Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.

Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on arterial compliance and distensibility in patients with mild-to-moderate chronic kidney disease.

BACKGROUND: Arterial stiffness is increased in chronic kidney disease (CKD). Intervention studies aimed at reduction of arterial stiffness in dialysis patients have been disappointing. We therefore investigated the effect of pravastatin, vitamin E, and homocysteine lowering on arterial compliance and distensibility coefficients in mild-to-moderate CKD. METHODS: This is a sub-study of the ATIC study, a randomized, double-blind trial in 93 CKD patients. The treatment group received pravastatin to which vitamin E supplementation was added after 6 months and homocysteine lowering therapy after another 6 months. Measurement of the distensibility coefficient (DC) and the compliance coefficient (CC) of the common carotid (CCA), femoral (FA) and brachial artery (BA) was performed at 0, 6, 12, 18 months. Young's elastic modulus (YEM) was measured in the common carotid artery. RESULTS: After 18 months, CCA-DC increased from mean (SD) 15.15 (6.67) to 16.52 (6.37) × 10-3kPa-1 in the treatment and decreased from 18.44 (8.19) to 16.26 (7.35) in the placebo group (p = 0.057). CCA-CC increased from 0.64 (0.24) to 0.71 (0.26) mm2kPa-1 in the treatment and decreased from 0.77 (0.28) to 0.69 (0.25) in the placebo group (p < 0.0001). FA-DC had increased from 6.64 (3.45) to 11.46 (6.83) in the treatment group, and from 6.46 (2.85) to 7.08 (2.73) in the placebo group (p = 0.0001). FA-CC had increased from 0.46 (0.24) to 0.74 (0.44) in the treatment group, and from 0.48 (0.27) to 0.53 (0.21) in the placebo group (p = 0.008). BA-DC and CC, and CCA YEM were not significantly different between the groups. CONCLUSION: In patients with mild-to-moderate CKD, 18 months of treatment consisting of pravastatin, vitamin E and homocysteine lowering resulted in significant improvement of compliance and distensibility in CCA and FA. Since pravastatin was used throughout the observation period, it remains unclear whether the beneficial effects are attributable solely to the ongoing effect of pravastatin treatment, or if the additional interventions further slowed the progression of vascular stiffness. Therefore, larger studies with a longer period of follow-up observing the separate effects are needed.