Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

Regulation of astrocyte glutamine synthetase in epilepsy

“…Because GS is intimately involved with regulation of neurotransmitter cycling (in particular, glutamate-glutamine and glutamate-GABA-glutamine cycling) (Chowdhury et al, 2007; Jain et al, 2011; Sibson et al, 2001), it is not surprising that several metabolites associated with neurotransmitter cycling, including the substrates and products of the synthetic reaction catalyzed by GS, play key roles in regulating this enzyme. To better appreciate how the catalytic activity of and flux of substrates through GS can be regulated, it is important to briefly discuss the mechanistic outcome of the kinetic investigations of the purified brain GS (Cooper et al, 1983; Meister, 1985).…”

“…Of relevance to the regulation of brain GS is the finding that significant levels of the elevated Mn are likely detected in astrocytes, because these cells are known to accumulate Mn avidly (Lai et al, 1999; Lai et al, 2000; Wedler et al, 1994). Consequently, the elevation of astrocytic Mn levels may exert modulatory effects on GS activity and flux and ultimately on glutamate-glutamine and glutamate-GABA-glutamine cycling in those disease states (Chowdhury et al, 2007; Jain et al, 2011; Lai et al, 1999; Lai et al, 2000; Sibson et al, 2001; Wedler et al, 1994). A case in point is hepatic encephalopathy (Lai et al, 1999; Lai et al, 2000) (see below).…”

Synthesis and anticancer activity evaluation of substituted carbazole bearing thiosemicarbazide derivatives against human glioma U87 MG cell line

“…GBM is a most deadly, aggressive and undifferentiated type of tumor originated from glial cell in the brain. The current treatment standard is a multimodal approach combining neurosurgery, fractionated radiation therapy, and chemotherapy [3,4]. However, GBM patients usually have a median survival of approximately 14 to 15 months from the diagnosis [3].…”

“…The current treatment standard is a multimodal approach combining neurosurgery, fractionated radiation therapy, and chemotherapy [3,4]. However, GBM patients usually have a median survival of approximately 14 to 15 months from the diagnosis [3]. Temozolomide (TMZ), is the only anticancer drug has been reported to improve the survival in a phase III study of GBM when administered concomitant with the radiotherapy [5].…”

Apoptotic Events in Glioma Activate Metalloproteinases and Enhance Invasiveness

“…More recent clinical studies employing surgery with the use of chemotherapeutic regimens in combination with radiation therapy or by receptor mediated growth hormone deprivation are slightly more effective in increasing median survival times, but again have had limited success in increasing the overall survival rate in patients being treated for primary or recurrent GBM [3][4][5][6][7]. Clinicians and neurosurgeons are diligently pursuing new treatments and provide hope for patients and their families [8,9]. However, the difficulties of complete resection, the resistance to radiation and other therapies and particularly the intractable malignant invasiveness still remains at the root of the very poor survival prognosis for patients with GBM and other high grade gliomas.…”