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Cell-Cycle Inhibitors

Mechanism Of Action

Progression through the cell cycle depends on numerous signaling pathways and checkpoints (e.g., the cyclin families of proteins, the cyclin-dependent kinases [CDKs]). Deregulation of these key cell-cycle checkpoints is observed in most cancer cells. Inhibition of these enzymes can result in cell-cycle arrest and, ultimately, cell death, usually by apoptosis. Targeting the machinery involved in the cell cycle aims to directly attack cells with a high turnover, such as cancer cells.

alvocidib (Flavopiridol)Alvocidib

Aventis and the National Cancer Institute (NCI) were developing alvocidib (Flavopiridol) together until Aventis discontinued its involvement in

February 2004. This synthetic flavenoid inhibits CDKs and is the first CDK inhibitor to enter trials; it is in Phase II trials for chronic lymphocytic leukemia. It has reached Phase III in France.

Preclinical research has demonstrated alvocidib’s ability to enhance both the radio- and chemosensitivity of a variety of cell lines and animal tumors. Ongoing experiments are analyzing this mechanism of action as well as further delineating alvocidib’s activity when administered alone. In a syngeneic mouse model of lym-phoma, alvocidib enhanced the tumor response to radiation, and in H460 human lung cancer cells, alvocidib enhanced the effects of docetaxel and radiation. Researchers examined the molecular pathway of alvocidib activity and found that this agent interacts synergistically with the tumor necrosis factor-related apoptosis-induced ligand (TRAIL). Alvocidib does so through a mechanism involving the downregulation of XIAP (X-linked inhibitor of apoptosis protein), resulting in apoptosis of human leukemia cells.

A Phase II study of alvocidib in patients with fludarabine-refractory chronic lymphocytic leukemia is complete. This trial was an open-label, multicenter study aiming to accrue up to 37 patients. Those registered before September 2000 received intravenous (IV) alvocidib continuously on days 1-3, and treatment was repeated every 14 days for a total of 12 courses in the absence of disease progression or unacceptable toxicity. Patients who were registered after September 2000 received IV alvocidib over one hour daily on days 1-3. Treatment was repeated every three weeks for a total of eight courses. Patients were to be followed every three months for the first year and then every six months for five years. The study aimed to assess toxicity, CR, PR, progression-free and overall survival, and the impact of alvocidib on normal T-cell subsets and immunoglobulinlevels. No data from this trial have been published.

A Phase I dose-escalation study is examining alvocidib combined with fludarabine and rituximab in patients with various lymphoproliferative disorders, including chronic lymphocytic leukemia. No data have been published.

Given the lack of data on the use of alvocidib for chronic lymphocytic leukemia, we examined results from Phase I and II studies of alvocidib as a single agent or in combination with chemotherapy in the treatment of other cancers. In a Phase II trial of single-agent alvocidib in patients with hormone-refractory metastatic prostate cancer, no objective responses were observed and only 11% of patients achieved stable disease as the best response. In addition, alvocidib administered at 40 or 50 mg/m2/day for a total of 72 hours was associated with significant toxicities that resulted in a high withdrawal rate from the study.

A single-agent Phase II study of alvocidib therapy involving 33 renal-cell carcinoma patients resulted in 1 CR, 2 PRs, and 13 stable disease, but the study’s response criteria were not met. Alvocidib is being investigated in a variety of combination regimens with agents such as irinotecan, docetaxel, 5-FU and leucovorin, and paclitaxel and carboplatin. The majority of trials completed have set out to establish alvocidib’s safety and maximum tolerated dose.

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