Sylwia Flis1, Jacek Spłwiński. 1. National Medicine Institute, Department of Pharmacology, Warsaw, Poland. sylwia.flis@yahoo.pl
Abstract
BACKGROUND: COX inhibitors appear to be promising agents in combination with cytostatics in the treatment of colorectal carcinoma (CRC). The aim of this study was to compare growth inhibitory effects of cytostatics (5-fluorouracil, 5-FU; oxaliplatin) and COX inhibitor sulindac sulfide (an active metabolite of sulindac), given alone or in combination, on several CRC cell lines. MATERIALS AND METHODS: A series of human CRC cell lines were incubated with various combinations of the test drugs used in concentrations from 3 to 200 microM. The cell survival was assessed by MTT assay. Isobolograms and median effect method of Chou and Talalay were used to assess the nature and quantitative aspects of interaction observed between studied drugs. Cell cycle progression and apoptosis were measured using flow cytometric methods. In addition, growth inhibitory effects of studied agents on CRC cell lines were compared with a normal (mouse fibroblast) cell line. RESULTS: Sulindac sulfide synergistically potentiated the inhibitory effects of 5-FU and oxaliplatin on CRC survival, parallel to the induction of apoptosis. A dose reduction effect for synergistic activity of sulindac sulfide with studied cytostatics (in the range of 5- to 14-fold, when compared to single agent) suggested that the inhibitory effect of cytostatics on CRC survival may be obtained at low doses. In addition, sulindac sulfide appeared to be more specific against CRC cells than normal cells. CONCLUSION: It was apparent that combination of 5-FU or oxaliplatin with sulindac sulfide results in a powerful inhibition of growth of colorectal carcinoma cells in vitro, which may be more specific for cancer than normal cells.
BACKGROUND:COX inhibitors appear to be promising agents in combination with cytostatics in the treatment of colorectal carcinoma (CRC). The aim of this study was to compare growth inhibitory effects of cytostatics (5-fluorouracil, 5-FU; oxaliplatin) and COX inhibitor sulindac sulfide (an active metabolite of sulindac), given alone or in combination, on several CRC cell lines. MATERIALS AND METHODS: A series of human CRC cell lines were incubated with various combinations of the test drugs used in concentrations from 3 to 200 microM. The cell survival was assessed by MTT assay. Isobolograms and median effect method of Chou and Talalay were used to assess the nature and quantitative aspects of interaction observed between studied drugs. Cell cycle progression and apoptosis were measured using flow cytometric methods. In addition, growth inhibitory effects of studied agents on CRC cell lines were compared with a normal (mouse fibroblast) cell line. RESULTS:Sulindac sulfide synergistically potentiated the inhibitory effects of 5-FU and oxaliplatin on CRC survival, parallel to the induction of apoptosis. A dose reduction effect for synergistic activity of sulindac sulfide with studied cytostatics (in the range of 5- to 14-fold, when compared to single agent) suggested that the inhibitory effect of cytostatics on CRC survival may be obtained at low doses. In addition, sulindac sulfide appeared to be more specific against CRC cells than normal cells. CONCLUSION: It was apparent that combination of 5-FU or oxaliplatin with sulindac sulfide results in a powerful inhibition of growth of colorectal carcinoma cells in vitro, which may be more specific for cancer than normal cells.
Authors: Koji Matsuo; Masato Nishimura; Justin N Bottsford-Miller; Jie Huang; Kakajan Komurov; Guillermo N Armaiz-Pena; Mian M K Shahzad; Rebecca L Stone; Ju Won Roh; Angela M Sanguino; Chunhua Lu; Dwight D Im; Neil B Rosenshien; Atsuko Sakakibara; Tadayoshi Nagano; Masato Yamasaki; Takayuki Enomoto; Tadashi Kimura; Prahlad T Ram; Kathleen M Schmeler; Gary E Gallick; Kwong K Wong; Michael Frumovitz; Anil K Sood Journal: Clin Cancer Res Date: 2011-07-07 Impact factor: 12.531
Authors: Hyang Sook Seol; Hyo Jeong Kang; Hyojeong Kang; Seul-I Lee; Na Eun Kim; Tae Im Kim; Sung Min Chun; Tae Won Kim; Chang Sik Yu; Young-Ah Suh; Shree Ram Singh; Suhwan Chang; Se Jin Jang Journal: Cancer Lett Date: 2013-12-11 Impact factor: 8.679