Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model

Abstract

Antiangiogenic therapy is a promising alternative for prostate cancer growth and metastasis and holds great promise as an adjuvant therapy. The present study evaluated the potential of stable expression of angiostatin and endostatin before the onset of neoplasia and during the early and late stages of prostate cancer progression in transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Groups of 5-, 10-, and 18-weekold male TRAMP mice received recombinant adeno-associated virus-6 encoding mouse endostatin plus angiostatin (E+A) by i.m. injection. The effects of therapy were determined by sacrificing groups of treated mice at defined stages of tumor progression and following cohorts of similarly treated mice for long-term survival. Results indicated remarkable survival after recombinant adeno-associated virus-(E+A) therapy only when the treatment was given at an earlier time, before the onset of high-grade neoplasia, compared with treatment given for invasive cancer. Interestingly, early-stage antiangiogenic therapy arrested the progression of moderately differentiated carcinoma to poorly differentiated state and distant metastasis.

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

“…S7B). This observation further supports our previous in vivo studies, indicating that the sustained systemic level of ES was more effective in exerting antitumor effects in a progressively developing mouse PCa model (15). With a short halflife of purified protein that requires high quantity of administration, a constant supply of ES through gene transfer would thus be an ideal approach to overcome the limitations.…”

“…In addition, studies with recombinant human ES fused with Zinc-binding peptide (ZBP-endostatin; Endostar) showed clinical benefit in patients with non-small-cell lung cancer (NSCLC) (11). Recently, we showed that systemically stable levels of ES by vector-mediated gene transfer in vivo significantly delayed tumor growth in the transgenic adenocarcinoma of mouse prostate model (15).…”

VEGF Inhibitors and Prostate Cancer Therapy

“…Although the exact mechanism for antiangiogenesis is not fully elucidated, a possible mechanism is through MMP-2 inhibition [68]. As MMPs are overexpressed and related to progression of prostate cancer [69], targeting this pathway could be a viable option for anticancer therapy, perhaps in the earlier stages [70,71]. Other agents that have been studied in prostate cancer though not with much success includes a metabolite of estradiol, named 2-Methoxyestradiol (2ME), which has been studied in a phase I trial in advanced malignancies [72], with the trial prematurely closing because of the extremely low plasma concentrations achieved relative to the doses administered without discernible effects on microvessel density, and another agent called TNP-470, which is an anti-angiogenic synthetic analog of fumagillin and has been studied in prostate cancer.…”

Extracellular influences on tumour angiogenesis in the aged host

“…In prostate cancer, while VEGF levels are not predictive of positive biopsy results (Peyromaure et al, 2005) higher plasma levels of VEGF are associated with metastases and a poorer prognosis (Duque et al, 1999). Using a transgenic mouse model of prostate cancer, Isayeva et al (2007) demonstrated that inhibitors of the VEGF2 receptor delayed tumour progression only when administered in the early stages of prostate cancer, before a significant rise in VEGF levels was observed. This same inhibitor was ineffective if administered during the later stages of prostate cancer, when VEGF levels were high (Isayeva et al, 2007).…”

“…Using a transgenic mouse model of prostate cancer, Isayeva et al (2007) demonstrated that inhibitors of the VEGF2 receptor delayed tumour progression only when administered in the early stages of prostate cancer, before a significant rise in VEGF levels was observed. This same inhibitor was ineffective if administered during the later stages of prostate cancer, when VEGF levels were high (Isayeva et al, 2007). Thus, the minimal effects on tumour progression in clinical trials of angiogenesis inhibitors may be due to the advanced stage of prostate cancer being targeted.…”