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Flavopiridol
Flavopiridol is a semisynthetic flavone (related to substances found naturally in plants). It acts as a cyclin-dependent kinase inhibitor, meaning that it inhibits progression of cells through the "cell cycle" leading to cell proliferation. [Cancer cells proliferate in an uncontrolled manner, thus causing tumor growth.] Flavopiridol also inhibits src kinases and survivin, and it transcriptionally represses expression of numerous genes. It has been studied in several Phase I and Phase II trials against various types of cancer. For a free-access paper describing some of the results, see Shapiro, 2004. Several Phase II trials have shown subsets of patients with prolonged stable disease.
Recently Sambol et al (2006) described preclinical (test tube) results using flavopiridol against GIST cell lines to see if it would prevent expression of KIT. This research group from Memorial Sloan Kettering Cancer Center found that flavopiridol could make GIST cells susceptible to apoptosis (cell death) by blocking the expression of KIT in the cells. This is a different strategy from imatinib (Gleevec), which blocks activation of KIT but does not reduce its expression in the cell.
Flavopiridol used alone (monotherapy) did not result in objective responses (at least 30% tumor shrinkage) but did provide stable disease in a portion of patients in a small trial for sarcoma patients (Morris et al, 2006). This paper is free-access at the journal Sarcoma using this link. In contrast, flavopiridol may be more effective when used together with another drug (combination therapy).
A Phase I trial of flavopiridol in combination with doxorubicin has been opened at Memorial Sloan Kettering. The protocol states that some patients may be continued on flavopiridol alone after achieving a certain cumulative dose of doxorubicin. For descriptions of this Phase I dose-finding trial, see the following links:
clinicaltrials.gov or cancer.gov
