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October 2001 Volume 4, Issue 7:
PS-341: An Emerging Role in the Treatment of Multiple Myeloma
By Paul G. Richardson, M.D. and Sundar Jagannath, M.D.
PS-341 (also known as LDP-341) is a new drug that is currently being assessed in clinical trials of various solid tumor types and hematologic malignancies. PS-341 has a novel mechanism of action through the inhibition of an enzyme system called the ?proteasome?. The proteasome is found in all cells of the body and plays a key role in protein degradation, cell cycle regulation, and gene expression. Cells flag unwanted proteins meant for degradation by attaching ubiqutin. The flagged proteins are broken down by the proteasome into smaller peptides that can be re-used to build new protein. Normal cell cycle regulation is mediated by a diverse array of proteins. Presence of these proteins at critical steps in cell cycle regulatory pathways is essential for smooth operation of cell division. The proteasome plays a pivotal role in this process; consequently, proteasome inhibition can lead to cell cycle dysregulation and ultimately so-called ?apoptosis? (programmed cell death).

Cancer cells have some internal switches that are ?turned on? to give them a growth advantage. One such switch that plays a critical role in myeloma cells is a protein called Nuclear Factor kappa B (NF-kB). NF-kB is a transcription factor that turns on the genes that produce:

1) Interleukin-6 (IL-6) ? a growth factor for myeloma cells,
2) tumor necrosis factor (TNF-a),
3) Vascular Endothelial Growth Factor (VEGF) that stimulates sprouting of capillaries or young blood vessels to nourish the myeloma cells in the marrow, and
4) cell adhesion molecules such as V-CAM, that allows anchoring of myeloma cells to the bone marrow stromal cells and endothelial cells.

Normally, NF-kB switch is in off position while bound to Inhibitory-kB protein (I-kB). However, in myeloma cells, NF-kB switch is turned ?on? by IL-6 and TNF-a from stromal cells. Cytokines, such as IL-6 and TNF-a, cause flagging of I-kB (ubiquitinization) and subsequent destruction by proteasome. When PS-341 poisons proteasome, I-kB cannot be degraded and stays bound to NF-kB and the switch is turned "off". With the result, stromal cells stop producing IL-6, TNF-a etc. and, myeloma cells undergo apoptosis (cell death). Furthermore, in pre-clinical studies, PS-341 has not only reduced tumor burden when given alone but also has been shown to have additive effects when combined with other therapeutic agents, including dexamethasone.

PS-341 has now been assessed in a variety of solid tumor types and in hematological malignancies in patients, including myeloma. In preliminary trials, PS-341 dosing has been guided by biologic and anti-tumor activity and a pharmacodynamic assay, which has been specifically designed to quantitate the percent proteasome inhibition seen in various tissues. Preliminary reports indicate that biologically active doses of PS-341 have been associated with both responses and manageable toxicity in myeloma patients as part of phase I studies. Multi-center trials of PS-341 as mono-therapy and in combination with dexamethasone in patients with multiple myeloma are now underway, with phase II studies of PS-341 in combination with standard chemotherapeutic agents for other cancers also in process. Regimens consisting of doses between 1mg and 1.3 mg/m2 given twice a week, at least 72 hours apart, for 2 weeks with one week off, for up to 6 months are being tested as part of the phase II trials in relapsed and relapsed, refractory multiple myeloma. Side effects have included fatigue, some suppression of blood counts including white blood cells and platelets, occasional fever and skin rash, and possibly exacerbation of pre-existing nerve damage. So far, these clinical studies have shown evidence of anti-tumor activity with an acceptable safety profile. Given the heavily pre-treated nature of the patients and the responses seen to date, PS-341 appears to have considerable promise as a new biologically derived therapy in the treatment of multiple myeloma.

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