Biomedical Engineering Reference
In-Depth Information
mainstream of brain tumor therapies. These are their non-
uniform and poorly predictable distribution in the brain, and
nonspecific associated toxicity to glial and neuronal cells
[20,25]. With the introduction of MRI-based functional
imaging and 3D volumetric techniques in routine clinical
practice, it will be possible to determine quantitatively brain
tumor volumes and volume of infusate in tumor and normal
brain [88,89]. Diffusion tensor imaging (DTI) is a new MRI
technique sensitive to directional movements of water mol-
ecules induced by tissue barriers [90]. CED makes use of the
extracellular space of the brain as a natural pathway for the
widespread distribution of agents infused in an aqueous
solution, and therefore, DTI could be used for imaging of
CED delivery without the need for contrast agents. Further
key developments in MRI and MR-related computer soft-
ware as well as infusion catheter design and computerized
simulation and delivery modeling within the brain may
provide much needed new resources to be combined with
the biologically targeted toxins [25].
To avoid unspecific toxicity to neural cells, future clinical
trials using targeted toxins may involve combinations of
agents with different targets expressed either on tumor cells
or on neovasculature, or on both. This should allow reduc-
tion of dose-based toxicity of individual toxins without
decrease in overall efficacy. Weaver and Laske [26] reported
the effects of an EGF targeted diphtheria toxin,
DAB389EGF, on brain tumor growth in an animal model.
When DAB389EGF was combined with TransMID at only
inhibitory doses of both toxins, a marked decrease in tumor
growth was seen, which was greater than the growth inhibi-
tion of each single drug. This preliminary study illustrates
the potential for combining at least two targeted toxins to
achieve a higher antitumor effect, while reducing toxicity
encountered with each individual treatment.
Clinical protocols have explored several points of pre-
sumed significance, such as the use of different numbers of
catheters, positioning of catheters, surgical resection of
tumor before or after toxin infusion, and single versus
repeated infusion, but there is no clear answer to any of
these questions. It remains unknown whether there are
benefits from combining targeted toxins with chemotherapy
and/or with fractionated external radiation. Protocols have
investigated patients with recurrent or progressing GBM; the
role of targeted toxin infusion in newly diagnosed malignant
glioma remains to be determined. Evidence of prolonged
survival and late local recurrences in treated glioma patients
has raised the question of periodically repeated application
of toxin for extended control of local recurrence and pro-
gression. The two Phase III randomized clinical trials were
able to provide some answers as to the efficacy of the
respective studied toxins and clinical protocol; however,
more clinical research is needed to address the aforemen-
tioned global issues.
DISCLOSURE
NGR has received research grants fromNeurocrine Inc. (San
Diego, CA) and IVAX Inc. (Miami, FL). The authors have
no financial interests in any of the biotechnology companies
mentioned in the review.
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