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1.
Eur J Pharmacol ; 712(1-3): 8-15, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23623934

ABSTRACT

Excessive secretion of parathyroid hormone-related protein (PTHrP) by tumors stimulates bone resorption and increases renal tubular reabsorption of calcium, resulting in hypercalcemia of malignancy. We investigated the ability of cinacalcet, an allosteric modulator of the calcium-sensing receptor, to attenuate hypercalcemia by assessing its effects on blood ionized calcium, serum PTHrP, and calcium-sensing receptor mRNA in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors. Cinacalcet effectively decreased hypercalcemia in a dose- and enantiomer-dependent manner; furthermore, cinacalcet normalized phosphorus levels, but did not affect serum PTHrP. Ribonuclease protection assay results demonstrated presence of PTHrP receptor, but not calcium-sensing receptor mRNA in C26-DCT tumors. The mechanism by which cinacalcet lowered serum calcium was investigated in parathyroidectomized rats (i.e., without PTH) made hypercalcemic by PTHrP. Cinacalcet attenuated PTHrP-mediated elevations in blood ionized calcium, which were accompanied by increased plasma calcitonin. Taken together these results suggest that the cinacalcet-mediated decrease in serum calcium is not the result of a direct effect on tumor cells, but rather is the result of increased calcitonin release. In summary, cinacalcet effectively reduced tumor-mediated hypercalcemia and corrected hypophosphatemia in mice. Further investigation of cinacalcet for treatment of hypercalcemia of malignancy is warranted.


Subject(s)
Colonic Neoplasms/pathology , Hypercalcemia/drug therapy , Leydig Cell Tumor/pathology , Naphthalenes/pharmacology , Animals , Calcitonin/metabolism , Calcium/blood , Calcium/metabolism , Cell Line, Tumor , Cinacalcet , Colonic Neoplasms/complications , Female , Gene Expression Regulation/drug effects , Hypercalcemia/etiology , Hypercalcemia/metabolism , Hypercalcemia/pathology , Leydig Cell Tumor/complications , Male , Mice , Naphthalenes/therapeutic use , Parathyroid Hormone-Related Protein/genetics , Parathyroid Hormone-Related Protein/metabolism , Rats , Receptors, Calcium-Sensing/genetics
2.
Mol Cancer ; 11: 70, 2012 Sep 19.
Article in English | MEDLINE | ID: mdl-22992329

ABSTRACT

BACKGROUND: Non-small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations. RESULTS: Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro. CONCLUSIONS: These data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung , Indoles/pharmacology , Lung Neoplasms , Niacinamide/analogs & derivatives , Taxoids/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/administration & dosage , Cisplatin/pharmacology , Docetaxel , Female , Gene Expression , Humans , Indoles/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Nude , Mutation , Niacinamide/administration & dosage , Niacinamide/pharmacology , Oligonucleotides , Taxoids/administration & dosage , Tumor Burden/drug effects , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor Assays
3.
Mol Cancer ; 11: 47, 2012 Jul 25.
Article in English | MEDLINE | ID: mdl-22830443

ABSTRACT

BACKGROUND: Successful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue. METHODS: We examined the correlation of panitumumab (an anti-epidermal growth factor [EGFR] antibody) tumor penetration and EGFR saturation, a potential obstacle in large molecule drug delivery, using pharmacokinetics, pharmacodynamics, and tumor growth rate in an A431 epidermoid carcinoma xenograft model of human cancer. To determine receptor saturation, receptor occupancy, and levels of proliferation markers, immunohistochemical and flow cytometric methods were used. Pharmacokinetic data and modeling were used to calculate growth characteristics of panitumumab-treated tumors. RESULTS: Treatment with panitumumab in vivo inhibited pEGFR, Ki67 and pMAPK levels vs control. Tumor penetration and receptor saturation were dose- and time-dependent, reaching 100% and 78%, respectively. Significant tumor inhibition and eradication (p < 0.05) were observed; plasma concentration associated with tumor eradication was estimated to be 0.2 µg/ml. The tumor inhibition model was able to describe the mean tumor growth and death rates. CONCLUSIONS: These data demonstrate that the antitumor activity of panitumumab correlates with its ability to penetrate into tumor tissue, occupy and inhibit activation of EGFR, and inhibit markers of proliferation and MAPK signaling.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Neoplasms/metabolism , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Humans , Ligands , Mice , Mice, Nude , Neoplasms/drug therapy , Neoplasms/pathology , Panitumumab , Phosphorylation/drug effects , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
4.
Mol Cancer Res ; 6(8): 1337-46, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18708365

ABSTRACT

Damage to the gastrointestinal mucosa is a common dose-limiting toxicity of several anticancer therapies. Until recently, adequate control of oral mucositis was considered a significant unmet medical need, with most available treatments providing only palliative benefits without protecting the gastrointestinal epithelium from the damaging effects of cancer therapy. In 2005, palifermin [recombinant human keratinocyte growth factor (KGF)] was approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Current trials are investigating the use of palifermin in solid tumor settings. The objective of this study was to determine whether combining palifermin with different chemotherapeutic or biological agents affected the antitumor activity of these agents in human head and neck (FaDu) and colorectal (HT29) carcinoma xenograft models. Nude CD1 mice were injected with 1 x 10(7) of either FaDu or HT29 cells, which express both KGF and epithelial growth factor receptors. Animals were treated with palifermin in various combinations with chemotherapeutic (5-fluorouracil and cisplatin) and/or biological (bevacizumab, cetuximab, and panitumumab) agents. Palifermin alone had no effect on either FaDu or HT29 tumor growth. Palifermin did not affect the therapeutic efficacy of 5-fluorouracil, cisplatin, cetuximab, bevacizumab, or panitumumab in any of the two- or three-way drug combinations tested in either model. The results of this study showed that palifermin did not promote the growth of two carcinoma cell lines that express functional KGF receptors and did not protect these tumor cells from the antitumor effects of several chemotherapeutic and biological agents.


Subject(s)
Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Fibroblast Growth Factor 7/therapeutic use , Head and Neck Neoplasms/drug therapy , Xenograft Model Antitumor Assays , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Bevacizumab , Cell Line, Tumor , Cell Proliferation/drug effects , Cetuximab , Cisplatin/pharmacology , Cisplatin/therapeutic use , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Drug Therapy, Combination , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Fibroblast Growth Factor 7/pharmacology , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Mice , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism
5.
J Med Chem ; 51(6): 1668-80, 2008 Mar 27.
Article in English | MEDLINE | ID: mdl-18324759

ABSTRACT

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.


Subject(s)
Antineoplastic Agents/pharmacology , Endothelial Cells/drug effects , Naphthalenes/pharmacology , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Corneal Neovascularization/blood , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Female , Humans , Inhibitory Concentration 50 , Injections, Intravenous , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Stereoisomerism , Structure-Activity Relationship
6.
J Med Chem ; 51(6): 1649-67, 2008 Mar 27.
Article in English | MEDLINE | ID: mdl-18324761

ABSTRACT

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.


Subject(s)
Antineoplastic Agents/pharmacology , Endothelial Cells/drug effects , Naphthalenes/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Corneal Neovascularization/blood , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Female , Humans , Inhibitory Concentration 50 , Injections, Intravenous , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Stereoisomerism , Structure-Activity Relationship
7.
Cancer Res ; 66(17): 8715-21, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16951187

ABSTRACT

The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Indoles/therapeutic use , Niacinamide/analogs & derivatives , Proto-Oncogene Proteins c-kit/drug effects , Animals , Carcinoma, Squamous Cell/drug therapy , Cell Line , Cell Line, Tumor , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Female , Fibroblasts/drug effects , Humans , Indoles/chemical synthesis , Leukemia, Megakaryoblastic, Acute/drug therapy , Mice , Mice, Nude , Niacinamide/chemical synthesis , Niacinamide/therapeutic use , Oligonucleotides , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Skin/drug effects , Transplantation, Heterologous , Umbilical Veins/physiology
8.
Endocrinology ; 146(8): 3235-43, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15845617

ABSTRACT

Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone by inducing the expression of receptor activator for nuclear factor-kappaB ligand (RANKL), a protein that is essential for osteoclast formation, activation, and survival. RANKL does not influence renal calcium reabsorption, so RANKL inhibition is a rational approach to selectively block, and thereby reveal, the relative contribution of bone calcium to HHM. We used the RANKL inhibitor osteoprotegerin (OPG) to evaluate the role of osteoclast-mediated hypercalcemia in two murine models of HHM. Hypercalcemia was induced either by sc inoculation of syngeneic colon (C-26) adenocarcinoma cells or by sc injection of high-dose recombinant PTHrP (0.5 mg/kg, s.c., twice per day). In both models, OPG (0.2-5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg). OPG also caused greater reductions in osteoclast surface and biochemical markers of bone resorption compared with either bisphosphonate. In both models, hypercalcemia gradually returned despite clear evidence of ongoing suppression of bone resorption by OPG. These data demonstrate that osteoclasts and RANKL are important mediators of HHM, particularly in the early stages of the condition. Aggressive antiresorptive therapy with a RANKL inhibitor therefore might be a rational approach to controlling HHM.


Subject(s)
Adenocarcinoma/prevention & control , Bone Resorption/prevention & control , Carrier Proteins/antagonists & inhibitors , Colonic Neoplasms/prevention & control , Diphosphonates/pharmacology , Glycoproteins/pharmacology , Hypercalcemia/prevention & control , Membrane Glycoproteins/antagonists & inhibitors , Adenocarcinoma/blood , Animals , Antineoplastic Agents/pharmacology , Calcium/blood , Cell Line, Tumor , Colonic Neoplasms/blood , Disease Models, Animal , Humans , Hypercalcemia/etiology , Ligands , Mice , NF-kappa B/metabolism , Osteoprotegerin , Pamidronate , Parathyroid Hormone-Related Protein/physiology , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear , Receptors, Tumor Necrosis Factor
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