Improved tumor vascular function following high-dose epidermal growth factor receptor tyrosine kinase inhibitor therapy.

PURPOSE: To determine if inhibitors of the human growth factor receptor (HER) family can be used to enhance tumor vascular permeability and perfusion and optimize the efficacy of cytotoxic chemotherapeutics. Poor tumor vascular function limits the delivery and efficacy of cancer chemotherapeutics and HER family tyrosine kinases mediate tumor-endothelial signaling in both of these compartments. MATERIALS AND METHODS: BT474 human breast cancer tumors were established in mice and the biologic effects of the HER tyrosine kinase inhibitor (TKI) gefitinib on tumor vascular function was determined by dynamic contrast-enhanced MRI (DCE-MRI), and on tumor vascular architecture and perfusion by immunofluorescence microscopy. RESULTS: A brief dose of gefitinib enhances the antitumor activity of paclitaxel in vivo but not in cell culture, suggesting that its chemoenhancing activity involves the in vivo microenvironment. A brief high dose of gefitinib induces a decrease in endothelial transfer constant (Kps) and a concomitant increase in tumor fractional plasma volume (fPV). These changes are accompanied by a rapid reduction in tumor volume, likely due to decreased tumor edema, and modestly improved tumor vascular architecture and perfusion on microscopy. CONCLUSION: These data suggest that HER family TKIs have the potential to optimize the tumor microenvironment for delivery of cytotoxic chemotherapeutics.

Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA.

In human cancers, telomeres are commonly maintained by elevated levels of the ribonucleoprotein enzyme telomerase, which contains an intrinsic templating RNA moiety (human telomerase RNA; hTER) and the core protein (human telomerase reverse transcriptase). We developed a lentiviral system for efficient overexpression of mutant-template human telomerase RNA (MT-hTer) to add mutant DNA to telomeres in cancer cells. We show that such MT-hTer overexpression rapidly inhibits cell growth and induces apoptosis in telomerase-positive precancerous or cancer cells but not in telomerase-negative cells. These rapid effects occurred independent of wild-type p53 and telomere length. Tumor growth and progression were significantly decreased in xenografts of human tumor cells overexpressing MT-hTers. Expression of a hairpin short-interfering RNA that specifically targeted the endogenous wild-type hTER template region, but spared the MT-hTers, also caused p53-independent cell growth inhibition and apoptosis, and when coexpressed with MT-hTer, synergistically killed cancer cells. Hence, anti-wild-type-hTER short-interfering RNA and MT-hTers may act through distinct pathways and, particularly in combination, represent a promising approach to anticancer therapies.