gms | German Medical Science

Objective: Insufficient drug delivery and chemoresistance limit response of gliomas to systemic therapy. JS-K, a diazeniumdiolate prodrug, allows specific release of nitric oxide (NO) after cleavage by GSTs. JS-K inhibits proliferation and induces apoptosis/necrosis in vitro and in vivo. The objective of this study was to investigate the effect of concomitant NO donor and temozolomide therapy on survival, tumor growth and various MRI parameters reflecting tumor physiology in an intracranial U87 xenograft model in vivo.

Methods: Immunodeficient nude rats (n = 10 / group, 3 treatment and 1 control group) were inoculated with 50.000 U87 cells into the right striatum. Treatment with JS-K (3.5 µmol/kg i.v.), TMZ (3.9 mg/rat i.p.), or a combination was performed 3 times per week starting on day 5. Serial MRI scans were performed in week 1, 2, 3, 7 and 10 after tumor inoculation (n = 5 / group). Tumor volume was assessed on T2-weighted multislice RARE scans. Dynamic contrast enhanced (DCE) MRI pre- and post-injection of Gd-DTPA was performed and analyzed by apparent diffusion coefficient (ADC) and initial area under the curve (iAUC). Post mortem analysis for apoptosis, necrosis and angiogenesis was performed by immunohistochemistry. Statistical analysis was performed by one way ANOVA, Tukey post-hoc test and Kaplan Meier survival statistics.

Results: Concomitant JS-K + TMZ therapy and TMZ monotherapy lead to a significant reduction in tumor volume compared to the control and JS-K groups (p < 0.05; week 3). This effect was more prominent up to week 10 with complete tumor regression in some animals (p < 0.001). JS-K monotherapy did not result in tumor control compared to untreated controls. JS-K injection caused an acute increase in iAUC reflecting a short-term NO effect on tumor perfusion and permeability. During follow-up, iAUC was significantly reduced in animals treated with TMZ (p < 0.01) or with JS-K + TMZ (p < 0.05, week 3). Long time survival up to 14 weeks was observed up to now after treatment with TMZ or TMZ+JS-K.

Conclusions: NO donor therapy with JS-K can be safely combined with TMZ chemotherapy in rats with intracranial gliomas. Serial MRI imaging confirmed a long-lasting antitumor effect of TMZ alone and TMZ+JS-K. Acute tumor-selective increase in blood flow and permeability was demonstrated after i.v. JS-K delivery. Whether long time survival is due to a synergistic effect of JS-K and TMZ or TMZ alone remains to be clarified by post mortem histological analysis.