving pemetrexed-based anticancer chemotherapy from May 2018 to October 2020 in a prospective multicentric observational and nonrandomized study. Multivariate Cox regression and propensity score (PS) adjustment, PS matching and inverse weighting on PS (IPTW) methods were used. RESULTS: PPI consumption (55 among 156 included patients) was associated with a significantly higher risk of severe hematological toxicity in the multivariable Cox regression model (hazard ratio HR = 2.51, 95% confidence interval [1.47-4.26]; p = 0.005). Similar results were found with PS adjustment (HR = 1.91 CI95% [1.14-3.20]; p = 0.002), PS-matching (HR = 1.93 CI95% [1.08-3.45]; p = 0.02) and IPTW method (HR = 2.06 CI95% [1.27-3.35]; p = 0.004). Severe neutropenia and anemia occurred in 32.7% and 14.1% of patients, respectively. This resulted in 48 anticancer chemotherapy postponements and 24 dose adjustments, 26 growth factor prescriptions, 24 red blood cell transfusions, and 20 hospitalizations. CONCLUSIONS: The results strongly suggest an association between PPI consumption and pemetrexed-related severe hematological toxicity. Deprescription of PPIs when feasible should be considered to prevent this DDI.

Screening of biochemical/histological changes associated to C6 glioma tumor development by FTIR/PCA imaging.

Principal components analysis (PCA) combined to Fourier transform infrared (FTIR) microspectroscopic imaging was used to screen biochemical changes associated to C6 glioma tumor from 7 to 19 days growth. Normal brain and tumor obtained at 7, 12, 19 days after C6 cell injection were used to develop a diagnostic model of brain glioma based on PCA analysis. This classification model was validated using extra-measurements on normal and tumor at 9 and 15 days post-implantation. The spatial and biochemical information obtained from FTIR/PCA maps can be used to improve the discrimination between normal and grading human glioma. The first 4 PCs which account for more than 93.6% of total spectral variance were used to construct pseudo-color scores maps and compared each map to the corresponding hematoxylin and eosin (H&E) staining. Our results reported that by correlating pseudocolor map scores with H&E staining it was possible to screen histological changes associated with tissue transformation. In fact, PC1 and PC4 were associated to the tumor, surrounding tumor and necrosis. Indeed, at day 7 after tumor implantation, FTIR investigations displayed a very small abnormal zone associated with the proliferation of C6 cells in the caudate putamen (CP). PC2 and PC3 described normal brain structures such as white matter (corpus callosum (CC) and commissura anterior (CA)) and some cortex layers (grey matter). After delipidation of the tissues, we were still able to differentiate between different tissue features based on nucleic acid and protein content. By comparing the patterns of the PC loads with the spectra of lipids extracted from white and gray matters, and DNA, we have identified some biochemical changes associated with tissue transformation. This work demonstrated that our classification model provides a successful histological classification of different brain structures.

Ex vivo and in vivo diagnosis of C6 glioblastoma development by Raman spectroscopy coupled to a microprobe.

The potential of Raman spectroscopy for ex vivo and in vivo classification of normal and glioblastoma brain tumor development was investigated. High-quality spectra of normal and tumor tissues were obtained using a portable Raman spectrometer coupled to a microprobe with a signal integration time of 5 s. Ex vivo results demonstrated that by using the biochemical information contained in the spectra, we were able to distinguish between normal brain features (white and gray matter), invasion, and tumor tissues with a classification accuracy of 100%. Differences between these features resulted from variations in their lipid signal contributions, which probably reflect differences in the level of myelinization. This finding supports the ability of in vivo Raman spectroscopy to delineate tumor margins during surgery. After implanting C6 cells in rat brain, we monitored, in vivo, the development of glioblastoma tumor from days 0 to 20 post-implantation (PI). The classification exhibited a clear separation of the data into two clusters: one cluster was associated with normal brain tissues (cortex), and the second was related to data measured from tumor evolution. The second cluster could be divided into two subclusters, one associated with tumor tissue from 4 to 13 days PI and the second related to tumor tissue from 15 to 20 days PI. Histological analysis reveals that the differences between these two subclusters are: the presence of a massive infiltration zone in the brain tissue from 4 to 13 days PI, and; a maturation of the tumor characterized by the appearance of edematous and necrotic zones, as well as a diminution in the proliferative and invasive area, from 15 days. This work demonstrates the potential of Raman spectroscopy to provide diagnostic information for the early detection of tumors in vivo.

Intratumoral distribution of YSNSG cyclopeptide in a mouse melanoma model using microdialysis.

The YSNSG peptide is a synthetic cyclopeptide targeting αvß3 integrin with antitumor activity. Previous study has determined main pharmacokinetic parameters in plasma and in tissue in healthy animals using microdialysis. First we aim to assess the impact of a 20 mg/kg dosage instead of 10 mg/kg in tumor growth inhibition. Secondly we aim to investigate the YSNSG peptide distribution in two different tumor regions in animals with melanoma. C57BL/6 mice were exposed at Days 8, 10 and 12 after melanoma cells implantation (B16F1) to different dosage of YSNSG peptide or control, respectively (n = 10 per group). Data analysis was performed at D16, 20 and 24 with a Nonlinear Mixed-Effects (NLME) approach. For pharmacokinetic study n = 8 mice (same disease condition) received YSNSG peptide by intravenous after insertion of two microdialysis probes in central peripheral region of tumor, respectively. Plasma and tissue samples were collected during 2 h. A non-compartmental analysis was performed to determine main pharmacokinetic parameters. There was a significant tumor growth inhibition in mice receiving 20 mg/kg vs Control (p < 0.02). Main plasma parameters were half-life elimination 25.8 ± 8.2 min, volume of distribution 11.9 ± 0.4 mL, clearance 19.8 ± 9.4 mL/h and area under the curve 1,173.6 µg.min/mL. Penetration rate of the YSNSG peptide from plasma to tumor tissue were 3.3 ± 2.1% and 3.4 ± 2.7% in central and peripheral, respectively. Contrary to subcutaneous distribution in healthy animals the distribution of the YSNSG peptide into tumoral tissue is low but seems non-heterogeneous between central and peripheral tumor region.

Monitoring of biochemical changes through the c6 gliomas progression and invasion by fourier transform infrared (FTIR) imaging.

We have investigated the spatial distribution of molecular changes associated with C6 glioma progression using Fourier transform infrared (FT-IR) microspectro-imaging in order to determine spectroscopic markers for early diagnosis of tumor growth. Our results showed that at day 7 after tumor implantation, FTIR investigations displayed a very small abnormal zone associated with the proliferation of C6 cells in the caudate putamen. From this day, rats developed solid and well-circumscribed tumors and invasive areas. The volume of peritumoral areas increased rapidly until day 19. The maturation of the tumor was accompanied by a diminution in its proliferative and invasive area. The presence of necrotic areas was visible from day 15. A non-negative least-squares algorithm was used to quantify spatial distribution of molecular changes in tissues (lipids, nucleic acids, and proteins) associated with glioma progression. Compared to those in normal brain, statistical tests on fit coefficients showed that the concentrations of sphingomyelin (SMY), nucleic acids, phosphatidylserine (PS), and galactocerebroside (GalC) were significantly affected during C6 glioma development. These constituents can be used as spectroscopic markers for C6 glioma progression. Indeed, the concentration of DNA decreased significantly from tumor to invasion, to normal brain tissues, the necrotic area has higher concentrations of the Galc than other areas. The PS content was significantly higher in the peritumoral zone and decreased in the tumor zones matter.

Discriminating healthy from tumor and necrosis tissue in rat brain tissue samples by Raman spectral imaging.

The purpose of this study was to investigate molecular changes associated with glioma tissues by Raman microspectroscopy in order to develop its use in clinical practice. Spectroscopic markers obtained from C6 glioma tissues were compared to conventional histological and histochemical techniques. Cholesterol and phospholipid contents were highest in corpus callosum and decreased gradually towards the cortex surface as well as in the tumor. Two different necrotic areas have been identified: a fully necrotic zone characterized by the presence of plasma proteins and a peri-necrotic area with a high lipid content. This result was confirmed by Nile Red staining. Additionally, one structure was detected in the periphery of the tumor. Invisible with histopathological hematoxylin and eosin staining, it was revealed by immunohistochemical Ki-67 and MT1-MMP staining used to visualize the proliferative and invasive activities of glioma, respectively. Hierarchical cluster analysis on the only cluster averaged spectra showed a clear distinction between normal, tumoral, necrotic and edematous tissues. Raman microspectroscopy can discriminate between healthy and tumoral brain tissue and yield spectroscopic markers associated with the proliferative and invasive properties of glioblastoma. Development of in vivo Raman spectroscopy could thus accurately define tumor margins, identify tumor remnants, and help in the development of novel therapies for glioblastoma.

Modeling and quantifying biochemical changes in C6 tumor gliomas by Fourier transform infrared imaging.

The purpose of the study was to investigate molecular changes associated with glioma tissues using FT-IR microspectroscopic imaging (FT-IRM). A multivariate statistical analysis allowed one to successfully discriminate between normal, tumoral, peri-tumoral, and necrotic tissue structures. Structural changes were mainly related to qualitative and quantitative changes in lipid content, proteins, and nucleic acids that can be used as spectroscopic markers for this pathology. We have developed a spectroscopic model of glioma to quantify these chemical changes. The model constructed includes individual FT-IR spectra of normal and glioma brain constituents such as lipids, DNA, and proteins (measured on delipidized tissue). Modeling of FT-IR spectra yielded fit coefficients reflecting the chemical changes associated with a tumor. Our results demonstrate the ability of FT-IRM to assess the importance and distribution of each individual constituent and its variation in normal brain structures as well as in the different pathological states of glioma. We demonstrated that (i) cholesterol and phosphatidylethanolamine contributions are highest in corpus callosum and anterior commissure but decrease gradually towards the cortex surface as well as in the tumor, (ii) phosphatidylcholine contribution is highest in the cortex and decreases in the tumor, (iii) galactocerebroside is localized only in white, but not in gray matter, and decreases in the vital tumor region while the necrosis area shows a higher concentration of this cerebroside, (iv) DNA and oleic acid increase in the tumor as compared to gray matter. This approach could, in the future, contribute to enhance diagnostic accuracy, improve the grading, prognosis, and play a vital role in therapeutic strategy and monitoring.

Structural characterization and in vivo pro-tumor properties of a highly conserved matrikine.

Elastin-derived peptides (EDPs) exert protumor activities by increasing tumor growth, migration and invasion. A number of studies have highlighted the potential of VGVAPG consensus sequence-derived elastin-like polypeptides whose physicochemical properties and biocompatibility are particularly suitable for in vivo applications, such as drug delivery and tissue engineering. However, among the EDPs, the influence of elastin-derived nonapeptides (xGxPGxGxG consensus sequence) remains unknown. Here, we show that the AGVPGLGVG elastin peptide (AG-9) present in domain-26 of tropoelastin is more conserved than the VGVAPG elastin peptide (VG-6) from domain-24 in mammals. The results demonstrate that the structural features of AG-9 and VG-6 peptides are similar. CD, NMR and FTIR spectroscopies show that AG-9 and VG-6 present the same conformation, which includes a mixture of random coils and ß-turn structures. On the other hand, the supraorganization differs between peptides, as demonstrated by AFM. The VG-6 peptide gathers in spots, whereas the AG-9 peptide aggregates into short amyloid-like fibrils. An in vivo study showed that AG-9 peptides promote tumor progression to a greater extent than do VG-6 peptides. These results were confirmed by in vitro studies such as 2D and 3D proliferation assays, migration assays, adhesion assays, proteinase secretion studies and pseudotube formation assays to investigate angiogenesis. Our findings suggest the possibility that the AG-9 peptide present in patient sera may dramatically influence cancer progression and could be used in the design of new, innovative antitumor therapies.

Conformation-dependent binding of a Tetrastatin peptide to αvß3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition.

Tetrastatin, a 230 amino acid sequence from collagen IV, was previously demonstrated to inhibit melanoma progression. In the present paper, we identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin in vivo and in vitro on melanoma cell proliferation, migration and invasion. We demonstrated that QS-13 binds to SK-MEL-28 melanoma cells through the αvß3 integrin using blocking antibody and ß3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with αVß3 integrin were analyzed by docking experiments to determine the binding areas and the QS-13 amino acids crucial for the binding. The in silico results were confirmed by in vitro experiments. Indeed, QS-13 binding to SK-MEL-28 was dependent on the presence of a disulfide-bound as shown by mass spectroscopy and the binding site on αVß3 was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PI3K/Akt pathway, a transduction pathway that is largely involved in tumor cell proliferation and migration. Taken together, our results demonstrate that the QS-13 peptide binds αvß3 integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through αVß3.

Brain tissue characterisation by infrared imaging in a rat glioma model.

Pathological changes associated with the development of brain tumor were investigated by Fourier transform infrared microspectroscopy (FT-IRM) with high spatial resolution. Using multivariate statistical analysis and imaging, all normal brain structures were discriminated from tumor and surrounding tumor tissues. These structural changes were mainly related to qualitative and quantitative changes in lipids (tumors contain little fat) and were correlated to the degree of myelination, an important factor in several neurodegenerative disorders. Lipid concentration and composition may thus be used as spectroscopic markers to discriminate between healthy and tumor tissues. Additionally, we have identified one peculiar structure all around the tumor. This structure could be attributed to infiltrative events, such as peritumoral oedema observed during tumor development. Our results highlight the ability of FT-IRM to identify the molecular origin that gave rise to the specific changes between healthy and diseased states. Comparison between pseudo-FT-IRM maps and histological examinations (Luxol fast blue, Luxol fast blue-cresyl violet staining) showed the complementarities of both techniques for early detection of tissue abnormalities.

First plasma and tissue pharmacokinetic study of the YSNSG cyclopeptide, a new integrin antagonist, using microdialysis.

The YSNSG peptide is a synthetic peptide targeting αvß3 integrin. This peptide exhibits promising activity in vitro and in vivo against melanoma. To determine pharmacokinetic parameters and predictive active doses in the central nervous system (CNS) and subcutaneous tissue (SC), we conducted microdialysis coupled with pharmacokinetic modeling and Monte Carlo simulation. After a recovery period of surgical procedures, a microdialysis probe was inserted in the caudate and in subcutaneous tissue. Plasma samples and dialysates collected 5h after YSNSG intravenous administration (10mg/kg) were analyzed by UPLC-MS/MS. A nonlinear mixed-effect modeling approach implemented in Monolix® 2016R1 was performed. Model selection and evaluation were based on the usual diagnostic plot, precision and information criteria. The primary plasma and tissue pharmacokinetic parameters were comparable with those of other integrin antagonists, such as cilengitide or ATN-161. Tissue/plasma and brain/plasma area under the curve (AUC) ratio were 66.2±21.6% and 3.6±4.7%, respectively. Two models of 2-compartments with an additional microdialysis compartment, parameterized as rate constants (k for elimination, k12/k21 and k13/k31 for distribution) and volumes (central V1 and peripheral microdialysis compartment V3) with zero-order input were selected to describe the dialysate concentrations in CNS and SC. The inter-individual variability (IIV) was described by exponential terms, and residual variability was described by a combined additive and proportional error model. Individual AUC (plasma and tissues) values were derived for each animal using the Empirical-Bayes-Estimates of the individual parameters. The regimens needed to achieve an in vitro predetermined target concentration in tissues were studied by Monte Carlo simulations using Monolix® 2016R1. YSNSG pharmacokinetic parameters show promising results in terms of subcutaneous disposition. Further investigations into such processes as encapsulation and intratumoral disposition are currently being conducted.

Encapsulated Ruthenium(II) Complexes in Biocompatible Poly(d,l-lactide-co-glycolide) Nanoparticles for Application in Photodynamic Therapy.

The elaboration, characterisation and efficiency of potential two-photon-excited photodynamic therapy (PDT) treatment of new poly(d,l-lactide-co-glycolide) nanoparticles loaded with ruthenium(II) complexs are presented. The materials are based on the encapsulation of RuII complexes through an all-biocompatible process. The size of the nanoparticles is around 100 nm. The internal concentration is several orders of magnitude higher than the overall concentration, which leads to a more efficient and targeted effect. The therapeutic potential for PDT of these nanoparticles has been studied in vitro on C6 glioma cells.

Etoposide encapsulation in surface-modified poly(lactide-co-glycolide) nanoparticles strongly enhances glioma antitumor efficiency.

Etoposide (VP-16) is a hydrophobic anticancer agent inhibiting Topoisomerase II, commonly used in pediatric brain chemotherapeutic schemes as mildly toxic. Unfortunately, despite its appropriate solubilization in vehicle solvents, its poor bioavailability and limited passage of the blood-brain barrier concur to disappointing results requiring the development of new delivery system forms. In this study, etoposide formulated as a parenteral injectable solution (Teva®) was loaded into all-biocompatible poly(lactide-co-glycolide) (PLGA) or PLGA/P188-blended nanoparticles (size 110-130 nm) using a fully biocompatible nanoprecipitation technique. The presence of coprecipitated P188 on encapsulation efficacies and in vitro drug release was investigated. Drug encapsulation was determined using HPLC. Inflammatory response was checked by FACS analysis on human monocytes. Cytotoxic activity of the various simple (Teva®) or double (Teva®-loaded NPs) formulations was studied on the murine C6 and F98 cell lines. Obtained results suggest that, although noninflammatory neither nontoxic by themselves, the use of PLGA and PLGA/P188 nanoencapsulations over pre-existing etoposide formulation could induce a greatly improved cytotoxic activity. This approach demonstrated a promising perspective for parenteral delivery of VP16 and potential development of a therapeutic entity.

Influence of C6 and CNS1 brain tumors on methotrexate pharmacokinetics in plasma and brain tissue.

PURPOSE: Comparison of the influence of two different brain tumors (C6 and CNS1 glioma) on methotrexate (MTX) disposition in plasma, brain, and tumor tissue extracellular fluid (ECF). METHODS: Serial collection of plasma samples and brain ECF dialysates after i.v. bolus administration of MTX (50 mg kg(-1)) for 4 h. Quantitation of MTX concentrations by HPLC-UV. RESULTS: Histological studies revealed a 3-fold higher number of blood vessels in CNS1 than in C6 tumor tissue. In vivo recoveries (reverse dialysis) were significantly different in tumor tissue (C6: 8.0 +/- 3.8%; CNS1: 4.9 +/- 2.5%), and in the contralateral hemisphere (C6: 6.0 +/- 4.0%; CNS1: 3.9 +/- 2.5%) between the two tumors. Area under the concentration-time curve (AUC) in plasma was 30% higher in CNS1 than in C6 due to a lower systemic clearance. Maximum MTX levels in brain tumor ECF were significantly higher in CNS1 than in C6, and decreased faster in CNS1 than in C6 tumor-bearing rats. Penetration in tumor ECF (AUC(ECF)/AUC(Plasma) ratio) was similar in CNS1 and C6. MTX concentrations in contralateral hemisphere were significantly lower than in tumor tissue and dependent on tumor model. CONCLUSION: C6 and CNS1 brain tumors have a distinct yet highly variable impact on MTX penetration in brain and brain tumor ECF.