In addition to antiviral effects, Type I interferons (IFN) have potent antiproliferative and immunomodulatory activities. Because of these properties IFNs have been evaluated as therapeutics for the treatment of a number of human diseases, including cancer. Currently, IFNs have been shown to be efficacious for the treatment of only a select number of cancers. The reason for this is unclear. Recent evidence has demonstrated that some cancer cell types seem to be defective in their ability to respond to IFN. It has been suggested that defects in IFN signaling is one mechanism by which cancer cells escape responsiveness to Type I IFNs and growth control in general. We report that transfection and enhanced expression of the Type I IFN receptor chain (IFNAR2c) in 3 different human cancer cell lines markedly increases the sensitivity of these cells to the antiproliferative effects of IFNs. In cancer cells transfected with IFNAR2c, dose response curves demonstrate a significant decrease in the concentrations of IFN required to achieve maximum cell death. Furthermore, in these transfected cells, we observe a significant increase in the number of cells undergoing apoptosis, as measured by DNA fragmentation and Caspase 3 activation. In addition, using an in vivo xenograft tumor model we show an increase in the effectiveness of systemically delivered Betaseron™ in decreasing tumor burden in animals in which solid tumors were generated from IFNAR2c transfected cells. These data show that specific regulation of IFN receptor expression can play a major role in determining the clinical outcome of IFN-based cancer therapeutics by regulating the relative sensitivity of cancer cells to IFN-dependent growth control.
1-(2-DeoxyKey words: 4Ј-thio-FAC; deoxycytidine analog; BxPC-3; capan-1; SK-OV-3; ES-2 Uncontrolled proliferation is a hallmark of cancer cells that is targeted by drugs that inhibit critical steps in cell cycle progression (e.g., cyclin-dependent kinase inhibitors) or DNA replication (e.g., DNA polymerase and topoisomerase inhibitors). Within this arsenal of anti-cancer drugs are the nucleoside anti-metabolites that inhibit DNA synthesis. 1 A number of approved purine (e.g., fludarabine, cladribine) and pyrimidine (e.g., cytarabine/araC) analogs are clinically effective against leukemias and lymphomas, but only one approved deoxycytidine analog (i.e., gemcitabine) has demonstrated efficacy against solid tumors in the clinic.The first line treatment for patients with advanced metastatic pancreatic carcinoma is currently gemcitabine, which was approved by the FDA in 1996 primarily on the basis of an enhanced clinical benefit response. Gemcitabine caused no objective tumor remissions, the partial response rate was 5.4%, and patient survival was extended 1.3 months longer than the median survival time (MST) of patients treated with 5-fluorouracil (i.e., 4.2 months). 2 Although there have been other treatment modalities (including nucleosides) evaluated for this indication, none have replaced gemcitabine. Unfortunately, the 5-year survival rate for this patient population is a dismal 4%, 3 making the need for new treatment modalities with a superior efficacy and toxicity profile to gemcitabine critical.Gemcitabine is also used as a single agent in the treatment of advanced ovarian carcinoma patients who have failed platinum and more recently, the taxane-based chemotherapeutic regimens. As the 10-year survival rate of this patient population is only ϳ20%, the critical need for new therapeutic agents for this indication is also emphasized.4Ј-Thio-FAC [1-(2-deoxy-2-fluoro-4-thio--D-arabinofuranosyl) cytosine] is a sulfur-and fluoro-substituted nucleoside analog that has been shown to be 100-fold more potent than gemcitabine in inhibiting DNA polymerase ␣ and also significantly inhibits DNA polymerase  with 10-fold less potency than for the ␣ enzyme. 4,5 The anti-proliferative/cytotoxic effects of 4Ј-thio-FAC have been demonstrated in a wide range of tumor cell lines, including lung, stomach, colon, breast, bladder, melanoma, osteosarcoma, and head and neck cancers. 6,7 4Ј-Thio-FAC has been shown to be a highly effective growth inhibitor of colorectal or gastric tumor xenografts implanted subcutaneously (s.c.) 6,7 as well as disseminated in the peritoneal cavity of nude mice. 8 Importantly, 4Ј-thio-FAC demonstrated superior activity to gemcitabine with respect to efficacy and tolerability when administered by identical routes and schedules to mice bearing colorectal or gastric tumor xenografts. 7 In the colon carcinoma model, intravenous (i.v.) administration of gemcitabine on a daily schedule at the same doses as 4Ј-thio-FAC was unacceptably toxic (i.e., causing lethality in the majority of mice). Oral administration...
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