A novel anti-pancreatic cancer agent, LY293111.
Arachidonic acid is metabolized by two major pathways, cyclooxygenases and lipoxygenases. The metabolites catalyzed by these enzymes are important mediators of acute and chronic inflammation. Both enzymes and their metabolites are well recognized to be involved in cancer development and progress. It is well documented that inhibition of cyclooxygenase 2 (COX-2) activity decreases cancer incidence and inhibits tumor growth. It has also been reported that 5-lipoxygenase is involved in cancer cell survival and proliferation. 5-lipoxygenase metabolites including both 5-HETE and leukotriene (LT) B4 directly mediate cancer cell growth. Although 5-HETE receptors are still elusive, two LTB4 receptor subtypes (BLT1 and BLT2) have been characterized. Both 5-lipoxygenase and LTB4 receptors are upregulated in both pancreatic cancer and early pancreatic cancer lesions; hence, these proteins are potential targets for cancer treatment and prevention. Recent studies have shown that an orally stable leukotriene (LT) B4 receptor antagonist, LY293111, has a potent anti-pancreatic cancer effect. LY293111 inhibits pancreatic cancer growth, induces tumor cell apoptosis both in vitro and in vivo, and enhances the anti-pancreatic cancer effect of gemcitabine. LY293111 exhibits its anti-cancer effects through LTB4 receptors and peroxisome-proliferator activated receptor-gamma. A phase I clinical trial indicated that LY293111 is well tolerated by patients with no significant side-effects. LY293111 may be a valuable drug for treatment of pancreatic cancer, especially in combination with gemcitabine. A double-blinded, placebo-controlled phase II clinical trial with LY293111 is currently underway. This review summarizes the current research status of LY293111 as an anti-cancer agent with a focus on pancreatic cancer.
Ding
Xian-Zhong
XZ
Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Talamonti
Marks S
MS
Bell
Richard H
RH
Adrian
Thomas E
TE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047495:PPAR gamma / Q000819:agonists; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001565:Benzoates; C094099:LY 293111; D047495:PPAR gamma; D018102:Receptors, Leukotriene B4