Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM

Alonso, Roberto; López‐Guerra, Mònica; Upshaw, Ramanda; Bantia, Shanta; Smal, Caroline; Bontemps, Françoise; Manz, Chantal Y.; Mehrling, Thomas; Villamor, Neus; Campo, Elı́as; Montserrat, Emili; Colomer, Dolors

doi:10.1182/blood-2009-02-207654

Cited by 49 publications

(47 citation statements)

References 49 publications

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“…Data with these stromal cells are consistent with recent results in normal lymphocytes. 51 Collectively, the MSC data (from current work) and normal lymphocytes 51 suggested that forodesine has some selectivity to CLL lymphocytes while sparing normal cells.…”

Section: Discussionmentioning

confidence: 70%

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Balakrishnan¹,

Burger

Quiroga

et al. 2010

Blood

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Section: Discussionmentioning

confidence: 70%

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Balakrishnan¹,

Burger

Quiroga

et al. 2010

Blood

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“…This is based on studies of genetic PNP-deficiency syndrome in which 2'-deoxyguanosine accumulates in plasma and deoxyguanosine triphosphate (dGTP) in lymphocytes, accordingly leading to dGTP-directed inhibition of DNA synthesis and cell death (37). Forodesine (BCX-1777) is a novel PNP inhibitor which induces apoptosis of chronic lymphocytic leukemia (CLL) cells (38 advanced, Fludarabine-refractory CLL (39). Silencing PNP inhibited proliferation of IMC-3 cells in our present study.…”

Section: Discussionmentioning

confidence: 72%

Identification of novel molecular targets regulated by tumor suppressive miR-1/miR-133a in maxillary sinus squamous cell carcinoma

Nohata

Hanazawa²,

Kikkawa³

et al. 2011

Int J Oncol

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Abstract. Based on our microRNA (miRNA) expression signature analysis of maxillary sinus squamous cell carcinoma (MSSCC), we found that miR-1 and miR-133a were significantly reduced in tumor tissues. Quantitative real-time RT-PCR revealed that the expression levels of miR-1 and miR-133a were significantly downregulated in clinical MSSCC tumor tissues compared with normal tissues. We focused on the functional significance of miR-1 and miR-133a in cancer cells and identification of the novel cancer networks regulated by these miRNAs in MSSCC. Restoration of downregulated miRNAs (miR-1 or miR-133a) in cancer cells revealed that both miRNAs significantly inhibited cancer cell proliferation and induced cell apoptosis. Molecular target identification of these miRNAs showed that transgelin 2 (TAGLN2) and purine nucleoside phosphorylase (PNP) were regulated by miR-1 and miR-133a. Both TAGLN2 and PNP mRNA expression levels were significantly upregulated in clinical MSSCC tumor tissues. Silencing studies of target genes demonstrated that both genes inhibited cancer cell proliferation. The identification of novel miR-1/miR133a-regulated cancer pathways could provide new insights into potential molecular mechanisms of MSSCC oncogenesis.

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“…Forodesine is a transition-state inhibitor of the purine nucleoside phosphorylase with anti-leukemic activity, bypassing TP53-mediated cell death. In vitro studies showed encouraging activity of single-agent forodesine and its combination with rituximab, regardless of ATM and TP53 status [32]. Lenalidomide has recently shown activity in relapsed patients with CLL with 11q or 17p deletions, with an ORR of 38%, CR of 19%, and median PFS of 12.1 months [33].…”

Section: Discussionmentioning

confidence: 99%

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

et al. 2013

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Treatment of patients with B-cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B-cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m 2 , Day 1), plus bendamustine (70 mg/m 2 , days 1-2), and cytarabine (800 mg/m 2 , Day 1-3; R-BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high-risk R/R CLL. All patients (median age 60 years, range 53-74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy-chain variable region, and were heavily pretreated (1-5, median three previous lines). Overall, R-BAC was well tolerated with limited non-hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow-up of 17 months, median progression-free survival was 16 months while median overall survival (OS) was not reached (1-year OS: 75 6 13%). R-BAC is an active regimen in R/R heavily pretreated high-risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy. Am. J.

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Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM

Cited by 49 publications

References 49 publications

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Identification of novel molecular targets regulated by tumor suppressive miR-1/miR-133a in maxillary sinus squamous cell carcinoma

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

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