Timothy J. Kennedy

Overexpression of 5-Lipoxygenase in Colon Polyps and Cancer and the Effect of 5-LOX Inhibitors In vitro and in a Murine Model

Purpose: Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studied. The purpose of this study was to evaluate the expression of 5-LOX in colonic polyps and cancer and the effect of 5-LOX inhibition on colon cancer cell proliferation. Experimental Design: Colonic polyps, cancer, and normal mucosa were evaluated for 5-LOX expression by immunohistochemistry. Reverse transcription-PCR was used to establish 5-LOX expression in colon cancer cells. Thymidine incorporation and cell counts were used to determine the effect of the nonspecific LOX inhibitor Nordihydroguaiaretic Acid and the 5-LOX inhibitor Rev5901 on DNA synthesis. A heterotopic xenograft model in athymic mice using HT29 and LoVo human colon cancer cells was used to evaluate the effect of the 5-LOX inhibitor zileuton on tumor growth. Results: 5-LOX is overexpressed in adenomatous polyps and cancer compared with that of normal colonic mucosa. LOX inhibition and 5-LOX inhibition decreased DNA synthesis in a concentration- and time-dependent manner in the Lovo cell line (P < 0.05). Inhibition of 5-LOX in an in vivo colon cancer xenograft model inhibited tumor growth compared with that of controls (P < 0.05). Conclusions: This study showed that 5-LOX is up-regulated in adenomatous colon polyps and cancer compared with normal colonic mucosa. The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer.

Lipoxygenase inhibitors for the treatment of pancreatic cancer.

Pancreatic cancer has a dismal prognosis with no effective medical therapy. Therefore, there is a need to search for novel targets for cancer prevention and treatment. The lipoxygenases oxygenate arachidonic acid and other 20-carbon fatty acids and their downstream metabolites have been found to mediate several aspects of pancreatic cancer development and growth. Therapeutic agents have been developed against various targets in the lipoxygenase pathways. Many of these were first developed for their anti-inflammatory properties and were subsequently found to have anticancer effects. Such agents include lipoxygenase and 5-lipoxygenase-activating protein inhibitors, leukotriene receptor antagonists and natural products with inhibitory effects on these pathways. Dual lipoxygenase and cyclooxygenase inhibition represents an exciting area of research and drug development.

Adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma

Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.

Neoadjuvante Chemotherapie und adjuvante Radiochemotherapie in der Behandlung des resezierten Adenokarzinoms des Magens: Eine Fallserie

Die Behandlung von Magenkrebs erfordert einen multimodalen Ansatz, um das Risiko eines lokoregionalen Rezidivs und einer Fernmetastasierung zu verringern. Der optimale Zeitpunkt von Chemotherapie, Operation und Bestrahlung wird derzeit in laufenden Studien untersucht. In den USA erhalten die Patienten im Anschluss an die chirurgische Resektion häufig eine adjuvante Radiochemotherapie oder eine Kombination aus neoadjuvanter und adjuvanter Chemotherapie. Wir berichten hier über 4 Patientinnen mit reseziertem Adenokarzinom des Magens, die mit einer Kombination dieser beiden Therapieansätze behandelt wurden und eine neoadjuvante Chemotherapie gefolgt von einer adjuvanten Radiochemotherapie erhielten. Übersetzung aus Case Rep Oncol 2017;10: 308-315 (DOI:10.1159/000464280).