Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

Abstract

Tumor-endothelial interaction contributes to local prostate tumor growth and distant metastasis. In this communication, we designed a novel approach to target both cancer cells and their ''crosstalk'' with surrounding microvascular endothelium in an experimental hormone refractory human prostate cancer model. We evaluated the in vitro and in vivo synergistic and/or additive effects of a combination of conditional oncolytic adenovirus plus an adenoviral-mediated antiangiogenic therapy. In the in vitro study, we demonstrated that human umbilical vein endothelial cells (HUVEC) and human C4-2 androgen-independent (AI) prostate cancer cells, when infected with an antiangiogenic adenoviral (Ad)-Flk1-Fc vector secreting a soluble form of Flk1, showed dramatically inhibited proliferation, migration and tubular formation of HUVEC endothelial cells. C4-2 cells showed maximal growth inhibition when coinfected with Ad-Flk1-Fc and Ad-hOC-E1, a conditional replication-competent Ad vector with viral replication driven by a human osteocalcin (hOC) promoter targeting both prostate cancer epithelial and stromal cells. Using a threedimensional (3D) coculture model, we found that targeting C4-2 cells with Ad-hOC-E1 markedly decreased tubular formation in HUVEC, as visualized by confocal microscopy. In a subcutaneous C4-2 tumor xenograft model, tumor volume was decreased by 40-60% in animals treated with Ad-Flk1-Fc or Ad-hOC-E1 plus vitamin D 3 alone and by 90% in a combined treatment group, compared to untreated animals in an 8-week treatment period. Moreover, three of 10 (30%) pre-established tumors completely regressed when animals received combination therapy. Cotargeting tumor and tumor endothelium could be a promising gene therapy strategy for the treatment of both localized and metastatic human prostate cancer.

Combined Therapeutic Effects of Vinblastine and Rapamycin on Human Neuroblastoma Growth, Apoptosis, and Angiogenesis

“…The first one that damages directly tumor cells by inhibiting tumor cell proliferation and inducing apoptosis; the second one that produces injuries to endothelial cells, with consequent effects on cancer cells. This conclusion is consistent with the concept that a strategy affecting both tumor vasculature and tumor cells themselves may be more efficacious (30,46,47) than approaches directed against only one of the two therapeutic targets.…”

Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers

“…Another likely scenario is that both NV1023 and NV1042 also infects and destroys proliferating tumor endothelial cells, as has been observed with an adeno virus vector. 49 Further investigations would be required to confirm this possibility.…”

Anti-angiogenic gene therapy of cancer: Current status and future prospects

“…Beyond their exploitation to deliver single anti-angiogenic factors such as angiostatin or endostatin, summarized below, it is worthwhile to consider two recent developments which may lead to an improvement of therapeutic efficacy. Jin et al (2005) tested the efficacy of anti-VEGF receptor gene therapy in an experimental hormone-refractory prostate cancer model. Their novel strategy combines tumor cell-specific killing using a conditionally replicating oncolytic virus, termed Ad-hOC-E1, with tumor endothelium-specific targeting using an Ad vector secreting Flk1-Fc, a soluble form of the VEGF receptor Flk1 fused to the Fc domain of immunoglobulins, which behaves as a VEGF-neutralizing agent.…”