A low dose blend of the non-steroidal anti-inflammatory drug celecoxib and the cholesterol-lowering medication Lipitor® dramatically limited the incidence of invasive and non-invasive colon adenocarcinomas, said Bandaru Reddy, D.V.M., Ph.D., research professor at Rutgers University, Piscataway, N.J.
"The combination of these drugs given to laboratory animal models inhibited 95 percent of the tumors that developed in untreated animals," Reddy said. "When used together, the drugs were most effective at doses substantially lower than when used alone.
"Using a combination of low doses of these chemopreventive agents that have differing action may be the most effective way to maximize the anti-cancer effect of the drug while also minimizing toxicity or harmful side effects."
Reddy's studies were conducted in an animal model that closely represents pathogenic, molecular and genetic events that occur in the development of cancer in the human colon. The doses of the drug combination ingested by the experimental rats were the equivalent of 120 mg/day for celecoxib and 40 mg/day for Lipitor®.
By itself, celecoxib at 600 parts per million (ppm) in the diet reduced the incidence, as well as the number, of colon adenocarcinomas by 80 percent. Lipitor® at 150 ppm alone reduced tumor incidence by 31 to 41 percent.
Together, at only 300 ppm of celecoxib and 100 ppm Lipitor®, the drugs reduced invasive and non-invasive adenocarcinomas by 95 percent. Low doses of Lipitor® and celecoxib in combination suppressed invasive adenocarcinomas, suggesting that the progression of non-invasive adenocarcinomas into the highly invasive type is inhibited by these two agents. The drug combination targeted different molecular pathways en route to preventing development of colon cancer, Reddy explained. The non-steroidal anti-inflammatory drug celecoxib targets the COX-2 inflammation pathway and has been shown both in experimental animal studies and in human trials to reduce the incidence and progression of colon cancer.
Lipitor®, a statin drug aimed at lowering cholesterol and used in humans primarily in support of cardiovascular health, reduces cholesterol that is processed into tumorogenic molecules in the intestine.
"Cholesterol is a substrate of the bile acid synthesis in the liver. With reduced levels of cholesterol, statins also inhibit the synthesis of bile acids. In the colon, the bile acids are modified by bacteria into secondary bile acids, which include two strong colon tumor promoters," Reddy said.
Celecoxib recently has been under scrutiny following the disclosure of an association between the NSAID and coronary disease in patients taking the drug to prevent colon cancer. Doses of celecoxib administered in those studies were generally 400 to 800 mg/day--much higher than the levels used in Reddy's studies.
"These studies indicate that in combination at very low doses we increase the efficacy of the drugs while at the same time reduce the toxicity," Reddy said.
This study was supported by the National Cancer Institute (NCI).
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