IntroductionThe nucleoside analog cytarabine, an effective and widely used agent for the treatment of acute myelogenous leukemia (AML), 1 induces remissions when administered on various schedules either as a single agent or in combination with other antileukemic drugs. 2,3 Unfortunately, despite the inclusion of cytarabine in a variety of induction and consolidation regimens, most patients with AML ultimately relapse and die with drug-resistant disease. [3][4][5][6] Accordingly, there is considerable interest in understanding the mechanisms of resistance to cytarabine and devising strategies for overcoming them. 6,7 Earlier studies identified a number of mechanisms of cytarabine resistance, including diminished uptake on nucleoside transporters, 8 increased degradation of cytarabine to uracil arabinoside, 9 diminished formation or retention of cytosine arabinoside triphosphate, [10][11][12] and reduced incorporation into DNA resulting from decreased passage of cells through S phase. 13 Strategies for overcoming several of these mechanisms have been successfully implemented in clinical trials. [14][15][16] Recent observations suggest that signaling by checkpoint kinase Chk1 might also contribute to cytarabine resistance. Chk1 is activated by a number of replication inhibitors. [17][18][19][20][21] According to current understanding, these inhibitors cause DNA polymerases to stall but allow DNA helicases to continue advancing. 22,23 The resulting single-stranded DNA then binds replication protein A, which recruits 2 protein complexes, one consisting of the ataxia telangiectasia mutated-and Rad3-related (ATR) kinase and its binding partner ATR-interacting protein (ATRIP) and another consisting of the Rad9-Rad1-Hus1 clamp. The Rad9-Rad1-Hus1 complex facilitates ATR-mediated phosphorylation and activation of Chk1. Once activated, Chk1 phosphorylates the phosphatase Cdc25A. [24][25][26][27] The resulting protease-mediated degradation of Cdc25A contributes to S-phase slowing by preventing phosphatasemediated activation of cyclin E/cyclin dependent kinase 2 complexes (reviewed by Sagata 28 ). In addition, Chk1-mediated phosphorylation stabilizes stalled replication forks until replication can resume. 18,21 The potential importance of these events in drug resistance is highlighted by the observation that Chk1 gene deletion or pharmacologic Chk1 inhibition sensitizes cells to replication inhibitors. 21,[29][30][31] Collectively, these observations have raised the possibility that disrupting Chk1 signaling might enhance nucleoside analog cytotoxicity and overcome Chk1-mediated drug resistance.Heat shock protein 90 (Hsp90) is currently receiving considerable attention as a potential anticancer drug target. 32 The Hsp90 complex is a chaperone that facilitates the initial folding and/or stabilization of a variety of polypeptides, which are known as Akt,37,38 and Bcr/abl, 39,40 play important roles in leukocyte biology and leukemogenesis. The ability of the Hsp90 complex to stabilize these clients is inhibited by the benzoqui...
Background: PARP inhibitors and topoisomerase I poisons (Top1p) synergize by an unknown mechanism. Results: Although Parp1 deletion fails to increase Top1p sensitivity, transfection with catalytically inactive PARP1 or its isolated DNA binding domain does sensitize. Conclusion: PARP inhibitors poison PARP1 to diminish repair of topoisomerase I-triggered DNA damage. Significance: These results predict that tumors with elevated PARP1 will be particularly sensitive to Top1p/PARP inhibitor combinations.
Mantle-cell lymphoma (MCL) is
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