Clinically Relevant Brain Tumor Model and Device Development for Experimental Therapeutics
Pages 5-12
Kamalakannan Palanichamy, Kirstin Acus, John R Jacob and Arnab Chakravarti
DOI: http://dx.doi.org/10.6000/1927-7229.2015.04.01.2
Published: 12 February 2015

Abstract: This paper assesses the subcutaneous, orthotopic, and transgenic mouse models used to study glioblastomas (GBMs) as well as delineates our model to overcome the limitations of these currently used models. Subcutaneous model involves the injection of GBM cells into hind leg or back of a mouse, whereas in orthotopic model, the injection of GBM cells into the cranium of mice is required. Neither subcutaneous nor orthotopic models accurately display the infiltrative growth pattern of the tumor into the brain parenchyma characteristic of GBMs in humans. Transgenic models are achieved by pronuclear microinjection (into the male pronucleus, immediately after fertilization) or the injection of DNA into embryonic stem cells. Transgenic models are similar to human GBMs in every way, except they are not as genetically complex. To overcome the limitations in these models, we have developed a brain tumor model that exhibits all the histologic hallmarks of human GBM. We used a flank model initially to enrich a tumorigenic population of GBM cells from patient biopsies and a subsequent intracranial implantation to achieve the characteristics of tumors similar to those observed in human patients. The cells enriched by this method were then implanted and subjected to standard treatments such as chemotheraphy and radiation. Subsequently, we determined the treatment efficacy and rate of recurrence. Currently, we are using this approach to determine the treatment resistance pathways leading to recurrence and for developing a better combinatorial approach by short-circuiting the aberrant signaling pathways that are up-regulated in the treatment resistance tumors.

The Neurotoxicity and Pharmacokinetics of Oral Ifosfamide
Pages 13-23
Martin S. Highley, Guido Momerency, Diane Sawyers, Ernst A. De Bruijn, Hans Prenen, Gunther Guetens, Gert De Boeck, Allan T. Van Oosterom, Janine L. Mansi, Peter R. Blake, Tim Mant, Robert A.A. Maes and Peter G. Harper

DOI: http://dx.doi.org/10.6000/1927-7229.2015.04.01.3
Published: 12 February 2015

Abstract: Purpose:Ifosfamide can cause an unexplained encephalopathy. The incidence after intravenous infusion is 10%, but is much higher after oral administration. This study assesses the pharmacokinetics of oral ifosfamide in relation to neurotoxicity.

Patients and Methods:Eleven patients received oral ifosfamide 500 mg twice daily for 14 days, with concurrent oral mesna. The concentrations of ifosfamide, isophosphoramide mustard, 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, carboxyifosfamide, ketoifosfamide, chloroethylamine and 3-oxazolidine-2-one were measured using GC-MS. Patients were evaluated clinically, and also with the EEG, psychometric testing, the national adult reading test, and the mini-mental state examination.

Results:A decrease in the electroencephalogram alpha frequency was observed, with the development of pathological slow wave activity. Psychometric performance was also impaired. Neurotoxicity was progressive during treatment, and the incidence of grade 3 neurotoxicity was 22%. The mean day 14 / day 1 Cmax ratios for 2-dechloroethylifosfamide and 3-dechloroethylifosfamide were 2.73 (± 2.11) and 2.04 (± 1.32) respectively. The metabolite with the lowest ratio was isophosphoramide mustard 1.07 (± 0.39). High chloroethylamine Cmax values were associated with lower alpha frequencies, and increased clinical neurotoxicity.

Conclusion:Oral ifosfamide 500 mg twice daily for 14 days causes unacceptable neurotoxicity. It was not possible to identify one particular metabolite responsible for the neurotoxicity, although the dechloroethyl metabolites and chloroethylamine are implicated.