Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia

Robak, Tadeusz; Kasznicki, Marek

doi:10.1038/sj.leu.2402531

Cited by 76 publications

(50 citation statements)

References 103 publications

(126 reference statements)

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“…More recently, the nucleoside analog fludarabine has proved useful, especially for the treatment of patients who fail to respond to chlorambucil. 9 Although high remission rates have been achieved using this drug, 10 myelosuppression has proved to be a critical dose-limiting factor. 11 Fludarabine is also highly toxic to T lymphocytes and results in prolonged depression of CD4 ϩ T cells, increasing the risk of opportunistic infections.…”

Section: Introductionmentioning

confidence: 99%

“…25,26 However, even CLL cells harboring intact p53 genes may be defective in p53-mediated apoptosis, resulting from the inactivation of the ATM protein kinase pathway, [27][28][29][30] which links DNA damage induction to p53 up-regulation. Because of the limitations of existing therapeutic options, [9][10][11][12][25][26][27][28][29][30] it is important to evaluate drugs that induce apoptosis of CLL cells via actions on novel cellular targets. 24 Optimal new drugs would display a high degree of selectivity for the malignant cells while sparing hematopoietic progenitors and T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

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Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs

Jones

Addison

North

et al. 2004

Blood

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IntroductionB chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5 ϩ CD19 ϩ B-lymphoid cells. Although CLL cells proliferate slowly, defective apoptosis results in progressive accumulation of the malignant clone. [1][2][3] The clinical course of CLL is highly variable. Although a proportion of patients survive for extended periods without the need for clinical intervention, others undergo rapid disease progression and require aggressive treatment. Recent studies have established that a subset of patients with CLL with unmutated immunoglobulin heavy chain variable (IgV H ) genes have an inferior clinical outcome compared to the subset with mutated IgV H genes. 4,5 Furthermore, expression of the protein tyrosine kinase ZAP-70 correlates well with an unmutated IgV H status, providing an accessible alternative criterion for the management of patients with CLL. [6][7][8] There is an urgent need to develop novel protocols for the treatment patients with a poor prognosis identified by IgV H mutation analysis or ZAP-70 expression.For many years, the nitrogen mustard chlorambucil has been the drug of choice in CLL. More recently, the nucleoside analog fludarabine has proved useful, especially for the treatment of patients who fail to respond to chlorambucil. 9 Although high remission rates have been achieved using this drug, 10 myelosuppression has proved to be a critical dose-limiting factor. 11 Fludarabine is also highly toxic to T lymphocytes and results in prolonged depression of CD4 ϩ T cells, increasing the risk of opportunistic infections. 11,12 Therefore, there has been considerable interest in identifying novel drugs that induce CLL apoptosis with greater selectivity. [13][14][15][16][17][18][19][20][21][22][23][24] Deletion of the p53 tumor suppressor gene, whose protein product is a key mediator of drug-induced apoptosis, predicts a poor response to cytotoxic drugs. 25,26 However, even CLL cells harboring intact p53 genes may be defective in p53-mediated apoptosis, resulting from the inactivation of the ATM protein kinase pathway, 27-30 which links DNA damage induction to p53 up-regulation. Because of the limitations of existing therapeutic options, [9][10][11][12][25][26][27][28][29][30] it is important to evaluate drugs that induce apoptosis of CLL cells via actions on novel cellular targets. 24 Optimal new drugs would display a high degree of selectivity for the malignant cells while sparing hematopoietic progenitors and T lymphocytes. Further advantageous characteristics include a p53-independent mode of action and synergistic actions with conventional cytotoxic drugs.The ansamycin antibiotics geldanamycin (GA) and herbimycin A (HMA) have attracted interest as potential anticancer agents. 31,32 These drugs target the adenosine triphosphate (ATP)-binding pocket of the cytosolic chaperone heat shock protein 90 (Hsp90). 33 Hsp90 ensures maintenance of the correctly folded conformation of a range of client proteins involved in signal transduction, including Akt, Raf-1, Erb B2, and...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs

Jones

Addison

North

et al. 2004

Blood

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“…2 CLL is currently an incurable disease but several drug therapies, including the purine analog fludarabine, are now known to cause clinical improvement in CLL patients. 3 Several in vitro studies indicate that in CLL cells fludarabine induces apoptosis, suggesting that programmed cell death is the mechanism of their therapeutic action. [4][5][6][7][8][9] As CLL cells are predominantly quiescent cells, the proapoptotic activity of fludarabine could be due to inhibition of RNA synthesis or alteration of DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

et al. 2004

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Fludarabine is considered the treatment of choice for most patients with chronic lymphocytic leukemia (CLL). We have analyzed the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in CLL cells. Among the known plasma membrane transporters, we have previously observed a significant correlation between fludarabine uptake via ENT carriers and ex vivo sensitivity of CLL cells to fludarabine, although mRNA amounts of the equilibrative nucleoside transporters hENT1 and hENT2 do not show any predictive response to treatment. In this study, using polyclonal monospecific antibodies we have observed a significant correlation between the expression of hENT2 by Western blot and fludarabine uptake via hENT carriers and also with ex vivo sensitivity of CLL cells to fludarabine. These results suggest that the equilibrative nucleoside transporter hENT2 plays a role in fludarabine responsiveness in CLL patients.

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“…3 CLL is currently incurable but several drugs, including pyrimidine and purine analogues, cause clinical improvement in CLL patients. 4 The two primary purine analogues in CLL therapy are fludarabine 5 and 2-chlorodeoxyadenosine (2-CdA). 6 These drugs have been used mostly alone, but also in combination, for the treatment of low-grade B-cell malignancies, including CLL, follicular lymphoma and hairy-cell leukaemia.…”

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confidence: 99%

Nucleoside transporters in chronic lymphocytic leukaemia

et al. 2004

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Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia

Cited by 76 publications

References 103 publications

Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs

Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

Nucleoside transporters in chronic lymphocytic leukaemia

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