Genomes and Genes
Summary: A nucleoside antibiotic isolated from Streptomyces antibioticus. It has some antineoplastic properties and has broad spectrum activity against DNA viruses in cell cultures and significant antiviral activity against infections caused by a variety of viruses such as the herpes viruses, the VACCINIA VIRUS and varicella zoster virus.
- Koike N, Pilon Thomas S, MULE J. Nonmyeloablative chemotherapy followed by T-cell adoptive transfer and dendritic cell-based vaccination results in rejection of established melanoma. J Immunother. 2008;31:402-12 pubmed publisher..This combination therapy also led to tumor regression and enhanced survival in mice bearing M05 melanoma. ..
- Stilgenbauer S, Zenz T, Winkler D, Bühler A, Schlenk R, Groner S, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27:3994-4001 pubmed publisher..In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations. ..
- Andersson B, de Lima M, Thall P, Wang X, Couriel D, Korbling M, et al. Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14:672-84 pubmed publisher..These results support replacing BuCy +/- ATG with Bu-Flu +/- rabbit-antithymocyte globulin (ATG), and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1. ..
- Brunstein C, Barker J, Weisdorf D, DeFor T, Miller J, Blazar B, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110:3064-70 pubmed..01) and use of 2 UCB units (P = .07). These findings support the use of UCB after a nonmyeloablative conditioning as a strategy for extending the availability of transplantation therapy, particularly for older patients. ..
- Motiwala T, Majumder S, Kutay H, Smith D, Neuberg D, Lucas D, et al. Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia. Clin Cancer Res. 2007;13:3174-81 pubmed..This study reveals the potential role of PTPRO methylation and silencing in CLL tumorigenesis and also provides a novel molecular target in the epigenetic therapy. ..
- Tam C, Wolf M, Prince H, Januszewicz E, Westerman D, Lin K, et al. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006;106:2412-20 pubmed..Collection of autologous stem cells during molecular remission is feasible and may facilitate future exploration of high-dose therapy in these patients. ..
- Bonin M, Pursche S, Bergeman T, Leopold T, Illmer T, Ehninger G, et al. F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bone Marrow Transplant. 2007;39:201-6 pubmed..There were no changes in PK parameters of fludarabine given before and after intake of busulfan. This implies that a clinically relevant busulfan-fludarabine drug interaction is unlikely. ..
- Gamberale R, Fernandez Calotti P, Sanchez Avalos J, Alberto M, Geffner J, Giordano M. The effect of fludarabine on interferon-gamma production by lymphoid cells from healthy donors and patients with B-cell chronic lymphocytic leukemia. Haematologica. 2006;91:574-6 pubmed..We here show that exposure of peripheral blood lymphocytes from healthy donors and B-CLL patients to fludarabine increases in vitro production of interferon-gamma, a key cytokine in the pathogenesis of AHA. ..
- Dudley M, Yang J, Sherry R, Hughes M, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233-9 pubmed publisher..Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies. ..
- Lin K, Tam C, Keating M, Wierda W, O Brien S, Lerner S, et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood. 2009;113:3168-71 pubmed publisher..8, P < .001). Our results suggest that postremission interventions should be targeted toward patients with unmutated IgV(H) status. ..
- Hewamana S, Lin T, Jenkins C, Burnett A, Jordan C, Fegan C, et al. The novel nuclear factor-kappaB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine. Clin Cancer Res. 2008;14:8102-11 pubmed publisher..Furthermore, it validates the concept of targeting nuclear factor-kappaB in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance. ..
- Ogawa H, Ikegame K, Yoshihara S, Kawakami M, Fujioka T, Masuda T, et al. Unmanipulated HLA 2-3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2006;12:1073-84 pubmed
- Shen W, Kim J, Kish P, Zhang J, Mitchell S, Gentry B, et al. Design and synthesis of vidarabine prodrugs as antiviral agents. Bioorg Med Chem Lett. 2009;19:792-6 pubmed publisher5'-O-D- and L-amino acid derivatives and 5'-O-(D- and L-amino acid methyl ester phosphoramidate) derivatives of vidarabine (ara-A) were synthesized as vidarabine prodrugs...
- Horie R, Watanabe M, Okamura T, Taira M, Shoda M, Motoji T, et al. DHMEQ, a new NF-kappaB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells. Leukemia. 2006;20:800-6 pubmed..Results of this study suggest that inhibition of constitutive and inducible NF-kappaB by DHMEQ in combination with fludarabine is a promising strategy for the treatment of CLL. ..
- Yang B, Akhter S, Chaudhuri A, Kanmogne G. HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood-brain barrier: modulatory effects of STAT1 signaling. Microvasc Res. 2009;77:212-9 pubmed publisher..Inhibition of STAT1 activation could provide a unique therapeutic strategy to decrease neuroinflammation and BBB dysfunction in HIV/AIDS. ..
- Mansour A, Chang V, Srinivas S, Harrison J, Raveche E. Correlation of ZAP-70 expression in B cell leukemias to the ex vivo response to a combination of fludarabine/genistein. Cancer Immunol Immunother. 2007;56:501-14 pubmed
- Anderlini P, Saliba R, Acholonu S, Giralt S, Andersson B, Ueno N, et al. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica. 2008;93:257-64 pubmed publisher..Optimizing pretransplant response status may improve patients' outcome. ..
- Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2009;:440-9 pubmed publisher..In addition, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current use of these different modalities in CLL therapy. ..
- Ungerechts G, Springfeld C, Frenzke M, Lampe J, Johnston P, Parker W, et al. Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine. Cancer Res. 2007;67:10939-47 pubmed..Cells from MCL patients were shown to be sensitive to infection. Thus, synergy of F-araAMP with a PNP-armed and CD20-targeted MV was shown in one lymphoma therapy model after systemic vector inoculation. ..
- Shimoni A, Hardan I, Shem Tov N, Rand A, Herscovici C, Yerushalmi R, et al. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse m. Leukemia. 2007;21:2109-16 pubmed..The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies. ..
- Suzuki M, Okuda T, Shiraki K. Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2006;72:157-61 pubmedAcyclovir and vidarabine both exhibit anti-herpetic activity...
- Inamoto Y, Oba T, Miyamura K, Terakura S, Tsujimura A, Kuwatsuka Y, et al. Stable engraftment after a conditioning regimen with fludarabine and melphalan for bone marrow transplantation from an unrelated donor. Int J Hematol. 2006;83:356-62 pubmed
- Vigouroux S, Michallet M, Porcher R, Attal M, Ades L, Bernard M, et al. Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica. 2007;92:627-34 pubmed..The 3-year cumulative incidences of TRM were 32%, 28% and 63%, respectively. The incidence of relapse was 9.6%. Although associated with significant TRM, RIC allogeneic SCT in advanced chemosensitive disease leads to long-term survival. ..
- Tam C, Keating M. Chemoimmunotherapy of chronic lymphocytic leukemia. Nat Rev Clin Oncol. 2010;7:521-32 pubmed publisher..We will also discuss how new developments in induction and consolidation strategies are leading the path towards cure. ..
- Elter T, Hallek M, Engert A. Fludarabine in chronic lymphocytic leukaemia. Expert Opin Pharmacother. 2006;7:1641-51 pubmed
- Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2006;:CD004270 pubmed..Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and hemolytic anemia. ..
- Hegde G, Peterson K, Emanuel K, Mittal A, Joshi A, Dickinson J, et al. Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol Cancer Res. 2008;6:1928-36 pubmed publisher..Together, these results reveal that Hh signaling is important in the pathogenesis of B-CLL and, hence, may be a potential therapeutic target. ..
- Johnson A, Lucas D, Muthusamy N, Smith L, Edwards R, De Lay M, et al. Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood. 2006;108:1334-8 pubmed
- O Brien S, Moore J, Boyd T, Larratt L, Skotnicki A, Koziner B, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007;25:1114-20 pubmed
- Podhorecka M, Halicka H, Klimek P, Kowal M, Dmoszynska A. Thalidomide induces phosphorylation of histone H2AX and increases rate of apoptosis caused by fludarabine in malignant lymphocytes of chronic lymphocytic leukemia in short-term cell cultures. Leuk Res. 2009;33:997-1000 pubmed publisher..The data suggest that oxidative DNA damage likely induced by thalidomide sensitizes CLL cells to undergo apoptosis in response to fludarabine. ..
- Flinn I, Neuberg D, Grever M, Dewald G, Bennett J, Paietta E, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25:793-8 pubmed..812). Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity. ..
- Bredeson C, Zhang M, Agovi M, Bacigalupo A, Bahlis N, Ballen K, et al. Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:993-1003 pubmed publisher..Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials...
- Iravani M, Evazi M, Mousavi S, Shamshiri A, Tavakoli M, Ashouri A, et al. Fludarabine and busulfan as a myeloablative conditioning regimen for allogeneic stem cell transplantation in high- and standard-risk leukemic patients. Bone Marrow Transplant. 2007;40:105-10 pubmed
- Rodriguez R, Nademanee A, Ruel N, Smith E, Krishnan A, Popplewell L, et al. Comparison of reduced-intensity and conventional myeloablative regimens for allogeneic transplantation in non-Hodgkin's lymphoma. Biol Blood Marrow Transplant. 2006;12:1326-34 pubmed
- Tam C, O Brien S, Wierda W, Kantarjian H, Wen S, Do K, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-80 pubmed publisher..5% per year for the third year onward. In a multivariate analysis of patients receiving fludarabine-based therapy at our center, FCR therapy emerged as the strongest independent determinant of survival. ..
- Dungarwalla M, Evans S, Riley U, Catovsky D, Dearden C, Matutes E. High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy. Haematologica. 2008;93:475-6 pubmed publisher..Despite its efficacy the combination is not easily manageable because of the high rate of opportunistic infections. ..
- Chae Y, Sohn S, Kim J, Cho Y, Moon J, Shin H, et al. New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Bone Marrow Transplant. 2007;40:541-7 pubmed..168; 0.035-0.807; P=0.026). The replacement of cyclophosphamide with fludarabine for myeloablative conditioning seems to be more effective in terms of short-term NRM, and GVHD compared to BuCy2 regimen in allogeneic transplantation. ..
- Catovsky D, Richards S, Matutes E, Oscier D, Dyer M, Bezares R, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370:230-9 pubmed..Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies. ..
- Tam C, Keating M. Chemoimmunotherapy of chronic lymphocytic leukemia. Best Pract Res Clin Haematol. 2007;20:479-98 pubmed..We review the evolution of modern chemoimmunotherapy for CLL, and discuss current research directions for further refining the potency of these regimens. ..
- de Viron E, Knoops L, Connerotte T, Smal C, Michaux L, Saussoy P, et al. Impaired up-regulation of polo-like kinase 2 in B-cell chronic lymphocytic leukaemia lymphocytes resistant to fludarabine and 2-chlorodeoxyadenosine: a potential marker of defective damage response. Br J Haematol. 2009;147:641-52 pubmed publisher
- Turgut B, Vural O, Pala F, Pamuk G, Tabakcioğlu K, Demir M, et al. 17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis. Leuk Lymphoma. 2007;48:311-20 pubmed..In conclusion, 17p deletion, which causes loss of p53 gene, is associated with resistance to fludarabine-induced apoptosis in vitro. New treatment modalities should be tried in B-CLL patients with 17p deletion. ..
- Tse E, Chan J, Pang A, Au W, Leung A, Lam C, et al. Fludarabine, mitoxantrone and dexamethasone as first-line treatment for T-cell large granular lymphocyte leukemia. Leukemia. 2007;21:2225-6 pubmed
- Yabe H, Inoue H, Matsumoto M, Hamanoue S, Koike T, Ishiguro H, et al. Allogeneic haematopoietic cell transplantation from alternative donors with a conditioning regimen of low-dose irradiation, fludarabine and cyclophosphamide in Fanconi anaemia. Br J Haematol. 2006;134:208-12 pubmed..The 1-year overall survival was 96.3% (95% CI, 89-100). This conditioning regimen exerted an immunosuppressive effect that enabled durable engraftment in alternative donor HCT without severe toxicity. ..
- Yavuz S, Paydas S, Disel U, SAhin B. IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience. Am J Ther. 2006;13:389-93 pubmed..High efficacy and a low-toxicity profile are preferable properties of this regimen, and this regimen has been found to be useful for cytoreduction, especially in candidates for allo-SCT. ..
- Dearden C, Wade R, Else M, Richards S, Milligan D, Hamblin T, et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood. 2008;111:1820-6 pubmed..In conclusion, DAT status at the time of initiation of therapy provides a new prognostic indicator, although FC may protect against AHA. This trial was registered at http://isrctn.org as no. 58585610. ..
- Ahmed N, Leung K, Rosenblatt H, Bollard C, Gottschalk S, Myers G, et al. Successful treatment of stem cell graft failure in pediatric patients using a submyeloablative regimen of campath-1H and fludarabine. Biol Blood Marrow Transplant. 2008;14:1298-304 pubmed publisher..Thus, the regimen that we describe can be used with minimal toxicity to effectively overcome graft failure after myeloablative HSCT in children. ..
- Zenz T, Häbe S, Denzel T, Mohr J, Winkler D, Bühler A, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood. 2009;114:2589-97 pubmed publisher..Alemtuzumab is effective irrespective of genetic high-risk subgroups with TP53 mutations. These clinical trials are registered at www.clinicaltrials.gov as #NCT00274976. ..
- Chaudhury S, Auerbach A, Kernan N, Small T, Prockop S, Scaradavou A, et al. Fludarabine-based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with Fanconi anaemia. Br J Haematol. 2008;140:644-55 pubmed publisher..These are encouraging results of T-cell-depleted transplants from alternative donors using fludarabine-based cytoreduction in 18 high-risk patients with Fanconi anaemia, with no evidence of rejection and minimal GVHD. ..
- Trachootham D, Zhang H, Zhang W, Feng L, Du M, Zhou Y, et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism. Blood. 2008;112:1912-22 pubmed publisher..Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation. ..
- Foon K, Boyiadzis M, Land S, Marks S, Raptis A, Pietragallo L, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:498-503 pubmed publisher..FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and our data demonstrated FCR-Lite can be safely administered in the community setting. ..
- Pepper C, Lin T, Pratt G, Hewamana S, Brennan P, Hiller L, et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood. 2008;112:3807-17 pubmed publisher..The close correlation between Mcl-1 expression and V(H) gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis. ..
- Cejkova S, Rocnova L, Potesil D, Smardova J, Novakova V, Chumchalova J, et al. Presence of heterozygous ATM deletion may not be critical in the primary response of chronic lymphocytic leukemia cells to fludarabine. Eur J Haematol. 2009;82:133-42 pubmed publisher..The presence of ATM (11q22-23) deletion in the CLL cells should not be considered an indication of resistance to fludarabine or its combination with rituximab. ..
- Phelps M, Lin T, Johnson A, Hurh E, Rozewski D, Farley K, et al. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood. 2009;113:2637-45 pubmed publisher..These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity. ..