There is growing evidence that combinations of antiangiogenic
proteins with other
antineoplastic treatments such as chemo- or
radiotherapy and suicide genes-mediated
tumor cytotoxicity lead to synergistic effects. In the present work, we tested the activity of two non-replicative herpes simplex virus (HSV)-1-based vectors, encoding human
endostatin::
angiostatin or
endostatin::kringle5 fusion
proteins in combination with HSV-1
thymidine kinase (TK) molecule, on endothelial cells (ECs) and
Lewis lung carcinoma (LLC) cells. We observed a significant reduction of the in vitro growth, migration and tube formation by primary ECs upon direct
infection with the two recombinant vectors or cultivation with
conditioned media obtained from the vector-infected LLC cells. Moreover, direct cytotoxic effect of HSV-1 TK on both LLC and ECs was demonstrated. We then tested the vectors in vivo in two experimental settings, that is, LLC
tumor growth or establishment, in C57BL/6 mice. The treatment of pre-established subcutaneous
tumors with the recombinant vectors with
ganciclovir (GCV) induced a significant reduction of
tumor growth rate, while the in vitro
infection of LLC cells with the antiangiogenic vectors before their implantation in mice flanks, either in presence or absence of GCV, completely abolished the
tumor establishment.