Cancer Degrading Drug!!!

News Article:
Drug Week (2006). Gastrointestinal Stromal Tumor; Gastrointestinal stromal tumor apoptosis induced by flavopiridol.

Primary research article:
Sambol, E. et. al (2006). Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells. Cancer Research, Vol.66, pp. 5858-5866.

Articles citing primary article:
Fornier, M.N. et. al (2007). Phase I Dose- Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors. Clinical cancer Research 13(19), pp. 5841-5846.

Guo, T. et. al (2007). Sorafenib Inhibits the Imatinib- Resistant KITT670I Gatekeeper Mutation in Gastrointestinal Stromal Tumor. Clinical Cancer Research 13(16), pp. 4874-4881.

Liu, Y. et. al (2007). Histone H2AX Is a Mediator of Gastrointestinal Stromal Tumor Cell Apoptosis following Treatment with Imatinib Mesylate. Cancer Research 67(6), pp. 2685-2692.

Mutation in the cKIT gene results in germ cell tumors, mastocytosis, small cell lung cancers, breast cancers and gastrointestinal stromal tumors. Imatinib mesylate is a tyrosine kinase inhibitor, which blocks the active mutated forms of KIT, bcr- abl receptors. Imatinib mesylate inhibits KIT kinase activity; and is highly active in KIT dependent GIST cell lines. Resistance of GIST cells to imatinib mesylate is hypothesized to occur because of amplification of KIT, secondary mutations cKIT gene product is a 145 kDa transmembrane protein. cKIT belongs to the type III receptor tyrosine kinase family.
Because GIST cells require the constant signaling of KIT. Researches wanted to know if flavopiridol could be an effective alternate to imatinib mesylate by inducing transcriptional suppression of the KIT receptor. Flavopridol is a cylin dependent kinase inhibitor. To evaluate the antiproliferative effect of drug exposure on GIST cells, the cells were plated in 96-well plates of a density of 2 X 10Ù4 cells per well and allowed to adhere overnight at 37 degrees Celsius. The cells were incubated with CyQuant dye and lysed. The cells were treated with varying concentrations of flavopiridol or imatinib mesylate. A DNA fragment of the human cKIT promoter was prepared by PCR amplification.
150 n/mol/L Flavopiridol had no effect on GIST cells at 24 and 48 hours. With 300nmol/L of flavopiridol there was an increase in apoptosis within 42% and 58% Annexin V staining at 24 and 48 hrs. The induction of apoptosis did not seem to increase with imatinib mesylate concentrations up to 10 u mol/L. activity, which was evidenced by the significant increase in cleaved product using a fluorescence based assay. KIT protein remained stable until 24 hours, and then it stared to reduce significantly. Because KIT down regulation occurred with apoptosis suggested that the down regulation of KIT may be required for cell death.
The primary article gives a lot of information. It discusses the methods on how the experiment was done, what the results of the experiment are, the secondary article is quoting the primary research. I trust both sources equally, because the secondary article is quoting directly from the primary article.


Of all the other cancer drugs out there why did they choose flavorpiridol to test on mutated KIT kinase?

Is there a drug other than flavorpiridol that causes the same effect on cKIT kinase?