Response of Patients with Leukemia to 8-Azaguanine

Colsky, Jacob; Meiselas, Leonard E.; Rosen, Sigmund J.; Schulman, Irving

doi:10.1182/blood.v10.5.482.482

Cited by 16 publications

(8 citation statements)

References 10 publications

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“…It may also be toxic due to its incorporation into RNA [ 35 ]. Despite some benefits to leukemia patients, adverse dermatological reactions, nausea and vomiting limit its use [ 36 ]. Additional analysis is required to assess possible benefits, if any, of 8-azaguanine either alone or in combination with PI3K antagonists or other inhibitors for Pten/p53-deficient TNBC.…”

Section: Discussionmentioning

confidence: 99%

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

et al. 2016

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BackgroundTriple-negative breast cancer (TNBC), an aggressive disease comprising several subtypes including basal-like and claudin-low, involves frequent deletions or point mutations in TP53, as well as loss of PTEN. We previously showed that combined deletion of both tumor suppressors in the mouse mammary epithelium invariably induced claudin-low-like TNBC. The effect of p53 mutation plus Pten deletion on mammary tumorigenesis and whether this combination can induce basal-like TNBC in the mouse are unknown.MethodsWAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated in which Pten is deleted and a p53-R270H mutation in the DNA-binding domain is induced upon expression of Cre-recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, transcriptional profiling [GEO-GSE75989], bioinformatics, high-throughput (HTP) FDA drug screen as well as orthotopic injection to quantify tumor-initiating cells (TICs) and tail vein injection to identify lung metastasis.ResultsCombined Pten deletion plus induction of p53-R270H mutation accelerated formation of four distinct mammary tumors including poorly differentiated adenocarcinoma (PDA) and spindle/mesenchymal-like lesions. Transplantation assays revealed highest frequency of TICs in PDA and spindle tumors compared with other subtypes. Hierarchical clustering demonstrated that the PDA and spindle tumors grouped closely with human as well as mouse models of basal and claudin-low subtypes, respectively. HTP screens of primary Pten∆:p53∆ vs. Pten∆:p53R270H spindle tumor cells with 1120 FDA-approved drugs identified 8-azaguanine as most potent for both tumor types, but found no allele-specific inhibitor. A gene set enrichment analysis revealed increased expression of a metastasis pathway in Pten∆:p53R270H vs. Pten∆:p53∆ spindle tumors. Accordingly, following tail vein injection, both Pten∆:p53R270H spindle and PDA tumor cells induced lung metastases and morbidity significantly faster than Pten∆:p53∆ double-deletion cells, and this was associated with the ability of Pten∆:p53R270H tumor cells to upregulate E-cadherin expression in lung metastases.ConclusionsOur results demonstrate that WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H mice represent a tractable model to study basal-like breast cancer because unlike p53 deletion, p53R270H mutation in the mouse does not skew tumors toward the claudin-low subtype. The WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H mice develop basal-like breast cancer that is enriched in TICs, can readily form lung metastasis, and provides a preclinical model to study both basal-like and claudin-low TNBC in immune-competent mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0668-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

et al. 2016

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“…SP1 Antimetabolite (8-Azaguanine) used for antineoplastic activity and anisomycin a protein synthesis inhibitor. 8azaguanine has been used in leukemia (Colsky et al, 1955).…”

Section: Drug Descriptionmentioning

confidence: 99%

Identification of structural features in chemicals associated with cancer drug response: a systematic data-driven analysis

et al. 2014

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Motivation: Analysis of relationships of drug structure to biological response is key to understanding off-target and unexpected drug effects, and for developing hypotheses on how to tailor drug therapies. New methods are required for integrated analyses of a large number of chemical features of drugs against the corresponding genome-wide responses of multiple cell models.Results: In this article, we present the first comprehensive multi-set analysis on how the chemical structure of drugs impacts on genome-wide gene expression across several cancer cell lines [Connectivity Map (CMap) database]. The task is formulated as searching for drug response components across multiple cancers to reveal shared effects of drugs and the chemical features that may be responsible. The components can be computed with an extension of a recent approach called Group Factor Analysis. We identify 11 components that link the structural descriptors of drugs with specific gene expression responses observed in the three cell lines and identify structural groups that may be responsible for the responses. Our method quantitatively outperforms the limited earlier methods on CMap and identifies both the previously reported associations and several interesting novel findings, by taking into account multiple cell lines and advanced 3D structural descriptors. The novel observations include: previously unknown similarities in the effects induced by 15-delta prostaglandin J2 and HSP90 inhibitors, which are linked to the 3D descriptors of the drugs; and the induction by simvastatin of leukemia-specific response, resembling the effects of corticosteroids.Availability and implementation: Source Code implementing the method is available at: http://research.ics.aalto.fi/mi/software/GFAsparseContact: suleiman.khan@aalto.fi or samuel.kaski@aalto.fiSupplementary Information: Supplementary data are available at Bioinformatics online.

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“…However, latamoxef has been associated with prolonged bleeding time and several cases of coagulopathy (Weitekamp & Aber, ; Brown et al ., ). 8‐azaguanine closely resembles guanine and appears to be competitive with it in the metabolism of living organisms (Colsky et al ., ). It has been shown to cause retardation of some malignant neoplasms when administered to tumours in animals (Colsky et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…8‐azaguanine closely resembles guanine and appears to be competitive with it in the metabolism of living organisms (Colsky et al ., ). It has been shown to cause retardation of some malignant neoplasms when administered to tumours in animals (Colsky et al ., ). Further study of the small molecules in our result may provide the groundwork for developing new therapies for the treatment of prostate cancer.…”

Section: Discussionmentioning

confidence: 97%

A computational bioinformatics analysis of gene expression identifies candidate agents for prostate cancer

Geng

et al. 2013

Andrologia

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Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males worldwide. Although great progress has been made, the molecular mechanisms of prostate cancer are far from being fully understood and treatment of this disease remains palliative. In this study, we sought to explore the molecular mechanism of prostate cancer and then identify biologically active small molecules capable of targeting prostate cancer using a computational bioinformatics analysis of gene expression. A total of 3068 genes, involved in cell communication, development, localisation and cell proliferation, were differentially expressed in prostate cancer samples compared with normal controls. Pathways associated with signal transduction, immune response and tumorigenesis were dysfunctional. Further, we identified a group of small molecules capable of reversing prostate cancer. These candidate agents may provide the groundwork for a combination therapy approach for prostate cancer. However, further evaluation for their potential use in the treatment of prostate cancer is still needed.

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Response of Patients with Leukemia to 8-Azaguanine

Cited by 16 publications

References 10 publications

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

Identification of structural features in chemicals associated with cancer drug response: a systematic data-driven analysis

A computational bioinformatics analysis of gene expression identifies candidate agents for prostate cancer

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