Preclinical and clinical studies of docetaxel and exisulind in the treatment of human lung cancer.
Lung cancer is the leading cause of cancer death in the United States. The majority of patients with non-small cell lung cancers present with inoperable disease because of the presence of metastases to regional lymph nodes or other metastatic sites. About one third of patients have stage IV disease with metastases to distant organs at the time of diagnosis. The prognosis for these patients is very poor. With best supportive care the median survival is only 4 months and the 1-year survival rate is 10% to 15%. Current chemotherapy combinations improve the survival and quality of life for patients with advanced non-small cell lung cancer. With two-drug combinations, median survival is increased to 8 months or more and 1-year survival is increased to 35% to 40%. Still, complete response rates are low and more than 80% of patients die within 1 year of diagnosis. The improvements created by current therapies led to studies of chemotherapy in the second-line setting. Docetaxel has been shown to improve survival of patients who failed platinum-based chemotherapy and was approved by the U.S. Food and Drug Administration for therapy in this setting. However, response rates were very low and survival very short. Therefore, new therapies are urgently needed. Exisulind is a novel oral anticancer agent that holds promise for the treatment of patients with advanced non-small cell lung cancer. Exisulind was originally developed as a chemoprevention agent for colorectal cancer. Preclinical studies showed that exisulind could prevent polyp formation and inhibit the growth of colorectal cancers. Subsequent preclinical studies showed that exisulind also inhibited the growth of human breast, prostate, and lung cancers. Phase I clinical studies showed that twice-daily oral doses could be given safely and would provide peak concentrations that were equivalent to those required for in vitro effects. These observations lead to the studies of the combination of exisulind and docetaxel in preclinical and clinical studies in human lung cancer described in this article.
Bunn
Paul A
PA
University of Colorado Cancer Center, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Chan
Daniel C
DC
Earle
Keith
K
Zhao
Tom L M
TL
Helfrich
Barbara
B
Kelly
Karen
K
Piazza
Gary
G
Whitehead
Clark M
CM
Pamukcu
Rifat
R
Thompson
William
W
Alila
Hector
H
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D004195:Disease Models, Animal; D000077143:Docetaxel; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016019:Survival Analysis; D043823:Taxoids; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D043823:Taxoids; D000077143:Docetaxel; D013467:Sulindac; C025463:sulindac sulfone; D017239:Paclitaxel