Introduction
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour in adults. Despite a multidisciplinary approach including surgery, concomitant radiation therapy, and chemotherapy to treat GBM, and extensive efforts to identify new therapeutic approaches, most patients experience poor prognosis limiting the median survival to 14.6 months. The standard chemotherapy treatment, temozolomide (TMZ), increases patient median survival by only 2.5 months.
Cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate (Fc2), an experimental prostate cancer drug, significantly outperforms TMZ in 2D and 3D cell culture experiments using three GBM cell lines.
Methods
Cell culture experiments with GBM cell lines U251 (astrocytoma), LN229 (GBM, right frontal parieto-occipital cortex), and T98G (brain) assessed cell viability using an MTS assay. Cell viability was assessed by drug treatment of 3D printed GBM microtumours. Cell migration experiments were also conducted to better understand their response to drug treatment.
Finally, mice treated with Fc2 were sacrificed and drug concentrations within liver, kidney and brain measured by LC-MS/MS.
Resuls
IC50s were calculated for Fc2 168.3 ± 3.2 and for TMZ as 417.3 ± 5.5 µM for U251. For LN229, Fc2 of 199.6 ± 5.5 and for TMZ as 430.2 ± 6.1 µM. And for T98G, Fc2 gave 330.8 ± 33.3, while TMZ showed poor potency even at concentrations as high as 100µM, and the IC50 was greater than 1000 µM.
For scratch assay experiments, in all three cell lines the wound size remained constant for Fc2, while TMZ and DMSO treated wells had similar rate of wound closure in LN229 and T98G.
For a 40mg/kg dose of Fc2 by IP injection, serum drug concentration averaged 115 ± 66 ng/mL (n = 5). For mouse tissues, 995 ± 46 ng/g in liver (n=3), 322 ± 132 ng/g in kidney (n=5) and 50 ± 14 ng/g in brain (n=4), using tissue wet weight.