Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models: Methods and results from the NCI chemoprevention drug development program

Abstract

In the NCI, Chemoprevention Branch drug development program, potential chemopreventive agents are evaluated for efficacy against chemical carcinogen-induced tumors in animal models. This paper summarizes the results of 144 agents in 352 tests using various animal efficacy models. Of these results, 146 were positive, representing 85 different agents.The target organs selected for the animals model are representative of high-incidence human cancers. The assays include inhibition of tumors induced by MNU in hamster trachea, DEN in hamster lung, AOM in rat colon (including inhibition of AOM-induced aberrant crypts), MAM in mouse colon, DMBA and MNU in rat mammary glands, DMBA promoted by TPA in mouse skin, and OH-BBN in mouse bladder.The agents tested may be classified into various pharmacological and chemical structural categories that are relevant to their chemopreventive potential. These categories include antiestrogens, antiinflammatories (e.g., NSAIDs), antioxidants, arachidonic acid metabolism inhibitors, GST and GSH enhancers, ODC inhibitors, protein kinase C inhibitors, retinoids and carotenoids, organosulfur compounds, calcium compounds, vitamin D3 and analogs, and phenolic compounds (e.g., flavonoids). The various categories of compounds have different spectra of efficacy in animal models. In hamster lung, GSH-enhancing agents and antioxidants appear to have high potential for inhibiting carcinogenesis. In the colon, NSAIDs and other antiinflammatory agents appear particularly promising. Likewise, NSAIDs are very active in mouse bladder. In rat mammary glands, retinoids and antiestrogens (as would be expected) are efficacious. Several of the chemicals evaluated also appear to be promising chemopreventive agents based on their activity in several of the animal models. Particularly, the ODC inhibitor DFh4O was active in the colon, mammary glands, and bladder models, while the dithiolthione, oltipraz, was efficacious in all the models listed above (ie., lung, colon, mammary glands, skin, and bladder).

Anticarcinogenic Effect of Panax ginseng C.A. Meyer and Identification of Active Compounds

“…Similar results of lack of efficacy were also observed in an ATBC trial using 29,133 randomly selected male smokers (21), a CARET trial studying more than 18,000 people at high risk of lung cancer (22,23), and a Physicians'Health Study which enrolled 22,071 American physicians (24). At the recommendation of the Chemoprevention Branch, Division of Cancer Chemoprevention and Control, US National Cancer Institute (25,26), researchers in Korea tested the effect of red ginseng extract on azoxymethane (AOM)-induced colon cancer and N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN)-induced bladder cancer, and the result were negative (unpublished). Moreover, 13-cis retinoic acid was also without benefit in the 9-week medium-term study (12,19,27) (Table 3).…”

Expression of cyclooxygenase‐1 and cyclooxygenase‐2 in bronchial epithelium and nonsmall cell lung carcinoma

“…Furthermore, NSAIDs also have been shown to inhibit experimental tumor formation not only in the colon but also in the bladder, skin, esophagus, lung, small intestine, pancreas, breast, and uterine cervix in animals. [13][14][15][16] In addition, Schreinemachers and Everson observed a reduced incidence of lung carcinoma in association with the increased use of aspirin. 17 Two isoforms of the Cox enzyme have been identified (Cox 1 and Cox 2) that share a Ͼ 60% homology at the amino acid level but have distinct physiologic functions.…”

Prevention of mouse lung tumors by targretin

“…The tumors from mice administered the control diet had an average diameter of 0.951 6 0.0082 and an area of 0.551 6 0.026. The longer duration of treatment for 21 weeks (4-25) that lasted until the mice were killed was more effective in reducing tumor size than a shorter duration of treatment for 15 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) weeks that was terminated 6 weeks prior to killing. Treatment for only 9 (4-13) weeks followed by a holding period of 12 weeks was not effective in decreasing the size of the tumors.…”