Drugs Today (Barc). 2004 Nov;40(11):931-4.
Gene therapy of brain tumor with endostatin.
Yamanaka R, Tanaka R.
Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata City,
Japan. ryaman@bri.niigata-u.ac.jp
Malignant brain tumors are the most vascularized tumors. Despite multimodal treatment
approaches, the prognosis remains dismal. Angiogenesis and vascular proliferation are
particularly important in the growth and progression of malignant brain tumors and are
used as indicators of the degree of malignancy. The continued growth of a brain tumor is
dependent on its angiogenic potential. Antiangiogenesis therapy may offer novel
strategies for brain tumor therapy. Treatment with Semliki Forest virus-mediated
endostatin inhibited the angiogenesis associated with established brain tumors. Gene
therapy with endostatin delivered via Semliki Forest virus may be a candidate for the
development of a new treatment for brain tumors.
Pediatr Radiol. 2005 Jan 28;
Comparison of gadobenate dimeglumine (Gd-BOPTA) with gadopentetate
dimeglumine (Gd-DTPA) for enhanced MR imaging of brain and spine
tumours in children.
Colosimo C, Demaerel P, Tortori-Donati P, Christophe C, Van Buchem M,
Hogstrom B, Pirovano G, Shen N, Kirchin MA, Spinazzi A.
Department of Clinical Sciences and Bioimaging, Section of Radiology, University, "G.
d'Annunzio", Chieti, Italy.
: Background: Gadobenate dimeglumine (Gd-BOPTA) demonstrates superior
enhancement of brain tumours in adult patients than Gd-DTPA. Objective: To determine
whether Gd-BOPTA has advantages over Gd-DTPA for enhanced MR imaging of
paediatric brain and spine tumours. Materials and methods: Sixty-three subjects, aged 6
months to 16 years, who were enrolled in a prospective, fully blinded, randomized
parallel-group phase III clinical trial, received 0.1 mmol/kg doses of either Gd-BOPTA
(n=29) or Gd-DTPA (n=34). The MR images were acquired before and within 10 min of
contrast agent injection. The primary objective was to compare the difference from predose to post-dose lesion visualization between Gd-BOPTA and Gd-DTPA. Lesion
visualization was determined as the sum of individual scores for three criteria of lesion
morphological characteristics (lesion border delineation, internal morphology, and
contrast enhancement), each assessed qualitatively using 4-point scales. Quantitative
evaluation compared changes in lesion-to-background (LBR) and contrast-to-noise
(CNR) ratios and per cent enhancement. Monitoring for adverse events and evaluation of
vital signs and laboratory values was performed. Results: Pre-dose to post-dose changes
in lesion visualization were significantly better for Gd-BOPTA for both lesion level
(2.68+/-2.17 vs. 1.05+/-1.90, P=0.0106) and patient level (2.55+/-2.18 vs. 1.14+/-1.68,
P=0.0079) comparisons. The mean pre-dose to post-dose change in CNR was greater for
Gd-BOPTA (9.13+/-15.36) than Gd-DTPA (2.18+/-9.90), but the difference was only
marginally significant (P=0.0779; 95% CI: -0.553, 14.454) because of wide variations of
signal intensity between lesions. Similar findings were obtained for LBR and per cent
enhancement. No differences between the agents were noted in terms of safety
parameters. Conclusions: At an equivalent dose Gd-BOPTA is significantly better than
Gd-DTPA for visualization of enhancing CNS tumours in paediatric patients.
Magn Reson Med. 2005 Jan;53(1):22-9.
Proton-decoupled 31P MRS in untreated pediatric brain tumors.
Albers MJ, Krieger MD, Gonzalez-Gomez I, Gilles FH, McComb JG, Nelson MD
Jr, Bluml S.
Department of Radiology, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los
Angeles, CA 90027, USA.
Proton-decoupled (31)P and (1)H MRS was used to quantify markers of membrane
synthesis and breakdown in eight pediatric patients with untreated brain tumors and in six
controls. Quantitation of these compounds in vivo in humans may provide important
indicators for tumor growth and malignancy, tumor classification, and provide prognostic
information. The ratios of phosphoethanolamine to glycerophosphoethanolamine
(PE/GPE) and phosphocholine to glycerophosphocholine (PC/GPC) were significantly
higher in primitive neuroectodermal tumors (PNET) (16.30 +/- 5.73 and 2.97 +/- 0.93)
when compared with controls (3.42 +/- 1.62, P < 0.0001 and 0.45 +/- 0.13, P < 0.0001)
and with other tumors (3.93 +/- 3.42, P < 0.001 and 0.65 +/- 0.30, P < 0.0001). Mean
PC/PE was elevated in tumors relative to controls (0.48 +/- 0.11 versus 0.24 +/- 0.05, P <
0.001), but there was no difference between PNET and other tumors. Total choline
concentration determined with quantitative (1)H MRS was significantly elevated (4.78
+/- 3.33 versus 1.73 +/- 0.56 mmol/kg, P < 0.05), whereas creatine was reduced in tumors
(4.89 +/- 1.83 versus 8.28 +/- 1.50 mmol/kg, P < 0.05). A quantitative comparison of
total phosphorylated cholines (PC+GPC)/ATP measured with (31)P MRS and total
choline measured with (1)H MRS showed that in tumors a large fraction of the choline
signal (>54 +/- 36%) was not accounted for by PC and GPC. The fraction of unaccounted
choline was particularly large in PNET (>78 +/- 7%). The pH of tumor tissue was higher
than the pH of normal brain tissue (7.06 +/- 0.03 versus. 6.98 +/- 0.03, P < 0.001).
Copyright 2004 Wiley-Liss, Inc.
Neurorx. 2005 Jan;2(1):139-150.
RNA Interference and Nonviral Targeted Gene Therapy of Experimental
Brain Cancer.
Boado RJ.
ArmaGen Technologies, Inc., Santa Monica, California 90401; and Department of
Medicine, UCLA, Los Angeles, California 90024.
The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid
cancer, including brain primary and metastatic cancers. Transvascular nonviral gene
therapy in combination with EGFR-RNA interference (RNAi) represents a new
therapeutic approach to silencing oncogenic genes in solid cancers. This is achieved with
pegylated immunoliposomes (PIL) carrying short hairpin RNA expression plasmids
driven by the U6 RNA polymerase promoter and directed to target EGFR expression by
RNAi. The PIL is comprised of a mixture of known lipids containing polyethyleneglycol
(PEG), which stabilizes the PIL structure in vivo in circulation. The tissue target
specificity of PILs is given by conjugation of approximately 1% of the PEG residues to
monoclonal antibodies (mAbs) that bind to specific endogenous receptors (i.e., insulin
and transferrin receptors) located in the brain vascular endothelium, which forms the
blood brain barrier (BBB), and brain cellular membranes, respectively. These mAbs are
known to induce 1) receptor-mediated transcytosis of the PIL complex through the BBB
and 2) transport to the brain cell nuclear compartment. Treatment of an experimental
human brain tumor model in scid mice is possible with weekly intravenous RNAi gene
therapy causing reduced tumor expression of EGFR and 88% increase in survival time of
these mice with advanced intracranial brain cancer. The availability of additional RNAi
tumor targets may improve the therapeutic efficacy of this new anticancer drug. The
accessibility to chimeric and/or humanized mAbs directed to human BBB and brain cell
specific-receptors may accelerate the application of this technology to the treatment of
human tumors.