Biology Reference
In-Depth Information
Currently, a gene therapy product of the human TNFα gene, called
TNFerade
TM
, is in phase II trials. TNFerade is an adenoviral vector that
expresses the human TNFα cDNA with the ligated radiation-inducible
gene promoter
Egr-1
. It is administered through intratumoral injection
and is being used in combination with radiation therapy in the treatment
of pancreatic cancer (Senzer
et al.
, 2004). In addition, administration of
TNFα in combination with IFN-γ during isolated limb perfusion has
shown some potential in fighting melanoma (Thom
et al.
, 1995).
Targeted delivery of TNFα attached to tumor-homing proteins is under
study as well. One coupled system called L19mTNFα contains the
peptide scFv L19, which targets the ED-B region of fibronectin, fused to
TNFα (Balza
et al.
, 2006). The ED-B domain of fibronectin, an ECM
protein, is commonly expressed at angiogenic sites, but is undetectable in
normal vasculature. Phase I studies of another adduct called NGR-TNF,
a couple between TNFα and a peptide containing a Cys-Asn-Gly-Arg-
Cys (CNGRC or NGR) motif, are underway. This particular motif is a
ligand of an isoform of CD13 (also known as aminopeptide N), which is
highly expressed in angiogenic vessels and in some normal cells, but
with a much lower affinity for the NGR ligand (Corti and Ponzoni, 2004,
Curnis
et al.
, 2002, Sacchi
et al.
, 2006). NGR-TNF was found to work
synergistically with the topoisomerase II blocker doxorubicin (
5
, also
known as adriamycin, see Fig. 6.3) by improving substantially its
permeability through murine B16 melanoma cell membranes. A third
entry, scFvMEL/TNF, is a covalent fusion construct between TNFα and
the single-chain antibody scFvMEL that is specific for the surface
domain of the gp240 peptide (Liu
et al.
, 2006, Rosenblum
et al.
, 1991,
Murray
et al.
, 1987). The gp240 glycoprotein has been found in 80% of
melanoma and 67% of lobular breast tumors, but not in normal cells.
scFvMEL/TNF was synergistic in its action with the antitumor agents
doxorubicin or 5-FU (
6
, Fluorouracil, see Fig. 6.3), a pyrimidine
analogue and thymidylate synthase inhibitor, against A375 melanoma
cells.
It should be mentioned that recent evidence, which connects chronic
synthesis of TNFα to initiation or progression of tumors, has been
reported (Szlosarek
et al.
, 2006, Yan
et al.
, 2006). Chronic inflammation
leads to over-replication of several cytokine genes in activated cells,
