[Bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human AML cells.]
>> Br J Haematol. 2007 Mar;136(6):814-828.
The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells.
Stapnes C, Doskeland AP, Hatfield K, Ersvaer E, Ryningen A, Lorens JB, Gjertsen BT, Bruserud O.
Institute of Medicine, University of Bergen and Division of Haematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
Proteasome inhibitors represent a new class of antineoplastic drugs that are considered in the treatment of haematological malignancies. We compared the effects of the reversible proteasome inhibitor bortezomib (Velcade(R)) and the epoxomicin derivative PR-171, an irreversible inhibitor, on primary human acute myeloid leukaemia (AML) cells. Both drugs inhibited autocrine- and cytokine-dependent proliferation of primary AML blasts when tested at nanomolar levels (0.1-100 nmol/l). The antiproliferative effect was independent of basal chymotrypsin-like proteasome activity (showing a 20-fold variation between patients), genetic abnormalities, morphological differentiation and CD34 expression when testing a large group of consecutive patients (n = 54). The effect was retained in cocultures with bone marrow stromal cells. In addition, both drugs enhanced apoptosis. The effect of PR-171 could be detected at lower concentrations than for bortezomib, especially when testing the influence on clonogenic AML cell proliferation. Both drugs had divergent effects on AML cells' constitutive cytokine release. Furthermore, both drugs caused a decrease in proliferation and viability when tested in combination with idarubicin or cytarabine. An antiproliferative effect on primary human acute lymphoblastic leukaemia cells was also detected. We conclude that nanomolar levels of the proteasome inhibitors tested had dose-dependent antiproliferative and proapoptotic effects on primary AML cells in vitro.<<
Which is interesting because PR-171 specifically inhibits the chymotrypsin-like protease in the proteasome. From the Proteolix website:
>>PR-171 is a proteasome inhibitor that inhibits the chymotrypsin-like protease in the core of the proteasome. PR-171 is a synthetic analog of epoxomicin, a natural product discovered in the early 1990’s to have potent anti-tumor activity. PR-171 has a novel mechanism of action and binds through a covalent, selective and stereo-specific linkage to the chymotryptic subunit of the protesome.
PR-171 can act potently on heme tumor cells and multiple myeloma patient cells, including those that are resistant to current therapies. Near-complete inhibition of proteasome activity (>90% in most tissues) is tolerated with intravenous dosing of this drug. Proteasome activity recovers completely with a half-life of 24 hours.
PR-171 can be administered on highly intensive daily dosing schedules that have not been possible with other proteasome inhibitors. The greater inhibition of proteasome activity achieved on these dose schedules led to improved efficacy in mouse tumor models. It is anticipated that the stronger and longer duration of inhibition of proteasome activity achieved with PR-171 will result in improved therapeutic efficacy in cancer patients.<<
Maybe there's something about "basal" I'm not getting. Whatever, it apparently works well enough. And, since proteasome acticity recovers after dosing is stopped, I'm not getting the irreversible part, either.
Cheers, Tuck |
