Efficacy of interstitial continuous vincristine infusion in a bioluminescent rodent intracranial tumor model

Abstract

Interstitial chemotherapeutic drug infusion can bypass the blood-brain barrier, and provide high regional drug concentrations without systemic exposure. However, toxicity and efficacy for drugs administered via interstitial continuous (i.c.) infusion have not been characterized. In the current study, vincristine (VIN) was infused into the right frontal lobes of healthy Fisher 344 rats at 30, 45, 60, and 120 μg/ml over a period of 7 days at 1 μl/h, using an Alzet osmotic pump to evaluate toxicity. C6 rat glioblastoma cells transduced with a luciferase gene were inoculated into the right frontal lobe of a second group of rats. VIN was administered to tumor bearing rats via i.c. infusion 7 days later and tumor growth was monitored by bioluminescence intensity (BLI) to assess VIN efficacy, intravenous (i.v.) drug administration was used as a comparison drug delivery method. The results suggested that VIN toxicity is dose-dependent. Efficacy studies showed increased BLI, which correlates with histopathological tumor size, in saline-infused and i.v.-treated tumor-bearing rats. These rats survived an average of 28 ± 0.85 days and 33 ± 1.38 days, respectively. Both groups had large tumors at the time of death. Animals treated with VIN via i.c. infusion survived until day 90, the observation endpoint for this study. This was significantly longer than average survival times in the previous two groups. These results demonstrate that VIN via i.c. infusion is effective in reducing C6 glioblastoma tumors and prolonging rodent survival time compared to i.v. injection and suggest that chemotherapeutic drug administration via i.c. infusion may be a promising strategy for treating malignant brain tumors.

Efficacy of vincristine administered via convection-enhanced delivery in a rodent brainstem tumor model documented by bioluminescence imaging

“…Based on previous work from our laboratory [5,30,31] and other studies [32][33][34][35], CED is an effective drug delivery method, allowing for 100% delivery of chemotherapeutic agents. It is a promising delivery method for large therapeutic agents such as monoclonal antibodies [36], antisense oligonucleotides [37], immunotoxins [38,39], or viral vectors [40,41].…”

Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment

“…[10][11][12] CED can bypass the BBB to deliver therapeutic agents to the brain tumors; reduce systemic drug levels to minimize side effects; and provide prolonged elevation of intracerebral chemotherapeutic agents relative to systemic administration. 13,14 Our laboratory 15,16 and others [17][18][19][20][21] have confirmed that CED is an effective delivery method for brain tumor treatment. However, even with this delivery method, sustained localized distribution and prolonged retention after drug delivery remain major challenges.…”

“…16 To evaluate the therapeutic effects of treatment, 5 μl of 0.9% saline, NDs(5 mg/ml), DOX(1 mg/ml) or ND(5 mg/ml)-Dox(1 mg/ ml) were administered via CED, 7 days after tumor inoculation into Fisher 344 rats, or 14 days after inoculation into NIH-RNU nude rats. The luciferase substrate, D-luciferin (150 mg of luciferin/kg of body weight), was injected intraperitoneally 10 min before direct visualization using IVIS Xenogen Imaging System.…”

“…Our previous study, 15,16 as well as work from other labs [38][39][40] had shown that bioluminescence is an ideal method for monitoring in vivo brain tumor therapeutic efficacy. In vitro results from this study showed a correlation between BLI and number of injected cells (Supplementary Figure 4).…”

Pediatric neurosurgery—science, art, and humility: reflection of personal experience

“…We tested the efficacy after interstitial treatment with various chemotherapy agents including carboplatin. Dr. Guifa Xi, who succeeded this research project in my lab, treated them with vincristine, and the results of efficacy and toxicity were published in 2011 [57]. For that study, first, vincristine toxicities after direct injection to the brain stem in a rat were tested to optimize the dosage [58].…”