No abstract

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.

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Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies.

It is extremely challenging to perform chemical analyses of the brain, particularly in humans, due to the restricted access to this organ. Imaging techniques are the primary approach used in clinical practice, but they only provide limited information about brain chemistry. Solid-phase microextraction (SPME) has been presented recently as a chemical biopsy tool for the study of animal brains. The current work demonstrates for the first time the use of SPME for the spatially resolved sampling of the human brain in vivo. Specially designed multi-probe sampling device was used to simultaneously extract metabolites from the white and grey matter of patients undergoing brain tumor biopsies. Samples were collected by inserting the probes along the planned trajectory of the biopsy needle prior to the procedure, which was followed by metabolomic and lipidomic analyses. The results revealed that studied brain structures were predominantly composed of lipids, while the concentration and diversity of detected metabolites was higher in white than in grey matter. Although the small number of participants in this research precluded conclusions of a biological nature, the results highlight the advantages of the proposed SPME approach, as well as disadvantages that should be addressed in future studies.

Alterations in the carnitine shuttle system may be an indication of the presence of cancer. As such, in-depth analyses of this pathway in different malignant tumors could be important for the detection and treatment of this disease. The current study aims to assess the profiles of carnitine and acylcarnitines in gliomas with respect to their grade, the presence of isocitrate dehydrogenase (IDH) mutations, and 1p/19q co-deletion. Brain tumors obtained from 19 patients were sampled on-site using solid-phase microextraction (SPME) immediately following excision. Analytes were desorbed and then analyzed via liquid chromatography–high-resolution mass spectrometry. The results showed that SPME enabled the extraction of carnitine and 22 acylcarnitines. An analysis of the correlation factor revealed the presence of two separate clusters: short-chain and long-chain carnitine esters. Slightly higher carnitine and acylcarnitine concentrations were observed in the higher-malignancy tumor samples (high vs. low grade) and in those samples with worse projected clinical outcomes (without vs. with IDH mutation; without vs. with 1p/19q co-deletion). Thus, the proposed chemical biopsy approach offers a simple solution for on-site sampling that enables sample preservation, thus supporting comprehensive multi-method analyses.

No abstract

Given that the extent to which genetics alters the metabolomic profile of tissues is still poorly understood, the current study aimed to characterize and investigate the metabolite profiles of brain, liver, kidney and skeletal muscle of two common mouse inbred strains (BALB/c, C57BL/6) and one outbred stock (CD1) for strain-specific differences. Male mice (n = 15) at the age of 12 weeks were used: BALB/c (n = 5), C57BL/6 (n = 5) and CD1 (n = 5). Solid phase microextraction (SPME) was applied for the extraction of analytes from the tissues. SPME fibers (approximately 0.2 mm in diameter) coated with a biocompatible sorbent (4 mm length of hydrophilic-lipophilic balanced particles) were inserted into each organ immediately after euthanasia. Samples were analyzed using liquid chromatography coupled to a Q-Exactive Focus Orbitrap mass spectrometer. Distinct interstrain differences in the metabolomic patterns of brain and liver tissue were revealed. The metabolome of kidney and muscle tissue in BALB/c mice differed greatly from C57BL/6 and CD1 strains. The main compounds differentiating all the targeted organs were alpha-amino acids, purine nucleotides and fatty acid esters. The results of the study indicate that the baseline metabolome of organs, as well as different metabolic pathways, vary widely among general-purpose models of laboratory mice commonly used in biomedical research.