Biomedical Engineering Reference
In-Depth Information
As a result, local hypoxia, due to increased proliferation or insufficient oxy-
gen supply, inactivation of tumor suppressors, oncogenes and growth fac-
tors, along with other cell types, such as macrophages, contribute to form
a tumor microenviroment capable of modulating the HIF response itself.
Antisense inhibition of HIF may be a strong target for anti-angiogenic ther-
apy. The authors study group has recently shown high expression levels of
PGES-1 (Prostaglandine E 1 Sinthase) and IL-8 in high grade glioma cells
and microglial cells, strongly correlate with the grading of a tumor [31, 201].
During progression gliomagenesis, leukocyte infiltration and necrosis are
two biological phenomena associated with the development of neovascu-
larization. In malignant gliomas, IL-8 further localizes in oxygen-deprived
cells surrounding necrosis. Macrophages are known to produce high lev-
els of IL-8, which has a tumorigenic activity, by inducing tumour growth
and angiogenesis. Tumor pseudopalisading cells secrete HIF which
induces
IL-8 secretion. IL-8-binding chemokine receptors CXCR1, CXCR2 and
the Duffy antigen receptor for chemokines (DARC) were found in all astro-
cytoma grades by reverse transcription/PCR analysis. These results support
a model in which IL-8 expression, by induction of inflammatory stimuli,
may be an early step in astrocytoma development. It seems that augmented
IL-8 directly and/or indirectly promotes angiogenesis by binding to DARC,
and induces leukocyte infiltration and activation by binding to CXCR1 and
CXCR2. The contemporary actions of IL-8 into glioma angiogenesis and
leukocyte infiltration, as well as macrophages, microglial cells, and ECM
components involvement, suggest IL-8 as a future interesting target in brain
tumor treatment.
6.1 Brain tumor drug targeting
As previously reported the limiting factor in brain tumor treatment is the
delivery of therapeutic agents to the brain across the BBB. A restricted num-
ber of liposoluble small molecules cross the BBB by free diffusion, while
other molecules must use specific systems to be transported across the BBB.
The rapid advances in molecular biology have propelled the development of
novel drug delivery systems that take advantage of a better understanding
of the BBB.
6.1.1 Systemic approaches
An intravenous route is the commonly practiced method for administration
of larger doses of drugs into the body. It delivers drugs directly into gen-
eral circulation by avoiding its first-pass metabolism, and has potential to
transport drugs to the brain [202]. The delivered drug can access the brain
by crossing the vascular barrier. However, there is little accumulation of the
drug in the brain because of the BBB and rapid clearance of the extracellular
fluid. In addition, the brain availability of the drug is largely affected by the
half life of the drug in the plasma, rapid metabolism, the level of non-specific
binding to plasma proteins, and the permeability of the compound across
