Combined modality therapy of gemcitabine and irradiation on human glioma spheroids derived from cell lines and biopsy tissue

Abstract

Multicellular tumor spheroids have been used to examine aspects of combined modality treatment since they often recreate the in vivo tumor environment much more closely than other models. The radioenhancement by gemcitabine (dFdC) on human glioma spheroids derived from cell lines (CLS) and biopsy tissue, grown as organotypic multicellular spheroids (OMS), was studied. CLS of GaMg and U87 and OMS of four glioblastoma patients were used. Radiochemosensitvity was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. Cell death (ethidium homodimer) was studied using a fluorescence cell viability assay. In CLS, combination treatment led to migration inhibition in GaMg and U87 of 85% and 62% (dFdC 46% and 52%, RT 21% and 43%) and proliferation inhibition of 83% and 85%, respectively. Following dFdC + RT in OMS (% of cases), apoptosis and p21 expression increased (50%), p53 expression increased (75%) and cell proliferation decreased (75%). Only minor morphological damage was observed. Confocal laser scanning microscopy identified an increased dead cell core after dFdC + RT (50%). In conclusion, dFdC can lead to an additively radioenhancement in CLS and individual OMS.

Colorectal cancer-derived tumor spheroids retain the characteristics of original tumors

“…These 3D tumor spheroids can be generated from both, established 2D cancer cell lines and fragments of tumor tissue. However, compared with 3D tumor spheroids derived from cancer cell lines, those derived from primary tumor tissues are better at mimicking the features of original tumors, such as tumor heterogeneity and complexity [3][4][5][6][7]. In addition, these primary tumor tissue-derived spheroids show some characteristics of cancer stem cells (CSCs) [1,7].…”

Folate-Conjugated pH-Responsive Nanocarrier Designed for Active Tumor Targeting and Controlled Release of Gemcitabine

“…Moreover, folate conjugated mesoporous silica nanoparticles have been reported in literature [17][18][19][20][21]. Herein, we designed a novel nanocarrier for targeting cancerous cells.…”

Three-Dimensional In Vitro Models in Glioma Research - Focus on Spheroids

“…However, a study by Glicklis et al (Glicklis et al, 2004) has described that hepatocyte spheroids with diameters up to 100 μm have a good oxygenation status. Other studies by Fehlauer et al (Fehlauer et al, 2005;Fehlauer et al, 2006;Fehlauer et al, 2007) have reported that by using glioma spheroids with diameters of 200-250 μm, there are only few hypoxic cells and no central necrosis present.…”

“…However, in fact Kaaijk et al reported that proliferation in three investigated organotypic multicellular spheroids was decreased 7-20 fold relative to untreated controls one week after hypofractionated radiation with a total of 40 Gy. Moreover, Fehlauer et al (Fehlauer et al, 2005;Fehlauer et al, 2006) described in two studies a decrease in the percentage of MIB-1 positive proliferative cells in organotypic multicellular spheroids following irradiation with 20 Gy. It has also been suggested that tumor stem cells might show increased radioresistance compared to more differentiated cells Phillips et al, 2006;Rich, 2007).…”

“…This may be explained by effects of hypoxia in vitro on proliferation of the tumor cells, spheroid formation and expression of stem cell markers, suggesting that also this aspect should be taken into consideration (Heddleston et al, 2009;Kolenda et al, 2010;McCord et al, 2009;Soeda et al, 2009). Several studies have used the different types of spheroids mentioned above for investigating the effects of chemotherapy and radiation on the tumor cells and in particular on the tumor stem-like cells Bauman et al, 1999;Fehlauer et al, 2005;Fehlauer et al, 2006;Fehlauer et al, 2007;Genc et al, 2004;Gliemroth et al, 2003;Haas-Kogan et al, 1996;Johannessen et al, 2009;Kaaijk et al, 1997;Khaitan et al, 2009;Sunayama et al, 2010;Terzis et al, 1997;Terzis et al, 1998;Wakimoto et al, 2009;Wang et al, 2010). After such treatments cell viability and cell proliferation assays as well as secondary spheroid formation assays have been used to evaluate induced effects.…”