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Sequence Matters When Using Novel Agent

Sequence Matters When Using Novel Agent
M. D. Anderson News Release 04/09/03

An experimental agent that targets a cancer cell's protein shredding machinery (the proteasome) should be given either before or with taxane-based chemotherapy drugs, but not after, say researchers at The University of Texas M. D. Anderson Cancer Center who conducted laboratory tests using prostate cancer cells.

The finding is important because the new therapy, known as PS-341 (Velcade), will likely be tried as new treatment for a number of cancers due to its effectiveness in multiple myeloma, says Christos Papandreou, M.D., Ph.D., assistant professor in the department of Genitourinary Medical Oncology.

"It appears PS-341 could become quite a hit as a novel proteasome inhibitor, a drug that increases the effectiveness of chemotherapy agents," Papandreou says. "We know that while the sequence it is used in doesn't matter with certain classes of chemotherapy drugs, it does with others. Hopefully, future clinical trials will reflect this new understanding."

The findings were published in the Proceedings for the 2003 Annual Meeting of the American Association for Cancer Research.
Last summer, the agent demonstrated a dramatic success when used to treat patients with multiple myeloma. Researchers at Dana-Farber Cancer Institute, where it was tested, said 70% of 78 patients with advanced multiple myeloma improved – an unheard of benefit in that disease. The agent is now being used in a Phase II clinical trial in advanced prostate cancer, and several Phase I clinical trials are underway, or have been completed, testing PS-341 in pancreatic, lung and colorectal cancers.  

The drug is designed to specifically inhibit proteasomes, the cell's enzymatic protein-shredding machinery, responsible for breaking down a variety of proteins, including many that regulate cell division.

M. D. Anderson researchers designed experiments in which they treated prostate cancer cells with PS-341 alone or in combination with one of three different chemotherapy drugs, Etoposide, Doxorubicin, and Paclitaxel.

Unlike Etoposide and Doxorubicin, which both have similar mechanism of action by disrupting the function of certain enzymes involved in DNA processing, Paclitaxel works by disrupting a microtubular system, which is key for the normal function of the cell.

The researchers found that it did not matter whether PS-341 was given first, last, or in combination with either Doxorubicin or Etoposide The combinations worked synergistically on both cell death and growth inhibition in cultures of advanced prostate cancer cells.

However, their findings with the third chemotherapy agent, Paclitaxel, argued that PS-341 should not be used after Paclitaxel because that order of use conferred a protective effect on cancer cells by reducing their rate of cell death. The reason for this is not completely understood yet,  "but it could partly be explained by the opposing effect Paclitaxel and PS-341 have on the key microtubular proteins MAP-4 and beta-Tubulin that are necessary for the anti-tumor activity of Paclitaxel," Papandreou says.
This may be important because taxane-based therapies, such as Taxol, and Taxotere, are widely used to treat many malignancies, including prostate and bladder cancers, he says.


© 2015 The University of Texas MD Anderson Cancer Center