Showing papers by "Michael B. Sporn published in 2002"

Chemoprevention: an essential approach to controlling cancer.

Abstract: Mortality that results from the common forms of cancer is still unacceptably high. Despite immense advances in the understanding of the mechanisms of carcinogenesis, in bringing potent new drugs to the clinic and in treating several relatively rare forms of cancer, overall mortality statistics are unlikely to change in a fundamental way until there has been a re-orientation of emphasis in cancer research that will direct greater resources towards prevention of new disease, rather than treatment of end-stage disease.

Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent Development: Recommendations of the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia

Abstract: Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.

Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells.

Abstract: Lung cancer continues to be the leading cause of cancer-related death in the United States. Therefore, new agents targeting prevention and treatment of lung cancer are urgently needed. In the present study, we demonstrate that a novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) is a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC) cells. The concentrations required for a 50% decrease in cell survival (IC50) ranged from 0.1 to 0.3 microM. CDDO-Me induced rapid apoptosis and triggered a series of effects associated with apoptosis including a rapid release of cytochrome c from mitochondria, activation of procaspase-9, -7, -6, and -3, and cleavage of poly(ADP-ribose) polymerase and lamin A/C. Moreover, the caspase-3 inhibitor Z-DEVD-FMK and the pan caspase inhibitor Z-VAD-FMK suppressed CDDO-Me-induced apoptosis. These results indicate that CDDO-Me induced apoptosis in human NSCLC cells via a cytochrome c-triggered caspase activation pathway. CDDO-Me did not alter the level of Bcl-2 and Bcl-xL proteins, and no correlation was found between cell sensitivity to CDDO-Me and basal Bcl-2 expression level. Furthermore, overexpression of Bcl-2 did not protect cells from CDDO-Me-induced apoptosis. These results suggest that CDDO-Me induces apoptosis in NSCLC cells irrespective of Bcl-2 expression level. In addition, no correlation was found between cell sensitivity to CDDO-Me and p53 status, suggesting that CDDO-Me induce a p53-independent apoptosis. Our results demonstrate that CDDO-Me may be a good candidate for additional evaluation as a potential therapeutic agent for human lung cancers and possibly other types of cancer.

Prevention and treatment of experimental breast cancer with the combination of a new selective estrogen receptor modulator, arzoxifene, and a new rexinoid, LG 100268.

Abstract: The selective estrogen receptor modulator arzoxifene and the rexinoid LG 100268 were active not only as single agents for prevention and treatment of breast cancer in the rat model that uses nitrosomethylurea as the carcinogen but also showed striking synergy, both preventively and therapeutically, in a series of six experiments with a total of 465 rats. Mechanistic studies in cell culture reported here suggest that enhancement of stromal-epithelial interactions may contribute to this synergy. The possible clinical use of the combination of arzoxifene and LG 100268 for prevention of breast cancer in women at high risk, for treatment of women in the adjuvant setting, or for treatment of end-stage disease should now be considered.

Design and synthesis of tricyclic compounds with enone functionalities in rings A and C: a novel class of highly active inhibitors of nitric oxide production in mouse macrophages.

Abstract: Novel tricyclic compounds with enone functionalities in rings A and C, which were designed on the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid, have been synthesized. Among them, 10 shows high inhibitory activity (IC(50) = 1 nM level) against production of nitric oxide induced by interferon-gamma in mouse macrophages and is orally active at 15 mg/kg (once) in a preliminary in vivo study using mouse peritoneal inflammation induced by thioglycollate and interferon-gamma.

Hobson's choice and the need for combinations of new agents for the prevention and treatment of breast cancer.

Abstract: The excellent article by O’Regan, Jordan, and colleagues in this issue of the Journal (1) highlights the “Hobson’s Choice” currently available for clinical prevention or treatment of early breast cancer.In the 1600s, Thomas Hobson ran a large stable and rented horses at Cambridge University.He compelled customers to rent the one horse that happened to be nearest the stable door or go without—hence the term “Hobson’s Choice.” In current parlance, it has the connotation of an apparently free choice when there is no real alternative.Presently, we are faced with the clinical equivalent of a Hobson’s Choice if we wish to use more than one experimental drug for prevention or adjuvant treatment of early breast cancer.In spite of numerous animal studies that indicate that treatment with combinations of two or more drugs is most effective, our current clinical choice appears to be the selection of a single experimental drug, not the oppor

A Novel Dicyanotriterpenoid, 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, Active at Picomolar Concentrations for Inhibition of Nitric Oxide Production

Abstract: New oleanane triterpenoids with various substituents at the C-17 position of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate were synthesized. Among them, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile shows extremely high inhibitory activity (IC50=1 pM level) against production of nitric oxide induced by interferon-γ in mouse macrophages. This potency is about 100 times and 30 times more potent than CDDO and dexamethasone, respectively.