• A Novel COX-2 Inhibitor Slows Cell Growth of Pancreatic Cancer Cells
Ahmed et al., pp. 734–742
Prostaglandins are potent mediators of inflammation. The conversion from arachidonic acid to prostaglandins is catalyzed by the family of cyclo-oxygenase enzymes (COX). While COX-1 is constitutively expressed in many tissues, COX-2 is induced by cytokines, mitogens and endotoxins and is responsible for the production of prostaglandins in inflammation. In addition, growing evidence shows that COX-2 is abnormally expressed in tumor cells, including pancreatic tumor tissue and pancreatic cancer cell lines. One important implication of this finding is that COX inhibitors might be effective in the treatment of pancreatic cancer, a disease known for its relative resistance to standard therapeutic approaches. However, conventional nonsteroidal anti-inflammatory drugs such as aspirin target not only COX-2 but also COX-1, which contributes to their widely known side effects, including stomach lesions and renal toxicity.
Ahmed and colleagues describe the synthesis and biological activity of a new selective COX-2 inhibitor (FPA-306). In molecular modeling studies, the authors show that FPA-306 is specifically anchored in the active site of COX-2 via its ketoprofen scaffold and occupies a similar position as another selective COX-2 inhibitor, SC-558. Treatment with FPA-306 suppressed cell growth and cell survival of pancreatic cancer cell lines in which COX-2 was expressed, but not of cell lines that lacked COX-2 expression. In addition, activation of the transcription factor NF-κB was reduced, leading to impaired expression of downstream effector genes such as Bcl-2 and COX-2 itself. These data support the concept that COX-2 inhibitors such as FPA-306 could become an important addition to the therapeutic regimen of patients with pancreatic cancer.
• Depriving Tumor Cells of Essential Amino Acids: Renal Cell Carcinoma and Arginosuccinate Synthetase
Yoon et al., pp. 897–905
Arginine is a semi-essential amino acid for humans. Arginine levels and availability for normal and cancerous tissues reflect the competing activities of synthetic and catabolic enzymes. Arginine deiminase (ADI) catalyzes the hydrolysis of L-arginine into L-citrulline and ammonia. In contrast, arginine can be synthesized from citrulline by a two-step process mediated first by argininosuccinate synthetase (ASS), the rate-limiting step, and second by argininosuccinate lyase (ASL). To deprive tumor cells of arginine, clinical trials have used pegylated ADI. Tumors in which ASS levels are low or undetectable were initially targeted since the presence of ASS in tumor cells could negate the effect of arginine degradation by allowing tumor cells to resynthesize arginine from its degradation product citrulline. Yoon and colleagues have analyzed the levels of ASS in various cancer cells and found that it is low in renal cell carcinoma cells. Treatment of these cancer cells with ADI showed growth retardation in a dose-dependent manner. Importantly, pegylated ADI showed in vivo antiproliferative activity on an allografted renal cell carcinoma cell line (RENCA) and prolonged the survival of tumor-bearing mice. These experiments indicate that arginine deprivation by ADI could represent a viable therapeutic alternative for the treatment of renal cell carcinoma in patients.
• Virotherapy of Breast Cancer: An Optimized Adenovirus-Based Vector with Enhanced Infectivity and Specific Replication
Stoff-Khalili et al., pp. 935–941
A new exciting approach in cancer therapy is the use of replicating viruses. These viruses are designed to replicate only in tumor cells, resulting in oncolysis and spread of viral progeny. Adenoviruses have shown particular promise as conditionally replicative adenoviral agents (CRAds) and have been rapidly introduced into human clinical trials. However, issues of efficacy and selectivity have hindered the clinical use of CRAds. In breast cancer cells, the transduction efficacy by adenovirus serotype 5 is particularly low because of the highly variable expression pattern of the receptor. In contrast, the adenovirus serotype 3 receptor is abundantly expressed in breast cancer cell lines and primary breast cancer cells isolated from patients.
The strategy of Stoff-Khalili and colleagues was to shift the tropism of an adenovirus serotype 5-based vector to the serotype 3 receptor by swapping domains in the fiber protein of the virus. The authors also exploited another characteristic of breast cancer cells, the high expression of the chemokine receptor CXCR4. They positioned the CXCR4 promoter upstream from the viral E1A protein, which is itself essential for viral replication. The resulting viral vector showed enhanced infectivity and oncolysis in established breast cancer cells as well as selective replication in precision-cut tissue slices from breast cancer samples. Significantly lower viral copy numbers were obtained in slices of normal breast tissue or liver, predicting low toxicity in future clinical applications.