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The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy.
Cancer Res. 2002 Sep 01; 62(17):4879-83.CR

Abstract

The c-kit tyrosine kinase inhibitor STI571 exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors respectively associated with constitutive activation of the BCR-ABL and c-kit tyrosine kinases. Human colorectal tumors also express the c-kit proto-oncogene. The present study focuses on the anticancer activity of STI571 in human colorectal tumor cells in vitro and in vivo. The c-kit receptor was identified as a M(r) 145,000 immunoreactive band in human colon cancer cells HT29, HCT8/S11, and HCT116. Cellular invasion induced by 10 ng/ml stem cell factor (EC(50) = 3 ng/ml) in HT29 cells was blocked by 1 micro M STI571 (IC(50) = 56 nM) and pharmacological inhibitors of several oncogenic signaling pathways, namely, phosphatidylinositol 3-kinase (LY294002), Rho GTPases (Clostridium botulinum exoenzyme C3 transferase), and Rho-kinase (Y27632). STI571 inhibited HT29 cell proliferation (IC(50) = 6 micro M) and induced apoptosis in vitro. These cellular effects were associated with a decrease in tumor growth. We also demonstrated that stem cell factor is a proangiogenic factor in vivo and in vitro. These encouraging results warrant further preclinical investigations and clinical trials on the use of the c-kit inhibitor STI571 as a chemotherapeutic agent in colon cancer prevention and in treatment of advanced colorectal cancers associated with liver metastases.

Authors+Show Affiliations

INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France. attoub@st-antoine.inserm.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12208734

Citation

Attoub, Samir, et al. "The C-kit Tyrosine Kinase Inhibitor STI571 for Colorectal Cancer Therapy." Cancer Research, vol. 62, no. 17, 2002, pp. 4879-83.
Attoub S, Rivat C, Rodrigues S, et al. The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Res. 2002;62(17):4879-83.
Attoub, S., Rivat, C., Rodrigues, S., Van Bocxlaer, S., Bedin, M., Bruyneel, E., Louvet, C., Kornprobst, M., André, T., Mareel, M., Mester, J., & Gespach, C. (2002). The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Research, 62(17), 4879-83.
Attoub S, et al. The C-kit Tyrosine Kinase Inhibitor STI571 for Colorectal Cancer Therapy. Cancer Res. 2002 Sep 1;62(17):4879-83. PubMed PMID: 12208734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. AU - Attoub,Samir, AU - Rivat,Christine, AU - Rodrigues,Sylvie, AU - Van Bocxlaer,Saskia, AU - Bedin,Monique, AU - Bruyneel,Erik, AU - Louvet,Christophe, AU - Kornprobst,Michel, AU - André,Thierry, AU - Mareel,Marc, AU - Mester,Jan, AU - Gespach,Christian, PY - 2002/9/5/pubmed PY - 2002/10/4/medline PY - 2002/9/5/entrez SP - 4879 EP - 83 JF - Cancer research JO - Cancer Res. VL - 62 IS - 17 N2 - The c-kit tyrosine kinase inhibitor STI571 exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors respectively associated with constitutive activation of the BCR-ABL and c-kit tyrosine kinases. Human colorectal tumors also express the c-kit proto-oncogene. The present study focuses on the anticancer activity of STI571 in human colorectal tumor cells in vitro and in vivo. The c-kit receptor was identified as a M(r) 145,000 immunoreactive band in human colon cancer cells HT29, HCT8/S11, and HCT116. Cellular invasion induced by 10 ng/ml stem cell factor (EC(50) = 3 ng/ml) in HT29 cells was blocked by 1 micro M STI571 (IC(50) = 56 nM) and pharmacological inhibitors of several oncogenic signaling pathways, namely, phosphatidylinositol 3-kinase (LY294002), Rho GTPases (Clostridium botulinum exoenzyme C3 transferase), and Rho-kinase (Y27632). STI571 inhibited HT29 cell proliferation (IC(50) = 6 micro M) and induced apoptosis in vitro. These cellular effects were associated with a decrease in tumor growth. We also demonstrated that stem cell factor is a proangiogenic factor in vivo and in vitro. These encouraging results warrant further preclinical investigations and clinical trials on the use of the c-kit inhibitor STI571 as a chemotherapeutic agent in colon cancer prevention and in treatment of advanced colorectal cancers associated with liver metastases. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/12208734/The_c_kit_tyrosine_kinase_inhibitor_STI571_for_colorectal_cancer_therapy_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12208734 DB - PRIME DP - Unbound Medicine ER -