demeclocycline and Glioma

Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

Topics: Antineoplastic Agents; Brain Neoplasms; Carcinogenesis; Cell Growth Processes; Cells, Cultured; Demeclocycline; Glioma; Humans; Monocytes; Neoplastic Stem Cells; Tumor-Associated Macrophages

Complete resection of brain tumors improves life expectancy and quality. Thus, there is a strong need for high-resolution detection and microscopically controlled removal of brain neoplasms. The goal of this study was to test demeclocycline as a contrast enhancer for the intraoperative detection of brain tumors. We have imaged benign and cancerous brain tumors using multimodal confocal microscopy. The tumors investigated included pituitary adenoma, meningiomas, glioblastomas, and metastatic brain cancers. Freshly excised brain tissues were stained in 0.75 mg ml(-1) aqueous solution of demeclocyline. Reflectance images were acquired at 402 nm. Fluorescence signals were excited at 402 nm and registered between 500 and 540 nm. After imaging, histological sections were processed from the imaged specimens and compared to the optical images. Fluorescence images highlighted normal and cancerous brain cells, while reflectance images emphasized the morphology of connective tissue. The optical and histological images were in accordance with each other for all types of tumors investigated. Demeclocyline shows promise as a contrast agent for intraoperative detection of brain tumors.

Topics: Brain; Brain Neoplasms; Contrast Media; Demeclocycline; Fluorescent Dyes; Glioblastoma; Glioma; Humans; Meningeal Neoplasms; Meningioma; Microscopy, Confocal; Neoplasm Metastasis; Optical Imaging; Pituitary Neoplasms; Radionuclide Imaging; Reproducibility of Results

Contrast agents have shown to be useful in the detection of cancers. The goal of this study was to compare enhancement of brain cancer contrast using reflectance and fluorescence confocal imaging of two fluorophores, methylene blue (MB) and demeclocycline (DMN). MB absorbs light in the red spectral range and fluoresces in the near-infrared. It is safe for in vivo staining of human skin and breast tissue. However, its safety for staining human brain is questionable. Thus, DMN, which absorbs light in the violet spectral range and fluoresces between 470 and 570 nm, could provide a safer alternative to MB. Fresh human gliomas, obtained from surgeries, were cut in half and stained with aqueous solutions of MB and DMN, respectively. Stained tissues were imaged using multimodal confocal microscopy. Resulting reflectance and fluorescence optical images were compared with hematoxylin and eosin histopathology, processed from each imaged tissue. Results indicate that images of tissues stained with either stain exhibit comparable contrast and resolution of morphological detail. Further studies are required to establish the safety and efficacy of these contrast agents for use in human brain.

Topics: Brain; Brain Chemistry; Brain Neoplasms; Contrast Media; Demeclocycline; Glioma; Humans; Image Processing, Computer-Assisted; Methylene Blue; Optical Imaging