E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma

Abstract

Most cancer chemotherapeutic agents are administered at the maximum-tolerated dose (MTD) in short cycles with treatment breaks. However, MTD-based chemotherapies are often associated with significant toxicity and treatment breaks allow the opportunity for tumor regrowth and acquisition of chemoresistance. To minimize these drawbacks, a metronomic strategy, in which chemotherapeutics are administered at doses significantly below the MTD without treatment breaks, has been suggested by many investigators. The antitumor effect of metronomic chemotherapy may be partially due to inhibition of tumor angiogenesis, and it could be enhanced by a combination therapy, including antiangiogenic agents. In this study, we evaluated the synergistic effect of E10A, an adenovirus carrying the endostatin gene, the most potent inhibitors of tumor angiogenesis, in combination with weekly low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma. The E10A induced mRNA and protein expressions of endostatin in H891 cells in vitro. E10A significantly enhanced the in vivo tumor growth inhibitory effect of cisplatin. Immunohistochemical analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay and anti-CD31 antibodies revealed that the combination of E10A and cisplatin induced high levels of cell apoptosis and inhibited tumor angiogenesis. Importantly, E10A increased the platinum concentrations in tumors to fivefold higher than that induced by cisplatin alone.

The antiangiogenic action of cisplatin on endothelial cells is mediated through the release of tissue inhibitor of matrix metalloproteinases-1 from lung cancer cells

“…Data obtained in rodents have highlighted antiangiogenesis induced by LDM treatment with cisplatin as a key mechanism of its tumor-regressive effect on liver cancer [ 21 ]. Another investigation showed that LDM treatment with cisplatin reduced vessel density in a xenograft model of head and neck squamous cell carcinoma [ 22 ] and inhibited tumor growth via an antiangiogenic action in a murine model of transitional cell carcinoma [ 23 ]. The mechanism that confers low-dose cisplatin-induced antiangiogenesis, however, remains unclear.…”

Antitumor efficacy of a recombinant adenovirus encoding endostatin combined with an E1B55KD-deficient adenovirus in gastric cancer cells

“…Therefore, endostatin gene therapy is convenient in clinical application, and a cumbersome daily injection is no longer needed like the application of endostatin proteins. Up to date, Ad-Endo has completed its preclinical, phase I and phase II clinical trials [21-27,52,53] and started its phase III clinical trial on head and neck squamous cell carcinoma in China. However, Ad-Endo showed only a limited or moderate effect in previous clinical trials due to the limited increase in the endostatin concentration [26,27].…”

Viral gene therapy for head and neck cancer

“…When delivered to a murine head and neck cancer model, endostatin, used in conjunction with low-dose cisplatin treatment, reduced in vivo tumour growth. 19 A vaccinia virus vector armed with an endostatin-angiostatin fusion gene demonstrated superior anti-tumour efficacy for head and neck cancer in a pre-clinical study. 20 Apoptosis is a tightly regulated process of programmed cell death.…”