Adenovirus(Ad) based viral vectors are extensively used for
gene delivery vehicles and tested for their ability to transgene expression is
desired gene therapy compared with other viral vector vehicles. Several of
these are in the pipeline for human malignant tumor gene therapy applications(168,169).
Adenovirus(Ad) based vectors are the most commonly applied to target the
control EphA2 and EA1 signaling in tumors.
Lower et.al first
developed human Ad serotype-5(Had5) and an extracellular domain of human EA1
ligand joined to Fc parts of the human IgG1 heavy chain (Had-EA1-Fc). Infection
of MDA-MB-231 breast cancer cells with Had-EA1-Fc decreased the tumorigenic
potentially via activation and degradation
EphA2, and transduced MDA-MB-231 cells were also significantly inhibited
in tumorigenicity in a nude mice xenograft model (170). Mouse breast cancer
cell lines (MT1A1) infected with HAd-EA1-Fc inhibited cell viability in
monolayer culture and soft agar colony formation assay in vitro via EphA2
activation and degradation. In vivo,
Implantation of Had-EA1-Fc infected
MT1A1 cells in an FVB/n mice failed to develop tumors(171).
Overexpression of EphA2
by Ad-EphA2 infected in non-transformed mammalian epithelial MCF10A has been noted increased proliferation and
invasiveness of MCF12A cells compared to parental cells. Moreover, in vitro,
HER2 positive MCF10A cells
(MCF10A.HER2) infected using
Ad-EphA2 reported increase cell
proliferation, invasion and ex-vivo transformed
MCF10A.HER2 enhanced tumor formation induced by ERBB2/HER2 in human breast epithelial cells
and may have co-related overexpression HER2 and EphA2(172).
In pancreatic tumor cells, low levels expression of
Coxsackie and adenovirus receptor (CAR)
reduced the transduction efficiency and safe pancreatic gene therapy.
Van Geer et al incorporated YSA peptide into the HI loop of the knob domain of
the fiber modified protein targeted adenovirus to alpha-beta integrins and
improved transduction, therapeutic efficacy in the EphA2 receptor expressing
Three inoculations of HAd-EA1-Fc reported the potent
inhibitory effect on an immunocompetent mouse model of breast tumor growth.
Mutually, Ad vectors expressing hematopoietic growth factor FMS-like tyrosine
kinase receptor ligand (Had-Flt3L), and
HAd-EA1-Fc increased inhibition of the tumor growth and proposed that
Flt3L may target different apoptosis pathways.This combination procedure
suggested that Flt3L have an additive
effect on the antitumor cytotoxic activity and a promising strategy to
efficiently promote breast tumor regression by
HAd vector-based therapy.(174).