Alvocidib (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.
Definition from the NCI drug dictionary: Alvocidib (flavopiridol) is a synthetic N-methylpiperidinyl chlorophenyl flavone compound. As an inhibitor of cyclin-dependent kinase, alvocidib induces cell cycle arrest by preventing phosphorylation of cyclin-dependent kinases (CDKs) and by down-regulating cyclin D1 and D3 expression, resulting in G1 cell cycle arrest and apoptosis. This agent is also a competitive inhibitor of adenosine triphosphate activity.
Sanofi-Aventis is developing this drug.
Activity against GIST: 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.
Alvocidib 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. 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 the peceding link. In contrast, flavopiridol may be more effective when used together with another drug (combination therapy).
Alvocidib is in numerous clinical trials for various types of cancer, both as a single agent and in combination trials. Some trials most relevant to GIST are listed below.
Vorinostat and Flavopiridol in Treating Patients With Advanced Solid Tumors
Phase I, NCT00324480
Gemcitabine and Flavopiridol in Treating Patients With Solid Tumors
Phase I, NCT00072436
Flavopiridol in Treating Patients With Locally Advanced or Metastatic Solid Tumors
Phase I, NCT00112684