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Conventional drug delivery systems suffer from poor absorption and poor bioavailability at the target site due to either very weak or very strong adsorption of drug on the carrier. Porous 2D nanostructures can offer better drug delivery system provided the system chosen has suitable cavity with heteroatoms for reasonable interaction with drug molecules. C2N is a surface of choice in this regard; therefore, potential of C2N surface as drug delivery system for nitrosourea and fluorouracil (drugs) is explored here. Both nitrosourea and fluorouracil interacted with the electron rich central cavity of C2N. Different structural and electronic parameters show that both drugs have good adsorption on C2N surface and thus can be carried to the target easily. Values of interaction and basis set superposition error (BSSE) corrected energies are slightly higher for nitrosourea@C2N as compared to fluorouracil@C2N. While all other properties such as non-covalent interaction (NCI), symmetry-adapted perturbation theory (SAPT0), quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO), electron density difference (EDD) and frontier molecular orbital (FMO) analyses illustrate that C2N is better carrier for nitrosourea than fluorouracil. The off-loading of drug is explored through molecular dynamics simulations which reveal that slightly elevated temperature can cause off-loading of the drug at the target cancer cell, which usually have temperature higher than the normal cells. MD simulations reveal that atomic interactions between the drugs and C2N are destabilized at higher temperatures. Comparison of the loading and off-loading mechanism with other surfaces reported in the literature reveal that C2N is a better carrier for these drugs. [ABSTRACT FROM AUTHOR]

The reactions of N-p-carboxyphenyl-β-D-glucopyranosylamine and N-p-carboxyphenyl-β-D-galactopyranosylamine with dicyclohexylcarbodiimide in the presence of tetrahydrofuran and triethylamine were studied for the first time. Interaction of the synthesised acylureas with sodium nitrite was used to obtain glycosylamines containing a nitroso (N=O) group. The synthesised compounds were studied within the framework of mathematical chemistry, using the method of quasi-PNS-matrices (PNS-). The influence of compounds: b-N-(p-carboxyphenylgalactopyranosyl)- acylurea and b-N-(p-carboxyphenylgalactopyranosyl)-nitrosourea on the growth and development of microorganism has been investigated. The antimicrobial properties of the synthesised compounds were studied on various microorganisms. [ABSTRACT FROM AUTHOR]

[Display omitted] • XC 3 monolayers' drug delivery performance (where X = B, N) for the nitrosourea was assessed. • The BC 3 layer holds onto nitrosourea better than the NC 3 layer. • The NC 3 layer works better for delivering the nitrosourea than the BC 3 layer. The pristine XC3 monolayers' drug delivery performance (where X = B, N) for the anticancer drug nitrosourea was assessed with DFT calculations. The researchers examined how nitrosourea drug attaches to XC 3 layers in the most stable direction and calculated the energy involved. The way nitrosourea sticks to XC 3 layers depends a lot on what type of element X is. The BC 3 layer holds onto nitrosourea better than the NC 3 layer. The BC 3 and NC 3 surfaces have the most stable complexes, with an adsorption energy of −1.88 eV and −1.11 eV, respectively. The study examined how drugs are released near cancer cells because of the lower pH compared to around healthy cells. In water, the BC 3 layer's solvent and adsorption energies matter more than those of the NC 3 layer. It has been confirmed that a thin layer called XC 3 can be used to carry a drug called nitrosourea, which is used to treat cancer. [ABSTRACT FROM AUTHOR]

BackgroundThe primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome.MethodsEligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met.ResultsMedian follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81).ConclusionsRT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival.

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM. [ABSTRACT FROM AUTHOR]

In the present investigation, the capability of the pristine pentagonal BCN (penta-BCN) nanosheet for sensing and drug delivery of the nitrosourea and hydroxyurea anticancer drugs has been examined through the periodic density functional theory. The adsorption and sense effect of these drug molecules on the structural and electronic virtues of the substrate are analyzed. The energy gap has been reduced by 57.63 % and 19.96 % after adsorbing the nitrosourea and hydroxyurea anticancer drugs respectively, so the penta-BCN nanosheet shows an electrical response to the presence of these drugs. The adsorption energy in the gas/water phases for the most stable nitrosourea/BCN and hydroxyurea/BCN complexes are −2.7/-1.21 and −2.53/-1.96 eV, respectively. The solvability of the drug, the surface, and the complexes in the aqueous solvent have also been examined. The thermal and dynamical stability of the structures at room temperature, by results of the NVT module of the molecular dynamics, has been confirmed. The drug release from the substrate near the target cells in an acidic environment has also been simulated. We can propose a pristine penta-BCN substrate as a potential carrier and sensor of nitrosourea and hydroxyurea anticancer drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • QTAIM and NCI analyses reveal that drug molecules are mainly stabilized through nonbonding interactions. • Loading of the anticancer drug FU on the cavitand nanocapsule improves the conductivity. • AIMDS analysis shows that cavitand capsules can efficiently carry the anti-cancerous drug to the targeted site. • Cavitand nanocapsule is a better carrier of fluorouracil drug compared to nitrosourea for drug delivery. The nanomaterials have been widely investigated as drug delivery system for a variety of anticancer drugs to limit their adverse effects while transporting to the target site. In the current study, we report the cavitand-based nanocapsules as a drug delivery vehicle for nitrosourea (NU) and fluorouracil (FU) anti-cancer drugs. FU and NU drugs interact with the nanocapsules with the interaction energies in gas phase (solvent) −24.78 kcal/mol (–22.39 kcal/mol) and −21.58 kcal/mol (-20.45 kcal/mol), respectively. The results of Quantum theory of atoms in molecules (QTAIM) and noncovalent index (NCI) analyses indicate that the FU@Capsule and NU@Capsule complexes are mainly stabilized through hydrogen bonding and van der Waals interactions. Electron density difference (EDD) and natural bond order (NBO) analyses reveal that significant amount of charge is transferred from the nanocapsule to drug molecules. Frontier molecular orbital (FMO) analysis also reveals slight reduction in the energy gap. AIMDS analysis shows that cavitand capsules can efficiently carry the anti-cancerous drug to their target site without distorting complexes. The dipole moments and pH effect are studied to understand the drug release mechanism of considered anticancer drugs. The decrease in adsorption energy and increase in interaction distances indicate that anticancer drugs can easily be off-loaded from the carrier (nanocapsule) at the target site due to the low pH of cancerous cells compared to the normal cells. Therefore, cavitand nanocapsule can be employed as an excellent drug delivery carrier in smart targeted drug delivery. [ABSTRACT FROM AUTHOR]

Here we report a density functional theory study on the alkali metal doped borospherenes M@C4B32 (M = Li, Na, and K) as high-performance materials for drug delivery applications. Inspired by interesting results of a new class of borospherenes which were designed by doping four C atoms in the B 36 4 − nanocage (C4B32), we suggest the alkali metal-doped C4B32 nanoclusters as suitable materials for the drug delivery applications. The main objective of the present work is to investigate the interaction of pristine M@C4B32 nanoclusters with an anti-cancer drug (nitrosourea) by means of the density functional theory. Our ultraviolet–visible calculations reveal that the electronic spectra of the drug/nanocluster complexes show a red shift toward higher wavelengths (lower energies). Consequently, our results represented that the K@C4B32 could be used as potential carriers for the delivery of the nitrosourea drug. [ABSTRACT FROM AUTHOR]

Background: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. Methods: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O6-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression. Results: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002). Conclusions: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of alternative fotemustine administration schedule in elderly patients with recurrent glioblastoma. Patients & methods: Patients aged >65 years with recurrent glioblastoma received fotemustine (80 mg/m2; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety. Results: 58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3–4 hematological toxicities occurred. Conclusion: The alternative fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.

Aim: To identify patients with recurrent glioblastoma after temozolomide (TMZ) concurrent with and adjuvant to radiotherapy who could benefit from TMZ rechallenge at the time of disease progression. Methods:We retrospectively evaluated 106 glioblastoma patients who had nonprogressive disease at first magnetic resonance imaging after completion of TMZ concurrent with and adjuvant to radiotherapy, a treatment-free interval (TFI) of at least 8 weeks and received TMZ rechallenge or a nitrosourea at the time of progression. Results: In patients with TFI ≥5 months, median survival was 17.7 and 11.6 months and median progression-free survival was 8.1 and 5.8 months in the TMZ and nitrosourea group, respectively. Longer TFI was associated with reduced risk for death (p = 0.002) and for disease progression (p = 0.005). Conclusion: TFI ≥5 months represents a predictor of retained TMZ sensitivity. [ABSTRACT FROM AUTHOR]

In this study, oxygenated triarylmethyl (oxTAM) is investigated by DFT calculations as a drug carrier framework for Nitrosourea (NU) and Fluorouracil (FU) drugs. Based on the adsorption analysis i.e. , energies and distances between interacting atoms, it is found that oxTAM exhibits excellent carrier abilities for the delivery of FU (−1.53 eV & 2.00 Å) and NU (−1.33 eV & 2.12 Å) drugs. NCI and QTAIM results indicate the presence of hydrogen bonding in drug-carrier complexes. The values of dipole moment and global chemical descriptors show the significant reactivity of oxTAM for NU and FU drugs. Based on electronic property analysis, FU@oxTAM has a higher adsorption trend for complexation with oxTAM as compared to NU@oxTAM. Moreover, FU can easily release from the carrier due to the decreasing adsorption stability after protonation under an acidic environment as well as a short recovery time observed for the oxTAM carrier surface. Keeping in view all the above parameters, we inferred that oxTAM can serve as a potential drug delivery system for anticancer drugs including, Nitrosourea and Fluorouracil drugs. [ABSTRACT FROM AUTHOR]

Background: Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier. Objective: To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model. Methods: Toxicity studies were performed in 42 rats following the administration of 4 μl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED ( n = 8); saline i.v. ( n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically. Results: The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses ( P < 0.05; log-rank test). Conclusions: ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma. [ABSTRACT FROM AUTHOR]

Background: We evaluated O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET and MRI for early response assessment in recurrent glioma patients treated with lomustine-based chemotherapy., Methods: Thirty-six adult patients with WHO CNS grade 3 or 4 gliomas (glioblastoma, 69%) at recurrence (median number of recurrences, 1; range, 1-3) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (not later than two cycles). Tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of new distant hotspots with a mean TBR >1.6 at follow-up, and the dynamic parameter time-to-peak were derived from all FET PET scans. PET parameter thresholds were defined using ROC analyses to predict PFS of ≥6 months and OS of ≥12 months. MRI response assessment was based on RANO criteria. The predictive values of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates., Results: After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Relative changes of TBR, MTV, and RANO criteria predicted a significantly longer PFS (all P ≤ .002) and OS (all P ≤ .045). At follow-up, the occurrence of new distant hotspots (n ≥ 1) predicted a worse outcome, with significantly shorter PFS (P = .005) and OS (P < .001). Time-to-peak changes did not predict a significantly longer survival. Multivariate survival analyses revealed that new distant hotspots at follow-up FET PET were most potent in predicting non-response (P < .001; HR, 8.578)., Conclusions: Data suggest that FET PET provides complementary information to RANO criteria for response evaluation of lomustine-based chemotherapy early after treatment initiation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The adequate second-line therapy of patients with glioblastoma (GBM) is a matter of ongoing debate. This particularly applies to patients with a non-methylated MGMT promotor who are known to have a poor response to alkylating chemotherapy. In some countries, antiangiogenic therapy with BEV is applied as second-line therapy, and in others nitrosourea therapy is second-line choice. It is an open question whether the delay of BEV to third-line therapy has a negative impact on survival. Methods: A total of 61 adult patients (median age 56.9 years) with MGMT-non-methylated relapsed GBM treated with BEV ( n = 45) or nitrosourea ( n = 16) as second-line therapy were analyzed retrospectively and compared regarding progression-free survival (PFS) and overall survival (OS). Results: Patients treated with second-line BEV had longer median PFS (107 days, 95 % CI 80.7-133.2 days) than patients with second-line nitrosourea (52 days, 95 % CI 36.3-67.7 days, P = 0.011, logrank test). However, there was no significant difference in overall survival (BEV median 170 days, 95 % CI 87.2-252.8 days; nitrosourea median 256 days, 95 % CI 159.9-352.0 days, P = 0.468). PFS was similar after BEV third-line therapy (median 117 days, 95 % CI 23.6-210.4 days) as compared to second-line BEV therapy (median 107 days, 95 % CI 80.7-133.3 days, P = 0.584). Conclusion: Our findings suggest that early treatment with BEV in patients with MGMT-non-methylated relapsed GBM is associated with a better PFS, but not with superior OS, possibly implicating that the early, i.e., second-line, use of BEV is not mandatory and BEV treatment may safely be delayed to third-line therapy in this subgroup of patients. [ABSTRACT FROM AUTHOR]

Introduction Standards of care are not yet defined in recurrent glioblastoma. Methods We reviewed the literature on clinical trials for recurrent glioblastoma available in PubMed and American Society of Clinical Oncology (ASCO) abstracts until June 2015. Results Evidence is limited due to the paucity of randomized controlled studies. Second surgery or re-irradiation are options for selected patients. Alkylating chemotherapy such as nitrosoureas or temozolomide and the vascular endothelial growth factor (VEGF) antibody, bevacizumab, exhibit comparable single agent activity. Phase III data exploring the benefit of combining bevacizumab and lomustine are emerging. Novel approaches in the fields of targeted therapy, immunotherapy, and tumor metabolism are coming forward. Several biomarkers are being explored, but, except for O 6 -methylguanine DNA methyltransferase ( MGMT ) promoter methylation, none has assumed a role in clinical practice. Conclusion Proper patient selection, development of predictive biomarkers and randomized controlled studies are required to develop evidence-based concepts for recurrent glioblastoma. [ABSTRACT FROM AUTHOR]

The spin-labeled chloroethylnitrosourea containig glycine SLCNUgly is an analogue of the clinically used nitrosourea drug lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU), showing promising properties and features in vitro as well as in vivo . In this work the interaction of SLCNUgly with a lipid model membrane is investigated. The presented results indicate penetration of the drug in the membranes without causing defects of the lipid structure and reveal the potential of both SLCNUgly and electrode-supported lipid films as models for investigating nitrosourea drugs-membrane interactions. [ABSTRACT FROM AUTHOR]

[Display omitted] • C 3 Al nanosheet is studied as drug delivery system for anticancer drugs. • The solvation energy reveals the solubility of the studied drug in the aqueous medium. • The highest change in dipole moment of NU after adsorption indicates its high hydrophilicity. • C 3 Al nanosheet can be suitable nanocarrier for the drug delivery of NU. In comparison to conventional macro systems, two-dimensional (2D) sheet-like materials, such as aluminum carbide (C 3 Al), are superior drug delivery systems (DDSs) because of their bioavailability and adsorption. The bioavailability and absorption of most drug molecules can be improved by the surface of 2D materials with an average adsorption energy. Hence, the possibility of using 2D C 3 Al for the drug delivery of nitrosourea (NU) was investigated. Based on the adsorption energy (E ads) analysis, the NU molecules had an interaction with C 3 Al with a medium interaction energy that is a prerequisite for a suitable DDS. The adsorption energies in NU@C 3 Al were approximately − 21.81 and −11.14 kcal/mol for different complexes. At the end of NU adsorption, the dipole moment (μ) of the surface was enhanced, which facilitated solubility and was essential for the delivery of drugs in living systems. The HOMO-LUMO energy gap of C 3 Al reduced from 3.45 eV to 2.69 eV after the adsorption of NU. According to all computational findings, C 3 Al seems to be a suitable candidate for the delivery of the anticancer drug NU. This research provides useful insights into the development of an experimental C 3 Al-based drug delivery system for NU. [ABSTRACT FROM AUTHOR]

A novel fluorous polystyrene (FPS) MR-resin was applied to a fluorous solid-phase (FSP) reaction. The MR-FPS resin actually was developed previously and possessed excellent chemical resistance to acids and alkalis, and a fluorous-tagged compound was homogeneously and loosely immobilized on the resin. The synthesis of an antitumor drug, an N -methyl- N -nirosourea conjugated 3-amino-β-carboline derivative, was accomplished with a high yield by using this new fluorous reaction system. Using only filtration, the fluorous 3-amino-β-carboline derivatives immobilized on the MR-FPS resin were easily recovered from the reaction mixtures. As an extention of this approach, a diversity synthesis of 3-amino-9-benzyl-β-carboline derivatives was applied to the FSP method giving high yields. Finally, the FSP synthesis was compared with the corresponding conventional solid- and liquid-phase methods of synthesis. The FSP reaction was superior in terms of the reactivity of the substrate and the ease of product separation. [ABSTRACT FROM AUTHOR]

Anaplastic glioma (AG) is divided into three morphology-based groups (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma) as well as three molecular groups (glioma-CpG island methylation phenotype [G-CIMP] negative, G-CIMP positive non-1p19q codeleted tumors and G-CIMP positive codeleted tumors). The RTOG 9402 and EORTC 26951 trials established radiotherapy plus (procarbazine, lomustine, vincristine) chemotherapy as the standard of care in 1p/19q codeleted AG. Uni- or non-codeleted AG are currently best treated with radiotherapy only or alkylator-based chemotherapy only as determined by the NOA-04 trial. Maturation of NOA-04 and results of the currently accruing studies, CODEL (for codeleted AG) and CATNON (for uni or non-codeleted AG), will likely refine current up-front treatment recommendations for AG. [ABSTRACT FROM AUTHOR]

High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • CTF-0 covalent organic framework is studied as drug delivery system for anticancer drugs. • The adsorption energy is higher for FU (−17.45 kcal/mol) as compared to NU (−14.83 kcal/mol). • The highest change in dipole moment of FU after adsorption indicates its high hydrophilicity. • CTF-0 can be suitable carrier for the drug delivery of FU. 2D sheet like materials such graphene are superior drug delivery systems compared to the conventional macro systems due to good adsorption and reasonable bioavailability. The adsorption and bioavailability can be further improved with periodic cavity containing 2D materials which can bind with drug molecules with moderate binding energies. Therefore, we have studied for the first time the potential of 2-dimensional porous covalent triazine framework (CTF-0) for the delivery of anticancer drugs fluorouracil (FU) and nitrosourea (NU). Adsorption energy analysis shows that the drug molecules bind with CTF-0 with moderate interaction energies which is prime requirement of a good drug delivery system. However, FU@CTF-0 complex (−17.45 kcal/mol) is more stable than NU@CTF-0 (−14.83 kcal/mol), and that the dipole moment of surface increases after adsorption of drugs. The increase in dipole moment after complex formation helps to improve the solubility, which is necessary for drug delivery in biological systems. Symmetry adapted perturbation theory confirms the stability of drug-loaded complexes, where the contribution from dispersion interactions is the highest. The HOMO-LUMO energy gap (E H-L) of CTF-0 decreases from 4.5 eV to 4.1 eV and 4.0 eV after loading of FU and NU respectively. The pH in cancerous tissues is typically low, which can lead to protonation of a drug and hence aid its delivery to target cells. The nature of the attraction between the CTF-0 surface and different drugs has been evaluated on the bases of noncovalent interactions (NCI) and also the quantum theory of atoms in molecules (QTAIM). QTAIM results confirm that FU has a stronger affinity towards CTF-0 than NU. Based on all our calculated results, CTF-0 appears to be a viable candidate for the delivery of the anticancer drug FU. Previously reported surface for FU and NU drugs has much higher interaction energy which is problematic for the release of drug from the carrier in the biological system. This study provides useful information that may assist the experimental formulation of a CTF-0-based DDS for FU. [ABSTRACT FROM AUTHOR]

The histological and immunohistochemical type of chemically induced (injection of N-methyl-N-nitrosourea into the mammary gland) breast tumor was studied in Wistar females. The tumor induced by N-methyl-N-nitrosourea was moderately differentiated adenocarcinoma with infiltrative growth lacking estrogen-α and human epidermal growth factor receptors, and expressing progesterone receptors; tumor cells were characterized by high proliferative activity. This variant of chemically induced breast tumor corresponds to human breast cancer luminal type B. [ABSTRACT FROM AUTHOR]

Abstract: Twenty-one types of novel ellipticine derivatives and pyridocarbazoles (5-methoxycarbonyl-11-methyl-6H-pyrido[4,3-b]carbazoles) with a nitrosourea moiety, linked by an oxydiethylene unit at the 2 position, were synthesized, and their cytotoxicity against HeLa S-3 cells was evaluated. Some of these new compounds exhibited potent antitumor activity by comparison with that of ellipticine. [Copyright &y& Elsevier]

Background: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking. Methods: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m2, day 1/42) and VM26 (45-60 mg/m2, days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity. Results: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed. Conclusion: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Study Objective As chemotherapy with teniposide and a nitrosourea is commonly used for the treatment of patients with recurrent glioma but can be associated with severe myelotoxicity, we sought to determine if prophylactic administration of pegfilgrastim could reduce leukopenia or infectious complications in patients receiving this chemotherapeutic regimen. Design Retrospective medical record review. Setting University-affiliated neurooncology hospital in Frankfurt, Germany. Patients Sixty-four patients who received at least one cycle of a nitrosourea agent (nimustine or lomustine) and teniposide for recurrent glioma between 2008 and 2012; of these patients, 28 did not receive prophylactic pegfilgrastim (cohort A), and 36 patients received prophylactic pegfilgrastim (cohort B). Measurements and Main Results Blood counts, hospitalizations due to infection or myelosuppression, use of intravenous antibiotics, and survival parameters were analyzed. Leukopenia was more frequently observed before day 30 (early nadir) versus from 30 days until the next cycle (late nadir). In cohort B, Common Terminology Criteria for Adverse Events grade 3 leukopenia in the early nadir occurred less often compared with cohort A (9% in cohort B vs 31% in cohort A). However, the frequency of grade 4 leukopenia, number of days in the hospital due to infection or myelosuppression, days on intravenous antibiotics, progression-free survival, and overall survival were similar between the cohorts. Conclusion Moderate, but not severe, leukopenia or related complications could be prevented by prophylactic pegfilgrastim in patients treated with a nitrosourea and teniposide for recurrent glioma. Our results, therefore, do not support routine prophylactic use of pegfilgrastim in these patients. [ABSTRACT FROM AUTHOR]

Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p = 0.03). Survival times were similar for patients with grade III ( n = 9) and grade IV ( n = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs. [ABSTRACT FROM AUTHOR]