Biomedical Engineering Reference
In-Depth Information
of contrast-enhancing areas, subsequent fractionated exter-
nal radiotherapy up to a total dose of 60 Gy, and concomitant
and adjuvant chemotherapy in WHO grade 4 tumors, with
various combinations of these three approaches in grade 3
tumors [5,10,14]. The use of chemotherapy in addition to
surgery and radiation was considered somewhat controver-
sial until recent studies demonstrated significantly improved
outcome for patients with previously untreated GBM receiv-
ing radiotherapy plus concomitant and adjuvant chemo-
therapy after surgery [17]. However, in all clinical
studies, significant improvements in overall survival are
demonstrated mostly in selected subpopulations of patients
with somewhat better prognostic factors, such as higher
Karnofsky Performance Status (KPS) and younger age, or
with specific genetic alterations [9,15,16,18].
Perhaps the most prominent feature which renders malig-
nant glioma a preferred target for tumor selective drugs and
local treatments is the unique combination of high mitotic
activity of tumor cells on the background of the mostly post-
mitotic environment of the adult brain [6,8]. In addition,
malignant gliomas do not metastasize systemically, but are
extremely aggressive in their local environment within the
closed compartment of the CNS. Distinct biological features
common in malignant gliomas, but unusual in normal brain
tissue, have been the subject of many research studies. Such
therapeutically useful features are specific genetic altera-
tions in glioma cells. Expression of specific proteins com-
mon for malignant glioma cells but uncommon in normal
brain cells, and aberrant activation of signal transduction
cascades, seems to provide the best opportunity for selective
molecular targeting of therapeutic modalities to tumor cells
[8]. All these features make gliomas a unique model disease
for the design and testing of novel treatments with tumor-
selective toxicity and intracerebral rather than systemic
mode of administration.
This review summarizes the most recent clinically rele-
vant experimental approaches to intracerebral immunotoxin
therapy of malignant gliomas. All of these were employed in
an adjuvant setting in addition to the aforementioned and
well-established standard modalities of surgery and frac-
tionated external radiotherapy with chemotherapy.
with receptor signaling properties, such as epidermal growth
factor receptor (EGFR), transferrin receptor (TfR), interleu-
kin-13 receptor (IL-13R), or interleukin-4 receptor (IL-4R).
The toxin part of the molecule in all clinically used toxins is
a polypeptide derived from bacteria (Corynebacterium diph-
theriae, Pseudomonas aeruginosa), which has been modi-
fied by deleting the native targeting and internalization
domains of the polypeptide and replacing them with one
of the above ligands (Figure 20.1) [18-20].
The mechanism of action of targeted toxins may have
important advantages over that of radiation and classic
chemotherapeutic agents. Toxins are effective against radi-
ation-resistant hypoxic tumor cells and far more potent than
any chemotherapy drug—one single molecule of toxin is
sufficient to cause tumor cell death independent of any
malignancy-associated genetic alterations and/or mutations
(Figure 20.2) [21]. Multidrug resistance and apoptosis
resistance are therefore not an issue with toxins—after
receptor binding and internalization, no tumor cell is able
to survive the toxin part of the molecule [22-24]. A few
targeted toxins have advanced from the laboratory to the
stage of clinical studies, with two of these reaching Phase III
trials.
20.3 DELIVERY MODE AND
PHARMACOKINETICS OF TARGETED
TOXINS IN THE BRAIN
The therapeutic success of a targeted toxin will depend not
only on its ability to selectively target tumor cells but to a
high degree also on the delivery mode and distribution
throughout the tumor and the surrounding normal brain
tissue [25,26]. Diffusion of peptide molecules such as
recombinant toxins in tissue is a rather inefficient way of
distribution and will depend not only on the concentration of
the compound but also on its molecular weight, polarity, and
its avidity for the target receptor [27]. The time required for a
molecule to diffuse a distance L can be approximated by the
formula L
2
/4D, where D is the diffusion coefficient of that
particular molecule [28]. For example, the time required for
an IgG antibody to diffuse a distance of 1mm will be
2
days. To circumvent this limitation, distribution of toxins by
convection-enhanced delivery (CED), a much more efficient
and fast mode for interstitial delivery by high-flow infusion,
has been studied in several animal models [28].
Morrison et al. [29] published a paper on mathematical
modeling of the pharmacodynamics of high-flow (0.5-
6.0
m
L/h) microinfusion of macromolecules in the brain.
For a representative protein of 180-kDa molecular weight
infused into homogenous brain tissue at a constant flow rate
of 3
m
L/min, delivery of the molecule within 12 h would
occur to a sphere with 1.5 cm radius from the infusion tip.
Tissue doses were described as rather uniform, with the
20.2 TARGETED TOXINS—GENERAL
CONSIDERATIONS
Targeted toxins (immunotoxins) represent a new class of
anticancer agents providing high specificity for tumor cells
selectively overexpressing some surface proteins [18,19].
Clinically used toxins are recombinant polypeptide mole-
cules consisting of a tumor-selective ligand coupled to a
highly potent peptide toxin, which is truncated to abolish
native toxicity. The most frequently used and best
researched ligands bind to tumor-associated molecules
Search WWH ::
Custom Search