A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models

Emanuel, Stuart L.; Gruninger, Robert H.; Fuentes‐Pesquera, Angel R.; Connolly, Peter J.; Seamon, Jennifer A.; Hazel, Susan J.; Tominovich, Rose; Hollister, Beth; Napier, Cheryl; D’Andrea, Michael R.; Reuman, Michael; Bignan, Gilles; Tuman, Robert W.; Johnson, Dana L.; Moffatt, D. L.; Batchelor, Mark; Foley, Anne; O’Connell, James P.; Allen, Rodger A.; Perry, Mark; Jolliffe, Linda K.; Middleton, Steven A.

doi:10.1124/mol.104.000638

Cited by 41 publications

(34 citation statements)

References 33 publications

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“…The effect of JNJ-7706621 on the growth of tumors in female nu/nu mice was done as previously reported (21). Briefly, animals were implanted s.c. with 1 mm 3 A375 tumor fragments in the hindflank.…”

Section: Methodsmentioning

confidence: 99%

“…The Aurora kinase assays were done with 10 Amol/L ATP and a peptide containing a dual repeat of the kemptide phosphorylation motif. Assays for inhibition of additional kinases were done as described (21). Antiproliferative activity was assessed in a cell proliferation assay measuring 14 C-thymidine incorporation into cellular DNA as described (21).…”

Section: Methodsmentioning

confidence: 99%

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The In vitro and In vivo Effects of JNJ-7706621: A Dual Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases

et al. 2005

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Modulation of aberrant cell cycle regulation is a potential therapeutic strategy applicable to a wide range of tumor types. JNJ-7706621 is a novel cell cycle inhibitor that showed potent inhibition of several cyclin-dependent kinases (CDK) and Aurora kinases and selectively blocked proliferation of tumor cells of various origins but was about 10-fold less effective at inhibiting normal human cell growth in vitro. In human cancer cells, treatment with JNJ-7706621 inhibited cell growth independent of p53, retinoblastoma, or P-glycoprotein status; activated apoptosis; and reduced colony formation. At low concentrations, JNJ-7706621 slowed the growth of cells and at higher concentrations induced cytotoxicity. Inhibition of CDK1 kinase activity, altered CDK1 phosphorylation status, and interference with downstream substrates such as retinoblastoma were also shown in human tumor cells following drug treatment. Flow cytometric analysis of DNA content showed that JNJ-7706621 delayed progression through G 1 and arrested the cell cycle at the G 2 -M phase. Additional cellular effects due to inhibition of Aurora kinases included endoreduplication and inhibition of histone H3 phosphorylation. In a human tumor xenograft model, several intermittent dosing schedules were identified that produced significant antitumor activity. There was a direct correlation between total cumulative dose given and antitumor effect regardless of the dosing schedule. These results show the therapeutic potential of this novel cell cycle inhibitor and support clinical evaluation of JNJ-7706621. (Cancer Res 2005; 65(19): 9038-46)

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The In vitro and In vivo Effects of JNJ-7706621: A Dual Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases

et al. 2005

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“…(A) Blockade of bFGF and VEGF with neutralizing antibodies or signal transduction antagonists significantly decreases the angiogenic response of the explants (Villaschi and Nicosia, 1993;Nicosia et al, 1997;Emanuel et al, 2004). (B) Pharmacologic inhibition or genetic disruption of CXCR2, the receptor of CXCL1, CXCL2, and CXCL3, reduces aortic angiogenesis (Gelati et al, 2008).…”

Section: Angiogenesis In the Aortic Ring Model Is Induced By Injurymentioning

confidence: 99%

Paracrine regulation of angiogenesis by different cell types in the aorta ring model

Nicosia¹,

Zorzi²,

Ligresti³

et al. 2011

Int. J. Dev. Biol.

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The development of blood vessels during angiogenesis is the result of paracrine interactions between tube-forming endothelial cells and angiogenic factor-producing nonendothelial cells. This process can be reproduced and studied under chemically defined culture conditions by culturing vascular explants in three-dimensional gels of extracellular matrix. Rings of rat or mouse aorta cultured in collagen, fibrin or basement membrane gels produce angiogenic outgrowths composed of a mixed population of endothelial cells and nonendothelial cells. Aortic angiogenesis is regulated by endogenous angiogenic factors, inflammatory cytokines, chemokines, extracellular matrix molecules, and proteolytic enzymes produced by cells of the vessel wall in response to the injury of the dissection procedure. In this paper, we review how macrophages, mural cells and fibroblasts regulate different stages of the angiogenic process, from the formation of immature endothelial sprouts to the reabsorption of the neovessels. We also describe how aortic cultures can be used to study interactions between angiogenic outgrowths and nonvascular cell types such as bone marrow macrophages, platelets or cancer cells. Morphologic, genetic and functional studies of this model have provided invaluable information on how vessels form, mature, interact with nonvascular cell types, and are eventually reabsorbed. Further analysis of the paracrine cross-talk between aortic endothelial and nonendothelial cells is likely to provide new insights into the angiogenic process and its key mechanisms.

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“…Antiproliferative activity was assessed in a cell proliferation assay that measured 14 C-thymidine incorporation into cellular DNA as previously described (22). All cell types used in the assay were plated at 4,000 cells/well and exposed to compound for either 48 or 96 hours.…”

Section: Cell Proliferation Assays and Determination Of Resistance Famentioning

confidence: 99%

Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor

Seamon

Rugg

Emanuel

et al. 2006

Molecular Cancer Therapeutics

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Cell cycle kinase inhibitors have advanced into clinical trials in oncology. One such molecule, JNJ-7706621, is a broad-spectrum inhibitor of the cyclin-dependent kinases and Aurora kinases that mediate G 2 -M arrest and inhibits tumor growth in xenograft models. To determine the putative mechanisms of resistance to JNJ-7706621 that might be encountered in the clinic, the human epithelial cervical carcinoma cell line (HeLa) was exposed to incrementally increasing concentrations of JNJ-7706621. The resulting resistant cell population, designated HeLa-6621, was 16-fold resistant to JNJ-7706621, cross-resistant to mitoxantrone (15-fold) and topotecan (6-fold), and exhibited reduced intracellular drug accumulation of JNJ-7706621. ABCG2 was highly overexpressed at both the mRNA (f163-fold) and protein levels. The functional role of ABCG2 in mediating resistance to JNJ-7706621 was consistent with the following findings: (a) an ABCG2 inhibitor, fumitremorgin C, restored the sensitivity of HeLa-6621 cells to JNJ-7706621 and to mitoxantrone; (b) human embryonic kidney-293 cells transfected with ABCG2 were resistant to both JNJ-7706621 and mitoxantrone; and (c) resistant cells that were removed from the drug for 12 weeks and reverted to susceptibility to JNJ-7706621 showed near-normal ABCG2 RNA levels. ABCG2 is likely to limit the bioavailability of JNJ-7706621 because oral administration of JNJ-7706621 to Bcrp (the murine homologue of ABCG2) knockout mice resulted in an increase in the plasma concentration of JNJ-7706621 compared with wild-type mice. These findings indicate that ABCG2 mediates the resistance to JNJ-7706621 and alters the absorption of the compound following administration.

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A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models

Cited by 41 publications

References 33 publications

The In vitro and In vivo Effects of JNJ-7706621: A Dual Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases

The In vitro and In vivo Effects of JNJ-7706621: A Dual Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases

Paracrine regulation of angiogenesis by different cell types in the aorta ring model

Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor

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