The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo.

Abstract:

:Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC(50) values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.

journal_name

Mol Cancer Ther

authors

Wickström M,Johnsen JI,Ponthan F,Segerström L,Sveinbjörnsson B,Lindskog M,Lövborg H,Viktorsson K,Lewensohn R,Kogner P,Larsson R,Gullbo J

doi

10.1158/1535-7163.MCT-07-0156

subject

Has Abstract

pub_date

2007-09-01 00:00:00

pages

2409-17

issue

9

eissn

1535-7163

issn

1538-8514

pii

6/9/2409

journal_volume

6

pub_type

杂志文章
  • ANG4043, a novel brain-penetrant peptide-mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice.

    abstract::Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrie...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0399

    authors: Regina A,Demeule M,Tripathy S,Lord-Dufour S,Currie JC,Iddir M,Annabi B,Castaigne JP,Lachowicz JE

    更新日期:2015-01-01 00:00:00

  • Meeting report on the second targeted tumor therapies.

    abstract::This meeting report on the fourth Fabisch Symposium for Cancer Research and Molecular Biology describes the aims of the international meeting, the main topics of the presentations, and the highlights of the conference. The fourth Fabisch Symposium was the second on Targeted Tumor Therapies and held from April 1-3, 200...

    journal_title:Molecular cancer therapeutics

    pub_type:

    doi:10.1158/1535-7163.MCT-09-0491

    authors: Bachran C,Fuchs H

    更新日期:2010-01-01 00:00:00

  • The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells.

    abstract::DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1α (HIF-1α) activity in human cancer cells. In particular, we provi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0729

    authors: Bertozzi D,Marinello J,Manzo SG,Fornari F,Gramantieri L,Capranico G

    更新日期:2014-01-01 00:00:00

  • Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones.

    abstract::Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0760

    authors: Whibley CE,McPhail KL,Keyzers RA,Maritz MF,Leaner VD,Birrer MJ,Davies-Coleman MT,Hendricks DT

    更新日期:2007-09-01 00:00:00

  • JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling.

    abstract::Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and t...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0502

    authors: Song L,Rawal B,Nemeth JA,Haura EB

    更新日期:2011-03-01 00:00:00

  • DNAzyme technology and cancer therapy: cleave and let die.

    abstract::Novel molecules are constantly being discovered and developed to find better means of managing debilitating and fatal diseases, which include cancer in its multiple forms. Among these molecules, and as a direct consequence of a better understanding of the molecular basis of diseases, are those falling within the class...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-07-0510

    authors: Dass CR,Choong PF,Khachigian LM

    更新日期:2008-02-01 00:00:00

  • FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer.

    abstract::Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor FLIP is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell d...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0211

    authors: McLaughlin KA,Nemeth Z,Bradley CA,Humphreys L,Stasik I,Fenning C,Majkut J,Higgins C,Crawford N,Holohan C,Johnston PG,Harrison T,Hanna GG,Butterworth KT,Prise KM,Longley DB

    更新日期:2016-10-01 00:00:00

  • Decreased miR-340 expression in bone marrow is associated with liver metastasis of colorectal cancer.

    abstract::Studies have shown the prognostic significance of disseminated tumor cells (DTC) in bone marrow of patients with colorectal cancer. However, the molecular characteristics of DTCs, including their miRNA expression profiles, remain mostly unknown. In this study, we analyzed the miRNA expression of DTCs in bone marrow. E...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0571

    authors: Takeyama H,Yamamoto H,Yamashita S,Wu X,Takahashi H,Nishimura J,Haraguchi N,Miyake Y,Suzuki R,Murata K,Ohue M,Kato T,Takemasa I,Mizushima T,Ishii H,Mimori K,Doki Y,Mori M

    更新日期:2014-04-01 00:00:00

  • TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies.

    abstract::Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effect...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-0558

    authors: Rodríguez-Ruiz ME,Rodríguez I,Mayorga L,Labiano T,Barbes B,Etxeberria I,Ponz-Sarvise M,Azpilikueta A,Bolaños E,Sanmamed MF,Berraondo P,Calvo FA,Barcelos-Hoff MH,Perez-Gracia JL,Melero I

    更新日期:2019-03-01 00:00:00

  • Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo.

    abstract::The advent of multikinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor has revolutionized the treatment of highly angiogenic malignancies such as renal cell carcinoma. Interestingly, several such inhibitors are commercially available, and they each possess diverse specific beneficial and...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0119

    authors: Liu JY,Park SH,Morisseau C,Hwang SH,Hammock BD,Weiss RH

    更新日期:2009-08-01 00:00:00

  • PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer.

    abstract::PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mecha...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-0444

    authors: Carpinelli P,Ceruti R,Giorgini ML,Cappella P,Gianellini L,Croci V,Degrassi A,Texido G,Rocchetti M,Vianello P,Rusconi L,Storici P,Zugnoni P,Arrigoni C,Soncini C,Alli C,Patton V,Marsiglio A,Ballinari D,Pesenti E,Fan

    更新日期:2007-12-01 00:00:00

  • Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer-binding protein delta-dependent pathway.

    abstract::Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells. This up-regulation is dependent on signaling by phospho-Stat3 (signal transducers and activators of transcription). ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Hutt JA,DeWille JW

    更新日期:2002-06-01 00:00:00

  • Aurora kinase inhibitors--rising stars in cancer therapeutics?

    abstract::Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-09-0765

    authors: Dar AA,Goff LW,Majid S,Berlin J,El-Rifai W

    更新日期:2010-02-01 00:00:00

  • Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells.

    abstract::Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0298

    authors: Wang R,Li Y,Gong P,Gabrilove J,Waxman S,Jing Y

    更新日期:2018-09-01 00:00:00

  • Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer.

    abstract::Constitutively activated STAT3 and STAT5 are expressed in a wide variety of human malignancies including solid and hematopoietic cancers and often correlate with a poor prognosis and resistance to multiple therapies. Given the well established role of STAT3 in tumorigenesis, inhibition of Janus-activated kinase 2 (JAK...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0951

    authors: Seavey MM,Lu LD,Stump KL,Wallace NH,Hockeimer W,O'Kane TM,Ruggeri BA,Dobrzanski P

    更新日期:2012-04-01 00:00:00

  • Comparative Oncology Evaluation of Intravenous Recombinant Oncolytic Vesicular Stomatitis Virus Therapy in Spontaneous Canine Cancer.

    abstract::Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single-sh...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0432

    authors: Naik S,Galyon GD,Jenks NJ,Steele MB,Miller AC,Allstadt SD,Suksanpaisan L,Peng KW,Federspiel MJ,Russell SJ,LeBlanc AK

    更新日期:2018-01-01 00:00:00

  • Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.

    abstract::Vascular endothelial growth factor (VEGF)-induced endothelial cell migration is an important component of tumor angiogenesis. Rho and Rho-associated kinase (ROCK) are key regulators of focal adhesion, stress fiber formation, and thus cell motility. Inhibitors of this pathway have been shown to inhibit endothelial cell...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0689

    authors: Yin L,Morishige K,Takahashi T,Hashimoto K,Ogata S,Tsutsumi S,Takata K,Ohta T,Kawagoe J,Takahashi K,Kurachi H

    更新日期:2007-05-01 00:00:00

  • BH3-only proteins Mcl-1 and Bim as well as endonuclease G are targeted in spongistatin 1-induced apoptosis in breast cancer cells.

    abstract::Spongistatin 1, a marine experimental substance with chemotherapeutic potential, induces apoptosis and inhibits clonogenic survival of MCF-7 cells. Regarding the apoptotic signaling pathways of spongistatin 1, we present two major facts. Firstly, spongistatin 1-induced cell death, mainly caspase-independent, involves ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-1179

    authors: Schneiders UM,Schyschka L,Rudy A,Vollmar AM

    更新日期:2009-10-01 00:00:00

  • Inhibition of AKT Sensitizes Cancer Cells to Antineoplastic Drugs by Downregulating Flap Endonuclease 1.

    abstract::DNA repair mechanisms are crucial for cell survival. It increases the cancer cell's ability to resist DNA damage. FEN1 is involved in DNA replication and repair, specifically long-patch base excision repair. Although the gene function and post-translational modification of FEN1 are well studied, the regulatory mechani...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-1215

    authors: Zhu H,Wu C,Wu T,Xia W,Ci S,He W,Zhang Y,Li L,Zhou S,Zhang J,Edick AM,Zhang A,Pan FY,Hu Z,He L,Guo Z

    更新日期:2019-12-01 00:00:00

  • Azacytidine causes complex DNA methylation responses in myeloid leukemia.

    abstract::Aberrant DNA methylation patterns play an important role in the pathogenesis of hematologic malignancies. The DNA methyltransferase inhibitors azacytidine and decitabine have shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), but their precise mode of action remains to be establish...

    journal_title:Molecular cancer therapeutics

    pub_type: 临床试验,杂志文章

    doi:10.1158/1535-7163.MCT-08-0411

    authors: Stresemann C,Bokelmann I,Mahlknecht U,Lyko F

    更新日期:2008-09-01 00:00:00

  • Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft

    abstract:OBJECTIVE:Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Raben D,Bianco C,Damiano V,Bianco R,Melisi D,Mignogna C,D'Armiento FP,Cionini L,Bianco AR,Tortora G,Ciardiello F,Bunn P

    更新日期:2004-08-01 00:00:00

  • Inhibition of Nucleotide Synthesis Targets Brain Tumor Stem Cells in a Subset of Glioblastoma.

    abstract::Inhibition of both the de novo (DNP) and salvage (NSP) pathways of nucleoside synthesis has been demonstrated to impair leukemia cells. We endeavored to determine whether this approach would be efficacious in glioblastoma. To diminish nucleoside biosynthesis, we utilized compound DI-39, which selectively targets NSP, ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0982

    authors: Laks DR,Ta L,Crisman TJ,Gao F,Coppola G,Radu CG,Nathanson DA,Kornblum HI

    更新日期:2016-06-01 00:00:00

  • Mechanism of drug efficacy within the EGF receptor revealed by microsecond molecular dynamics simulation.

    abstract::The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine k...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0644-T

    authors: Wan S,Wright DW,Coveney PV

    更新日期:2012-11-01 00:00:00

  • DCLK1-Isoform2 Alternative Splice Variant Promotes Pancreatic Tumor Immunosuppressive M2-Macrophage Polarization.

    abstract::Tumor-associated M2-macrophages are one of the most abundant immunosuppressive cell types in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the molecular mechanisms responsible for the generation of M2-macrophages are unclear. Here, we demonstrated that overexpression of DCLK1-isofo...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-0776

    authors: Chandrakesan P,Panneerselvam J,May R,Weygant N,Qu D,Berry WR,Pitts K,Stanger BZ,Rao CV,Bronze MS,Houchen CW

    更新日期:2020-07-01 00:00:00

  • Inhibition of cell growth by NB1011 requires high thymidylate synthase levels and correlates with p53, p21, bax, and GADD45 induction.

    abstract::NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule anticancer agent. NB1011 is selectively active against tumor cells expressing high levels of thymidylate synthase (TS), a critical enzyme in DNA biosynthesis. NB1011 is different from the current TS-targeted drugs, ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Neuteboom ST,Karjian PL,Boyer CR,Beryt M,Pegram M,Wahl GM,Shepard HM

    更新日期:2002-04-01 00:00:00

  • Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival.

    abstract::We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Whitehead CM,Earle KA,Fetter J,Xu S,Hartman T,Chan DC,Zhao TL,Piazza G,Klein-Szanto AJ,Pamukcu R,Alila H,Bunn PA Jr,Thompson WJ

    更新日期:2003-05-01 00:00:00

  • Algorithmic guided screening of drug combinations of arbitrary size for activity against cancer cells.

    abstract::The standard treatment for most advanced cancers is multidrug therapy. Unfortunately, combinations in the clinic often do not perform as predicted. Therefore, to complement identifying rational drug combinations based on biological assumptions, we hypothesized that a functional screen of drug combinations, without lim...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0937

    authors: Zinner RG,Barrett BL,Popova E,Damien P,Volgin AY,Gelovani JG,Lotan R,Tran HT,Pisano C,Mills GB,Mao L,Hong WK,Lippman SM,Miller JH

    更新日期:2009-03-01 00:00:00

  • Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides.

    abstract::STAT3 has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of antitumor immunity. Given the ubiquity of dysregulated STAT3 activi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-20-0599

    authors: Shiah JV,Grandis JR,Johnson DE

    更新日期:2020-11-17 00:00:00

  • Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy.

    abstract::The tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular eve...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0627

    authors: Li Y,Guessous F,DiPierro C,Zhang Y,Mudrick T,Fuller L,Johnson E,Marcinkiewicz L,Engelhardt M,Kefas B,Schiff D,Kim J,Abounader R

    更新日期:2009-02-01 00:00:00

  • Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells.

    abstract::TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor (FGF)-inducible 14 (Fn14) are a TNF superfamily ligand-receptor pair involved in many cellular processes including proliferation, migration, differentiation, inflammation, and angiogenesis. The Fn14 receptor is expressed at relatively low levels i...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0161

    authors: Zhou H,Marks JW,Hittelman WN,Yagita H,Cheung LH,Rosenblum MG,Winkles JA

    更新日期:2011-07-01 00:00:00