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Docetaxel downside highlighted
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Combined treatment for drug-resistant multiple myeloma? MA, USA). “So we looked into the action of tubacin, which inhibits the aggresome pathway by blocking histone deacetylase 6 [HDAC6] activity, an enzyme that binds these misfolded proteins and the dynein motors that pass them to the aggresomes. We then tested it with bortezomib to see if this would improve the results obtained with the latter drug alone.” Tubacin alone inhibited the growth of both drug-sensitive and drug-resistant MM cells by caspase-dependent apoptosis without increasing cytotoxicity in normal peripheral blood mononuclear cells (PMBCs). In combination with bortezomib, the cytotoxicity induced in bone–marrow plasma cells from a patient with MM was twice that noted for bortezomib alone, again with no effect on healthy PMBCs. “Hopefully we will see the same in patients”, says Schreiber. “We hope to start clinical trials soon.”
“Targeting HDAC6 certainly shows potential”, comments Karel van Wely (National Center for Biotechnology, Madrid, Spain), “but its complex cellular role is not fully understood, so further trials testing the activity of tubacin and its side-effects might be needed”.
Adrian Burton
Courte4sy of Stuart Schreiber
The combination of bortezomib with tubacin kills multiple myeloma (MM) cells in vitro more efficiently than does either drug alone, without increasing cytotoxicity in healthy blood cells (Proc Natl Acad Sci USA, 2005; 102: 8567–72). The finding might provide a new approach for treating this disease. Bortezomib prevents proteosomes from removing the excess of unfolded and misfolded ubiquitinated proteins produced by MM cells. As these proteins accumulate, the growing toxic stress eventually induces apoptosis. However, about 65% of patients do not respond to bortezomib, since removal of these proteins appears to continue via a newly discovered mechanism involving aggresomes—specialised vesicles that transport them to the lysosomes. “If both of these systems were inhibited at the same time there might be no escape”, explains study leader Stuart Schreiber (Harvard University, Boston,
Tubacin acetylates tubulin (green), blocking the aggresome pathway
Docetaxel downside highlighted Patients with intermediate-risk breast cancer had life-threatening sepsis after they were given adjuvant doxorubicin plus docetaxel, according to French researchers. The Reposant sur des Arguments Pronostiques et Prédictifs (RAPP)-01 trial was stopped early after two patients died from causes related to drug toxic effects and one patient developed peritonitis. “We did not include primary prophylaxis for febrile neutropenia in our protocol”, explains lead investigator Etienne Brain (René Huguenin Cancer Center, Saint-Cloud, France), “because the expected rate of febrile neutropenia was less than 40%, the recommended threshold for providing granulocyte colony-stimulating factor support. But, given our experience, without prophylaxis, the combination of docetaxel and doxorubicin is too myelotoxic for treatment of patients with early breast cancer”. Paclitaxel and docetaxel were first http://oncology.thelancet.com Vol 6 July 2005
approved for adjuvant use in advanced breast cancer 10 years ago. Recently, a combination of cyclophosphamide, docetaxel, and doxorubicin received approval in the USA and European Union to treat early breast cancer based on data from the Breast Cancer International Research Group (BCIRG) 001 trial (N Engl J Med 2005; 352: 2302–13; 2346–48). RAPP-01, which started in June, 1999, planned to enrol 700 women with unilateral operable breast cancer who were high risk, node negative or had fewer than three positive lymph nodes. In March, 2000, after 45 patients had been enrolled, a patient developed febrile neutropenia and died of suspected mesenteric infarction. In January, 2001, when a second patient developed non-fatal gastrointestinal problems and septic shock, the study was temporarily stopped while data from other trials
were analysed. Then, in January, 2003, after 627 patients had been enrolled, a second woman died from complications of febrile neutropenia. The trial was immediately terminated because of the unexpectedly high toxic mortality (JAMA 2005; 293: 2367–71). “I am not surprised by these findings”, says breast-cancer specialist Edith Perez (Mayo Clinic, Jacksonville, FL, USA). “It is well known that docetaxel alone or in combination with other chemotherapy agents can be very myelosupressive.” The results of both RAPP-01 and BCIRG 001 trials, conclude Perez and Brain, show that prophylactic growth-factor support is needed for patients who are given chemotherapy regimens containing docetaxel, an expensive undertaking that might limit the usefulness of these drug combinations.
Jane Bradbury 447
Combined treatment for drug-resistant multiple myeloma? MA, USA). “So we looked into the action of tubacin, which inhibits the aggresome pathway by blocking histone deacetylase 6 [HDAC6] activity, an enzyme that binds these misfolded proteins and the dynein motors that pass them to the aggresomes. We then tested it with bortezomib to see if this would improve the results obtained with the latter drug alone.” Tubacin alone inhibited the growth of both drug-sensitive and drug-resistant MM cells by caspase-dependent apoptosis without increasing cytotoxicity in normal peripheral blood mononuclear cells (PMBCs). In combination with bortezomib, the cytotoxicity induced in bone–marrow plasma cells from a patient with MM was twice that noted for bortezomib alone, again with no effect on healthy PMBCs. “Hopefully we will see the same in patients”, says Schreiber. “We hope to start clinical trials soon.”
“Targeting HDAC6 certainly shows potential”, comments Karel van Wely (National Center for Biotechnology, Madrid, Spain), “but its complex cellular role is not fully understood, so further trials testing the activity of tubacin and its side-effects might be needed”.
Adrian Burton
Courte4sy of Stuart Schreiber
The combination of bortezomib with tubacin kills multiple myeloma (MM) cells in vitro more efficiently than does either drug alone, without increasing cytotoxicity in healthy blood cells (Proc Natl Acad Sci USA, 2005; 102: 8567–72). The finding might provide a new approach for treating this disease. Bortezomib prevents proteosomes from removing the excess of unfolded and misfolded ubiquitinated proteins produced by MM cells. As these proteins accumulate, the growing toxic stress eventually induces apoptosis. However, about 65% of patients do not respond to bortezomib, since removal of these proteins appears to continue via a newly discovered mechanism involving aggresomes—specialised vesicles that transport them to the lysosomes. “If both of these systems were inhibited at the same time there might be no escape”, explains study leader Stuart Schreiber (Harvard University, Boston,
Tubacin acetylates tubulin (green), blocking the aggresome pathway
Docetaxel downside highlighted Patients with intermediate-risk breast cancer had life-threatening sepsis after they were given adjuvant doxorubicin plus docetaxel, according to French researchers. The Reposant sur des Arguments Pronostiques et Prédictifs (RAPP)-01 trial was stopped early after two patients died from causes related to drug toxic effects and one patient developed peritonitis. “We did not include primary prophylaxis for febrile neutropenia in our protocol”, explains lead investigator Etienne Brain (René Huguenin Cancer Center, Saint-Cloud, France), “because the expected rate of febrile neutropenia was less than 40%, the recommended threshold for providing granulocyte colony-stimulating factor support. But, given our experience, without prophylaxis, the combination of docetaxel and doxorubicin is too myelotoxic for treatment of patients with early breast cancer”. Paclitaxel and docetaxel were first http://oncology.thelancet.com Vol 6 July 2005
approved for adjuvant use in advanced breast cancer 10 years ago. Recently, a combination of cyclophosphamide, docetaxel, and doxorubicin received approval in the USA and European Union to treat early breast cancer based on data from the Breast Cancer International Research Group (BCIRG) 001 trial (N Engl J Med 2005; 352: 2302–13; 2346–48). RAPP-01, which started in June, 1999, planned to enrol 700 women with unilateral operable breast cancer who were high risk, node negative or had fewer than three positive lymph nodes. In March, 2000, after 45 patients had been enrolled, a patient developed febrile neutropenia and died of suspected mesenteric infarction. In January, 2001, when a second patient developed non-fatal gastrointestinal problems and septic shock, the study was temporarily stopped while data from other trials
were analysed. Then, in January, 2003, after 627 patients had been enrolled, a second woman died from complications of febrile neutropenia. The trial was immediately terminated because of the unexpectedly high toxic mortality (JAMA 2005; 293: 2367–71). “I am not surprised by these findings”, says breast-cancer specialist Edith Perez (Mayo Clinic, Jacksonville, FL, USA). “It is well known that docetaxel alone or in combination with other chemotherapy agents can be very myelosupressive.” The results of both RAPP-01 and BCIRG 001 trials, conclude Perez and Brain, show that prophylactic growth-factor support is needed for patients who are given chemotherapy regimens containing docetaxel, an expensive undertaking that might limit the usefulness of these drug combinations.
Jane Bradbury 447