Biomedical Engineering Reference
In-Depth Information
transmembrane domain, and an intracellular tyrosine kinase
domain. Binding of a ligand (EGF or TGF-
a
) to EGFR
causes receptor dimerization leading to tyrosine kinase
activation. The resultant receptor autophosphorylation initi-
ates signal-transduction cascades involved in cell prolifera-
tion and survival. After ligand binding, the whole receptor-
ligand complex undergoes endocytosis and is translocated to
the lysosomes, where the ligand dissociates from the recep-
tor [47]. The tyrosine kinase part of the receptor is required
for rapid internalization, transportation through the cell, and
amplification of gene synthesis. Studies of the amplification
of EGFR have shown that the transmembrane and tyrosine
kinase domains are invariably amplified, while the ligand-
binding domain and the entire gene are amplified intermit-
tently [48,49].
Human malignant gliomas and many malignant tumors
that metastasize to the brain express EGFR, and this is
commonly associated with amplification and/or mutation
of the EGFR gene during neoplastic transformation [50].
Amplification and high expression of EGFR in gliomas may
drive to a significant degree tumor growth and proliferation
[51]. By contrast, EGFR is expressed at very low levels or is
undetectable on normal human glial cells and neurons. The
ratio of EGFR expression in glioma versus normal control
brain specimens has been shown to be as high as 300-fold
[48].
EGFR-specific binding of TP-38 toxin has been investi-
gated in cell culture. TP-38 may inhibit the binding of
125
I-
EGF to EGFR-expressing nonsmall cell lung carcinoma at
an IC
50
of 100-2000 ng/mL, depending on the cell line
tested [52]. Concentration of TP-38 required to inhibit
protein synthesis in malignant tumor cells may range
from 5-6 ng/mL (in EGFR-expressing lung cancer cells)
to 0.005-0.5 ng/mL in GBM [53].
Animal studies with TP-38 have been carried out in
rodent and primate models. In tumor-bearing mice, a total
dose of 0.1
m
g TP-38 at a concentration of 5
m
g/mL was
found to be safe and efficacious in prolonging survival. The
MTD of intracerebral TP-38 in normal rats was 0.666
m
gata
toxin concentration of 33.3
m
g/mL. In nonhuman primates,
it was demonstrated that an intracerebral bolus dose of 2
m
g
TP-38 at a concentration of 10
m
g/mL is safe [44].
Sampson et al. [54] investigated TP-38 in a Phase I
clinical trial. The primary objective of the study was to
define MTD and dose-limiting toxicity of TP-38 delivered
by CED in patients with recurrent malignant glioma. A
secondary objective was to detect efficacy of the toxin. A
total of 20 patients were enrolled in the study and doses were
escalated from 25 to 100 ng/mL. TP-38 was infused by two
stereotactically placed catheters at a flow rate of 0.4mL/h
for each catheter. A total volume of 40mL was infused. TP-
38 was tolerated well, and a MTD was not established.
Nonspecific toxicity was not found at any of the dose levels.
Toxicity encountered was solely neurologic and mostly
related to infusion volume, recurrent tumor, or stereotactic
catheter placement, but not directly to TP-38. A total of 15 of
the patients in this study died from progressive disease.
When the study closed, four further patients did not have
recurrence of tumor and were 55, 56, 69, and 116 weeks
from the time of TP-38 therapy. Overall median survival
after TP-38 for all patients was 23 weeks, whereas for those
without radiographic evidence of residual disease at the time
of therapy, the median survival was 31.9 weeks. Overall, 3 of
15 patients with residual disease at the time of therapy have
demonstrated radiographic responses [54].
A multicenter randomized open-label Phase II study was
conducted in adult patients with recurrent GBM [55].
Patients were randomized to two dose levels of TP-38, 50
or 100 ng/mL, and toxin was administered by CED via
stereotactically placed catheters. Patients did not have to
undergo tumor resection prior to treatment. End points of the
study were time to progression, progression-free survival,
and overall survival. Three catheters were stereotactically
placed in investigator-determined locations within the
enhancing tumor area. The infusion rate was 200
m
L/h
per catheter. Each catheter delivered 13.4 mL over 67 h.
The total volume infused was
40 mL, and the total dose
of TP-38 infused was 2
m
g (50 ng/mL) or 4
m
g (100 ng/mL).
One patient had a complete response 48 weeks after
infusion, and another patient showed a partial response
stable over 60 weeks. A total of 24 patients remained stable.
Post-infusion MRI scans in most patients showed unspecific
treatment-related changes such as halo contrast enhance-
ment around the infusion sites, which made assessment of
response rather difficult. These changes usually resolved by
20 weeks post treatment. There were no grade 3 and 4
toxicities related to TP-38, and all adverse effects of the
treatment were reversible [55]. Currently, there is no Phase
III clinical protocol employing TP-38.
20.4.3 IL13-PE38
IL-13-PE38 (also known as cintredekin besudotox, Neo-
Pharm Inc., Lake Bluff, IL) is a recombinant chimeric toxin
consisting of human IL-13 fused to a mutated form of PE
[18-20]. Since domain Ia of PE binds to almost all types of
eukaryotic cells, several mutated forms of PE were gener-
ated in order to avoid binding to its original ubiquitous
receptors. One of the derivatives of PE was PE38QQR, in
which domain Ia (amino acids 1-252) and domain Ib (amino
acids 365-380) were deleted, and lysine (K) residues at
positions 590 and 606 were replaced by glutamine (Q) and at
position 613 by arginine (R). PE38QQR was fused to the
carboxy terminus of the human IL-13 (hIL-13) to produce
IL-13-PE38QQR (IL-13-PE38) [56-59].
The T-helper cell 2-derived immunoregulatory cytokine
interleukin-13 (IL-13) inhibits the production of inflamma-
tory cytokines in monocytes. The cell surface receptor for
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