|
1
|
Wagner AM, Lanier OL, Savk A, Peppas NA. Polybasic nanogels for intracellular co-delivery of paclitaxel and carboplatin: a novel approach to ovarian cancer therapy. RSC PHARMACEUTICS 2025; 2:553-569. [PMID: 39990011 PMCID: PMC11843545 DOI: 10.1039/d4pm00330f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 02/08/2025] [Indexed: 02/25/2025]
Abstract
Ovarian cancer is one of the leading causes of cancer-related deaths in women, with limited progress in treatments despite decades of research. Common treatment protocols rely on surgical removal of tumors and chemotherapy drugs, such as paclitaxel and carboplatin, which are capable of reaching cancer cells throughout the body. However, the effectiveness of these drugs is often limited due to toxic reactions in patients, nonspecific drug distribution affecting healthy cells, and the development of treatment resistance. In this study, we introduce a polybasic nanogel system composed of poly(diethylaminoethyl methacrylate-co-cyclohexyl methacrylate)-g-poly(ethylene glycol) designed for the targeted co-delivery of paclitaxel and carboplatin directly to ovarian cancer cells. These nanogel systems can respond to the cellular microenvironment to achieve controlled, on-demand drug release, reducing off-target effects and enhancing therapeutic uptake. Additionally, we investigated nanoparticle degradation and controlled drug release as a function of various crosslinkers, including tetraethylene glycol dimethacrylate, bis(2-methacryloyl)oxyethyl disulfide, poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid)dimethacrylate, and polycaprolactone dimethacrylate. Our results, using OVCAR-3 human ovarian cancer cells, demonstrated that this dual-delivery system outperformed free drugs in inducing cancer cell death, representing a promising advance in the field of nanoparticle-based therapies for ovarian cancer. By loading two chemotherapeutic agents into a single, environmentally responsive particle, this approach shows the potential to overcome common resistance mechanisms and achieve more effective tumor suppression. In summary, by delivering chemotherapy more precisely, it may be possible to enhance therapeutic outcomes while minimizing toxicity and nonspecific drug distribution, ultimately improving patient quality of life.
Collapse
Affiliation(s)
- Angela M Wagner
- McKetta Department of Chemical Engineering, The University of Texas at Austin Austin TX USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin Austin TX USA
| | - Olivia L Lanier
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin Austin TX USA
- Department of Biomedical Engineering, The University of Texas at Austin Austin TX USA
- Department of Chemical and Biological Engineering, University of New Mexico Albuquerque NM USA
- Department of Biomedical Engineering, University of New Mexico Albuquerque NM USA
- Cancer Therapeutics Program, University of New Mexico Comprehensive Cancer Center Albuquerque NM USA
| | - Ani Savk
- McKetta Department of Chemical Engineering, The University of Texas at Austin Austin TX USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin Austin TX USA
| | - Nicholas A Peppas
- McKetta Department of Chemical Engineering, The University of Texas at Austin Austin TX USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin Austin TX USA
- Department of Biomedical Engineering, The University of Texas at Austin Austin TX USA
- Department of Surgery and Perioperative Care, Dell Medical School, University of Texas at Austin Austin TX USA
- Department of Pediatrics, Dell Medical School, University of Texas at Austin Austin TX USA
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin Austin TX USA
| |
Collapse
|
|
2
|
Kumar S, Oien DB, Khurana A, Cliby W, Hartmann L, Chien J, Shridhar V. Coiled-Coil and C2 Domain-Containing Protein 1A (CC2D1A) Promotes Chemotherapy Resistance in Ovarian Cancer. Front Oncol 2019; 9:986. [PMID: 31632917 PMCID: PMC6779793 DOI: 10.3389/fonc.2019.00986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 09/16/2019] [Indexed: 12/13/2022] Open
Abstract
Recurrence within 6 months of the last round of chemotherapy is clinically defined as platinum-resistant ovarian cancer. Gene expression associated with early recurrence may provide insights into platinum resistant recurrence. Prior studies identified a 14-gene model that accurately predicted early or late recurrence in 86% of patients. One of the genes identified was CC2D1A (encoding coiled-coil and C2 domain containing 1A), which showed higher expression in tumors from patients with early recurrence. Here, we show that CC2D1A protein expression was higher in cisplatin-resistant ovarian cancer cell lines compared to cisplatin-sensitive cell lines. In addition, immunohistochemical analysis of patient tumors on a tissue microarray (n = 146) showed that high levels of CC2D1A were associated with a significantly worse overall and progression-free survival (p = 0.0002 and p = 0.006, respectively). To understand the contribution of CC2D1A in chemoresistance, we generated shRNA-mediated knockdown of CC2D1A in SKOV3ip and PEO4 cell lines. Cell death and clonogenic assays of these isogenic clonal lines clearly showed that downregulation of CC2D1A resulted in increased sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Moreover, nude mice bearing SKOV3ip xenografts with stably downregulated CC2D1A were more sensitive to chemotherapy as evidenced by a significantly longer survival time compared to xenografts derived from cells stably transduced with non-targeting shRNA. These results suggest CC2D1A promotes chemotherapy resistance in ovarian cancer.
Collapse
Affiliation(s)
- Sanjeev Kumar
- Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, United States
| | - Derek B Oien
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, United States
| | - Ashwani Khurana
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, United States
| | - William Cliby
- Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, United States
| | - Lynn Hartmann
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States
| | - Jeremy Chien
- Department of Biochemistry and Molecular Medicine, University of California Davis Health, Sacramento, CA, United States
| | - Viji Shridhar
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, United States
| |
Collapse
|
|
3
|
Ahlberg J, Giragossian C, Li H, Myzithras M, Raymond E, Caviness G, Grimaldi C, Brown SE, Perez R, Yang D, Kroe-Barrett R, Joseph D, Pamulapati C, Coble K, Ruus P, Woska JR, Ganesan R, Hansel S, Mbow ML. Retrospective analysis of model-based predictivity of human pharmacokinetics for anti-IL-36R monoclonal antibody MAB92 using a rat anti-mouse IL-36R monoclonal antibody and RNA expression data (FANTOM5). MAbs 2019; 11:956-964. [PMID: 31068073 PMCID: PMC6601564 DOI: 10.1080/19420862.2019.1615345] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Accurate prediction of the human pharmacokinetics (PK) of a candidate monoclonal antibody from nonclinical data is critical to maximize the success of clinical trials. However, for monoclonal antibodies exhibiting nonlinear clearance due to target-mediated drug disposition, PK predictions are particularly challenging. That challenge is further compounded for molecules lacking cross-reactivity in a nonhuman primate, in which case a surrogate antibody selective for the target in rodent may be required. For these cases, prediction of human PK must account for any interspecies differences in binding kinetics, target expression, target turnover, and potentially epitope. We present here a model-based method for predicting the human PK of MAB92 (also known as BI 655130), a humanized IgG1 κ monoclonal antibody directed against human IL-36R. Preclinical PK was generated in the mouse with a chimeric rat anti-mouse IgG2a surrogate antibody cross-reactive against mouse IL-36R. Target-specific parameters such as antibody binding affinity (KD), internalization rate of the drug target complex (kint), target degradation rate (kdeg), and target abundance (R0) were integrated into the model. Two different methods of assigning human R0 were evaluated: the first assumed comparable expression between human and mouse and the second used high-resolution mRNA transcriptome data (FANTOM5) as a surrogate for expression. Utilizing the mouse R0 to predict human PK, AUC0-∞ was substantially underpredicted for nonsaturating doses; however, after correcting for differences in RNA transcriptome between species, AUC0-∞ was predicted largely within 1.5-fold of observations in first-in-human studies, demonstrating the validity of the modeling approach. Our results suggest that semi-mechanistic models incorporating RNA transcriptome data and target-specific parameters may improve the predictivity of first-in-human PK.
Collapse
Affiliation(s)
- Jennifer Ahlberg
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Craig Giragossian
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Hua Li
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Maria Myzithras
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Ernie Raymond
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Gary Caviness
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Christine Grimaldi
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Su-Ellen Brown
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Rocio Perez
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Danlin Yang
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Rachel Kroe-Barrett
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - David Joseph
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Chandrasena Pamulapati
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Kelly Coble
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Peter Ruus
- b Translational Medicine, Clinical Pharmacology , Boehringer Ingelheim Pharma GmbH & Co. KG , Ingelheim am Rein , Germany
| | - Joseph R Woska
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Rajkumar Ganesan
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - Steven Hansel
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| | - M Lamine Mbow
- a Biotherapeutics Disccovery Research , Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield , CT , USA
| |
Collapse
|
|
4
|
Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression. Sci Rep 2019; 9:1405. [PMID: 30723259 PMCID: PMC6363760 DOI: 10.1038/s41598-018-38345-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/20/2018] [Indexed: 12/16/2022] Open
Abstract
Lung cancer remains the leading cause of cancer-related death, despite the advent of targeted therapies and immunotherapies. Therefore, it is crucial to identify novel molecular features unique to lung tumors. Here, we show that cyclopamine tartrate (CycT) strongly suppresses the growth of subcutaneously implanted non-small cell lung cancer (NSCLC) xenografts and nearly eradicated orthotopically implanted NSCLC xenografts. CycT reduces heme synthesis and degradation in NSCLC cells and suppresses oxygen consumption in purified mitochondria. In orthotopic tumors, CycT decreases the levels of proteins and enzymes crucial for heme synthesis, uptake, and oxidative phosphorylation (OXPHOS). CycT also decreases the levels of two regulators promoting OXPHOS, MYC and MCL1, and effectively alleviates tumor hypoxia. Evidently, CycT acts via multiple modes to suppress OXPHOS. One mode is to directly inhibit mitochondrial respiration/OXPHOS. Another mode is to inhibit heme synthesis and degradation. Both modes appear to be independent of hedgehog signaling. Addition of heme to NSCLC cells partially reverses the effect of CycT on oxygen consumption, proliferation, and tumorigenic functions. Together, our results strongly suggest that CycT suppress tumor growth in the lung by inhibiting heme metabolism and OXPHOS. Targeting heme metabolism and OXPHOS may be an effective strategy to combat lung cancer.
Collapse
|
|
5
|
Mollard S, Ciccolini J, Imbs DC, El Cheikh R, Barbolosi D, Benzekry S. Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis. Oncotarget 2018; 8:23087-23098. [PMID: 28416742 PMCID: PMC5410287 DOI: 10.18632/oncotarget.15484] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/07/2017] [Indexed: 11/25/2022] Open
Abstract
Bevacizumab is the first-in-class antiangiogenic drug and is almost always administrated in combination with cytotoxics. Reports have shown that bevacizumab could induce a transient phase of vascular normalization, thus ensuring a better drug delivery when cytotoxics administration is adjuvant. However, determining the best sequence remains challenging. We have developed a mathematical model describing the impact of antiangiogenics on tumor vasculature. A 3.4 days gap between bevacizumab and paclitaxel was first proposed by our model. To test its relevance, 84 mice were orthotopically xenografted with human MDA-231Luc+ refractory breast cancer cells. Two sets of experiments were performed, based upon different bevacizumab dosing (10 or 20 mg/kg) and inter-cycle intervals (7 or 10 days), comprising several combinations with paclitaxel. Results showed that scheduling bevacizumab 3 days before paclitaxel improved antitumor efficacy (48% reduction in tumor size compared with concomitant dosing, p < 0.05) and reduced metastatic spreading. Additionally, bevacizumab alone could lead to more aggressive metastatic disease with shorter survival in animals. Our model was able to fit the experimental data and provided insights on the underlying dynamics of the vasculature's ability to deliver the cytotoxic agent. Final simulations suggested a new, data-informed optimal gap of 2.2 days. Our experimental data suggest that current concomitant dosing between bevacizumab and paclitaxel could be a sub-optimal strategy at bedside. In addition, this proof of concept study suggests that mathematical modelling could help to identify the optimal interval among a variety of possible alternate treatment modalities, thus refining the way experimental or clinical studies are conducted.
Collapse
Affiliation(s)
- Severine Mollard
- SMARTc Unit, Inserm S_911 CRO2, Aix Marseille University, Marseille, France.,Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Joseph Ciccolini
- SMARTc Unit, Inserm S_911 CRO2, Aix Marseille University, Marseille, France
| | | | - Raouf El Cheikh
- SMARTc Unit, Inserm S_911 CRO2, Aix Marseille University, Marseille, France
| | | | | |
Collapse
|
|
6
|
Cavaco M, Goncalves J. Interactions Between Therapeutic Proteins and Small Molecules: The Shared Role of Perpetrators and Victims. Clin Pharmacol Ther 2017; 102:649-661. [PMID: 28002637 DOI: 10.1002/cpt.605] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 11/21/2016] [Accepted: 12/12/2016] [Indexed: 12/19/2022]
Abstract
Therapeutic proteins (TPs) are becoming increasingly important as therapeutic agents. A consequence of expanding their clinical indications is coadministration with well-established small-molecule drugs (sMDs), which could lead to unpredictable effects. According to the existing regulatory guidance, the development of an sMD includes the evaluation of potential drug-drug interactions (DDIs). For TPs, only a few drug interaction studies have been published. Limited clinically relevant models, long half-lives, and complex elimination pathways are among the associated difficulties.
Collapse
Affiliation(s)
- M Cavaco
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - J Goncalves
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| |
Collapse
|
|
7
|
Dall'Ara E, Boudiffa M, Taylor C, Schug D, Fiegle E, Kennerley AJ, Damianou C, Tozer GM, Kiessling F, Müller R. Longitudinal imaging of the ageing mouse. Mech Ageing Dev 2016; 160:93-116. [PMID: 27530773 DOI: 10.1016/j.mad.2016.08.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 07/30/2016] [Accepted: 08/04/2016] [Indexed: 12/13/2022]
Abstract
Several non-invasive imaging techniques are used to investigate the effect of pathologies and treatments over time in mouse models. Each preclinical in vivo technique provides longitudinal and quantitative measurements of changes in tissues and organs, which are fundamental for the evaluation of alterations in phenotype due to pathologies, interventions and treatments. However, it is still unclear how these imaging modalities can be used to study ageing with mice models. Almost all age related pathologies in mice such as osteoporosis, arthritis, diabetes, cancer, thrombi, dementia, to name a few, can be imaged in vivo by at least one longitudinal imaging modality. These measurements are the basis for quantification of treatment effects in the development phase of a novel treatment prior to its clinical testing. Furthermore, the non-invasive nature of such investigations allows the assessment of different tissue and organ phenotypes in the same animal and over time, providing the opportunity to study the dysfunction of multiple tissues associated with the ageing process. This review paper aims to provide an overview of the applications of the most commonly used in vivo imaging modalities used in mouse studies: micro-computed-tomography, preclinical magnetic-resonance-imaging, preclinical positron-emission-tomography, preclinical single photon emission computed tomography, ultrasound, intravital microscopy, and whole body optical imaging.
Collapse
Affiliation(s)
- E Dall'Ara
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK; INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK.
| | - M Boudiffa
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
| | - C Taylor
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
| | - D Schug
- Institute for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
| | - E Fiegle
- Institute for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
| | - A J Kennerley
- Biological Services Unit, University of Sheffield, Sheffield, UK.
| | - C Damianou
- Department of Electrical Engineering, Cyprus University of Technology, Limassol, Cyprus.
| | - G M Tozer
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
| | - F Kiessling
- Institute for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
| | - R Müller
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
| |
Collapse
|
|
8
|
Ricci JW, Lovato DM, Severns V, Sklar LA, Larson RS. Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts. Mol Cancer Ther 2016; 15:2853-2862. [PMID: 27671528 DOI: 10.1158/1535-7163.mct-15-0789] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 08/17/2016] [Accepted: 09/14/2016] [Indexed: 11/16/2022]
Abstract
Chemotherapeutic resistance remains a challenge in the treatment of ovarian carcinoma, especially in recurrent disease. Despite the fact that most patients with newly diagnosed tumors attain complete remission following cytoreductive surgery and chemotherapy, ovarian carcinoma has a recurrence rate that exceeds 75%. The ATP-binding cassette family G member 2 (ABCG2) efflux protein has been described as one mechanism that confers multiple-drug resistance to solid tumors and contributes to topotecan resistance in ovarian carcinoma. In fact, one clinical trial demonstrated ABCG2 expression in all patients with primary or recurrent ovarian carcinoma. On the basis of our previous work, we hypothesized that three compounds (CID44640177, CID1434724, and CID46245505), which represent a new piperazine-substituted pyrazolo[1,5]pyrimidine substructure class of ABCG2-specific antagonists, would restore chemosensitivity to drug-resistant ovarian cancer in vitro and in vivo To address the treatment difficulties associated with chemotherapeutic resistance in ovarian cancer, we combined each compound (CID44640177, CID1434724, and CID46245505) with topotecan and administered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice. We found that only nanomolar concentrations of each ABCG2 inhibitor in combination with topotecan were required to restore chemosensitivity to Igrov1/T8 cells in vitro In vivo, substantial tumor reduction was achieved with each compound in 4 days, with CID1434724 causing the largest reduction in excess of 60%. No signs of secondary toxic effects were observed with the ABCG2 antagonists. These novel compounds should be viewed as promising drug candidates to reverse ABCG2-mediated chemoresistance. Mol Cancer Ther; 15(12); 2853-62. ©2016 AACR.
Collapse
Affiliation(s)
- Jerec W Ricci
- Clinical and Translational Science Center, University of New Mexico, Albuquerque, New Mexico
| | - Debbie M Lovato
- Clinical and Translational Science Center, University of New Mexico, Albuquerque, New Mexico
| | - Virginia Severns
- Clinical and Translational Science Center, University of New Mexico, Albuquerque, New Mexico
| | - Larry A Sklar
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico
| | - Richard S Larson
- Clinical and Translational Science Center, University of New Mexico, Albuquerque, New Mexico.
| |
Collapse
|
|
9
|
de Leon M, Cardenas H, Vieth E, Emerson R, Segar M, Liu Y, Nephew K, Matei D. Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer. Gynecol Oncol 2016; 142:539-47. [PMID: 27374141 DOI: 10.1016/j.ygyno.2016.06.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/23/2016] [Accepted: 06/26/2016] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Epigenetic alterations have been implicated in the development of platinum resistance in ovarian cancer (OC). In this study, we aimed to identify DNA methylation changes in platinum resistant tumors and their functional implications. METHODS To identify DNA methylation alterations we used the Illumina 450k DNA methylation array and profiled platinum sensitive and resistant OC xenografts. Validation analyses employed RT-PCR and immunohistochemistry (IHC). RESULTS Genome-wide DNA methylation analysis of OC xenografts identified 6 genes (SSH3, SLC12A4, TMEM88, PCDHGC3, DAXX, MEST) whose promoters were significantly hypomethylated in resistant compared to sensitive (control) xenografts (p<0.001). We confirmed that TMEM88 and DAXX mRNA expression levels were increased in platinum resistant compared to control xenografts, inversely correlated with promoter methylation levels. Furthermore treatment of OC cells with SGI-110 (guadecitabine), a DNA methyl transferase (DNMT) inhibitor, increased TMEM88 mRNA expression levels, supporting that TMEM88 is transcriptionally regulated by promoter methylation. TMEM88 was detectable by IHC in all histological types of ovarian tumors and its knock-down by using siRNA promoted OC cell proliferation and colony formation and re-sensitized cells to platinum. Furthermore, TMEM88 knock down induced upregulation of cyclin D1 and c-Myc, known Wnt target genes, supporting that TMEM88 inhibits Wnt signaling. CONCLUSIONS Overall, our results support that OC platinum resistance was correlated with TMEM88 overexpression regulated through decreased promoter methylation. Our data suggest that TMEM88 functions as an inhibitor of Wnt signaling, contributing to the development of platinum resistance.
Collapse
Affiliation(s)
- Maria de Leon
- Indiana University, Obstetrics and Gynecology Department, Division of Gynecologic Oncology, United States
| | - Horacio Cardenas
- Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, United States
| | - Edyta Vieth
- Indiana University, Department of Medicine, United States
| | - Robert Emerson
- Indiana University, Department of Pathology, United States
| | - Matthew Segar
- Indiana University, Department of Biostatics, United States
| | - Yunlong Liu
- Indiana University, Department of Biostatics, United States
| | - Kenneth Nephew
- Medical Sciences, Indiana University, Bloomington, United States
| | - Daniela Matei
- Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, United States; Robert H. Lurie Cancer Center, United States.
| |
Collapse
|
|
10
|
Abstract
Among female-specific cancers worldwide, ovarian cancer is the leading cause of death from gynecologic malignancy in the western world. Despite radical surgery and initial high response rates to first-line chemotherapy, up to 70% of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. This review aims to assess current understanding of targeted therapy in ovarian cancer and evaluate the evidence for targeting growth-dependent mechanisms involved in its pathogenesis. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and PARP inhibitors.
Collapse
Affiliation(s)
- Hui Jun Lim
- Faculty of Medicine, University of New South Wales, Australia
| | - William Ledger
- School of Women's & Children's Health, University of New South Wales, Sydney 2031, New South Wales, Australia
| |
Collapse
|
|
11
|
Thomas VA, Balthasar JP. Sorafenib Decreases Tumor Exposure to an Anti-carcinoembryonic Antigen Monoclonal Antibody in a Mouse Model of Colorectal Cancer. AAPS JOURNAL 2016; 18:923-32. [PMID: 27029796 DOI: 10.1208/s12248-016-9909-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 03/19/2016] [Indexed: 01/08/2023]
Abstract
In this investigation, we test the hypothesis that treatment with sorafenib, an anti-angiogenic agent, decreases tumor vascularization and, consequently, hinders the delivery of monoclonal antibodies (mAb) to xenograft tumors. Severe combined immunodeficiency mice bearing carcinoembryonic antigen (CEA) expressing tumor xenografts were divided into control and sorafenib-treated groups. Sorafenib was administered to the latter group at 50 mg/kg IP every 48 h, starting 4 days post-tumor implantation. When tumors attained a size of 200-300 mm(3), mice were evaluated for (a) tumor microvessel density (using immunohistochemical analysis), (b) tumor macromolecular extravasation (using Evans Blue Dye (EBD)), (c) pharmacokinetics of an anti-CEA mAb, T84.66, following an intravenous dose of 10 mg/kg, and (d) intra-tumoral spatial distribution of T84.66 (using autoradiography). Sorafenib treatment resulted in a substantial reduction in tumor growth rate, a visible reduction in tumor microvessel density, and in a 46.4% decrease in EBD extravasation in tumor tissue (p < 0.0455). For control and treated mice, no significant difference was found for the area under the mAb plasma concentration-time curve (AUC(0-7d): 1.67 × 10(3) ± 1.28 × 10(2) vs. 1.76 × 10(3) ± 1.75 × 10(2) nM × day, p = 0.51). However, tumor AUC(0-7d) was reduced by 40.8% in sorafenib-treated mice relative to that observed in control mice (5.61 × 10(2) ± 4.27 × 10(1) vs. 9.48 × 10(2) ± 5.61 × 10(1) nM × day, p < 0.001). Sorafenib therapy was also found to markedly alter mAb tumor spatial distribution. The results collectively suggest that sorafenib treatment causes a significant reduction in mAb delivery to, and distribution within, solid tumors.
Collapse
Affiliation(s)
- Veena A Thomas
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, New York, 14214, USA
| | - Joseph P Balthasar
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, New York, 14214, USA.
| |
Collapse
|
|
12
|
An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nat Commun 2015; 6:7956. [PMID: 26234182 PMCID: PMC4532886 DOI: 10.1038/ncomms8956] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 06/29/2015] [Indexed: 02/07/2023] Open
Abstract
High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC. Despite normalization of the CA125 serum biomarker at the completion of carboplatin therapy the vast majority of patients with high grade serous ovarian cancers relapse. Here, Janzen et al., identify a sub-population of tumor cells that are CA125 negative, cancer initiating and platinum resistant but readily eliminated with the addition of apoptosis enhancing drugs to carboplatin.
Collapse
|
|
13
|
Zou J, Gundry S, Ganic E, Uyar MÜ. Mathematical models for absorption and efficacy of ovarian cancer treatments. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2015; 2014:3442-5. [PMID: 25570731 DOI: 10.1109/embc.2014.6944363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The creation of personal and individualized anti-cancer treatments has been a major goal in the progression of cancer discovery as evident by the continuous research efforts in genetics and population based PK/PD studies. In this paper we use our clinical decision support tool, called ChemoDSS, to evaluate the effectiveness of three treatments recommended by the NCCN guidelines for ovarian cancer using pre-clinical data from the literature. In particular, we analyze the treatments of PC (i.e., Paclitaxel and Cispaltin), DC (i.e., Docetaxel and Carboplatin), and PBC (i.e., Paclitaxel, Bevacizumab, and Carboplatin). Our in silico analysis of the ovarian cancer treatments shows that PC was the most effective regimen for treating ovarian cancer compared to DC and PBC, which is consistent with literature findings. We demonstrate that we can successfully evaluate the effectiveness of the selected ovarian cancer treatment regimens using ChemoDSS.
Collapse
|
|
14
|
Ahn J, Bishop JA, Akpeng B, Pai SI, Best SRA. Xenograft model for therapeutic drug testing in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 2014; 124:110-5. [PMID: 25124839 DOI: 10.1177/0003489414546400] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Identifying effective treatment for papillomatosis is limited by a lack of animal models, and there is currently no preclinical model for testing potential therapeutic agents. We hypothesized that xenografting of papilloma may facilitate in vivo drug testing to identify novel treatment options. METHODS A biopsy of fresh tracheal papilloma was xenografted into a NOD-scid-IL2Rgamma(null) (NSG) mouse. RESULTS The xenograft began growing after 5 weeks and was serially passaged over multiple generations. Each generation showed a consistent log-growth pattern, and in all xenografts, the presence of the human papillomavirus (HPV) genome was confirmed by polymerase chain reaction (PCR). Histopathologic analysis demonstrated that the squamous architecture of the original papilloma was maintained in each generation. In vivo drug testing with bevacizumab (5 mg/kg i.p. twice weekly for 3 weeks) showed a dramatic therapeutic response compared to saline control. CONCLUSION We report here the first successful case of serial xenografting of a tracheal papilloma in vivo with a therapeutic response observed with drug testing. In severely immunocompromised mice, the HPV genome and squamous differentiation of the papilloma can be maintained for multiple generations. This is a feasible approach to identify therapeutic agents in the treatment of recurrent respiratory papillomatosis.
Collapse
Affiliation(s)
- Julie Ahn
- Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | | | | | - Sara I Pai
- Harvard Medical School, Boston, Massachusetts, USA
| | - Simon R A Best
- Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
15
|
Kitayama J. Intraperitoneal chemotherapy against peritoneal carcinomatosis: current status and future perspective. Surg Oncol 2014; 23:99-106. [PMID: 24721661 DOI: 10.1016/j.suronc.2014.03.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 02/13/2014] [Accepted: 03/18/2014] [Indexed: 02/08/2023]
Abstract
Peritoneal carcinomatosis (PC), caused by advanced abdominal malignancies, such as those of the ovarian and gastrointestinal tracts, has an extremely poor prognosis. Intraperitoneal (IP) chemotherapy has been clinically applied for several decades, but its clinical efficacy has not been fully determined. An accumulating body of evidence suggests that cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the optimal treatment for selected patients with ovarian and colorectal cancers with PC. Recent studies suggest that IP administration of taxane with systemic chemotherapy in a neoadjuvant setting improves patient survival in gastric cancer with PC. The pharmacokinetics of IP-administered drugs should be primarily considered in order to optimize IP chemotherapy. Therefore, the development of specific IP drugs using newly emerging molecular targeted reagents or new drug delivery systems, such as nanomedicine or controlled absorption/release methods, is essential to improve the efficacy of IP chemotherapy.
Collapse
Affiliation(s)
- Joji Kitayama
- Department of Surgical Oncology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| |
Collapse
|
|
16
|
PK/TD modeling for prediction of the effects of 8C2, an anti-topotecan mAb, on topotecan-induced toxicity in mice. Int J Pharm 2014; 465:228-38. [PMID: 24508555 DOI: 10.1016/j.ijpharm.2014.01.038] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 12/30/2013] [Accepted: 01/29/2014] [Indexed: 12/31/2022]
Abstract
To facilitate the development of an inverse targeting strategy, where anti-topotecan antibodies are administered to prevent systemic toxicity following intraperitoneal topotecan, a pharmacokinetic/toxicodynamic (PK/TD) model was developed and evaluated. The pharmacokinetics of 8C2, a monoclonal anti-topotecan antibody, were assessed following IV and SC administration, and the data were characterized using a two compartmental model with nonlinear absorption and elimination. A hybrid PK model was constructed by combining a PBPK model for topotecan with the two-compartment model for 8C2, and the model was employed to predict the disposition of topotecan, 8C2, and the topotecan-8C2 complex. The model was linked to a toxicodynamic model for topotecan-induced weight-loss, and simulations were conducted to predict the effects of 8C2 on the toxicity of topotecan in mice. Increasing the molar dose ratio of 8C2 to topotecan resulted in a dose-dependent decrease in the unbound (i.e., not bound to 8C2) topotecan exposure in plasma (AUCf) and a decrease in the extent of topotecan-induced weight-loss. Consistent with model predictions, toxicodynamic experiments showed substantial reduction in the percent nadir weight loss observed with 30 mg/kg IP topotecan after co-administration of 8C2 (20 ± 8% vs. 10 ± 8%). The investigation supports the use of anti-topotecan mAb to reduce the systemic toxicity of IP topotecan chemotherapy.
Collapse
|
|
17
|
Emoto S, Sunami E, Yamaguchi H, Ishihara S, Kitayama J, Watanabe T. Drug development for intraperitoneal chemotherapy against peritoneal carcinomatosis from gastrointestinal cancer. Surg Today 2014; 44:2209-20. [PMID: 24482110 DOI: 10.1007/s00595-014-0848-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 10/21/2013] [Indexed: 12/23/2022]
Abstract
Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular-targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer.
Collapse
Affiliation(s)
- Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | | | | | | | | | | |
Collapse
|
|
18
|
Pavlidis ET, Pavlidis TE. Role of bevacizumab in colorectal cancer growth and its adverse effects: a review. World J Gastroenterol 2013; 19:5051-5060. [PMID: 23964138 PMCID: PMC3746376 DOI: 10.3748/wjg.v19.i31.5051] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/07/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis affects both wound healing and malignant cell growth through nutrients and oxygen. Vascular endothelial growth factor (VEGF) is the most important element involved in this complex process. Inhibition of VEGF influences angiogenesis and may restrict tumor growth and metastatic ability. Modern anti-angiogenic therapy is based on this theory. Bevacizumab is a recombinant humanized monoclonal antibody (immunoglobulin G1) which binds with VEGF-A forming a large molecule. It can not be bound with VEGF tyrosine kinase receptors preventing VEGF-A incorporation; thus its activity is inhibited inducing blockage of VEGF-mediated angiogenesis. Bevacizumab, in combination with chemotherapy or other novel targeted therapeutic agents, is currently used more frequently in clinical practice, mainly for managing advanced colorectal cancer. It is also used for managing other malignancies, such as breast cancer, pancreatic cancer, prostate cancer, non small-cell lung cancer, metastatic renal carcinoma and ovarian tumors. Although it is generally considered a safe treatment, there are reports of some rare side effects which should be taken into account. Recent experiments in rats and mice show promising results with a wider therapeutic range.
Collapse
|
|
19
|
Salvatorelli E, De Tursi M, Menna P, Carella C, Massari R, Colasante A, Iacobelli S, Minotti G. Pharmacokinetics of pegylated liposomal doxorubicin administered by intraoperative hyperthermic intraperitoneal chemotherapy to patients with advanced ovarian cancer and peritoneal carcinomatosis. Drug Metab Dispos 2012; 40:2365-73. [PMID: 22972909 DOI: 10.1124/dmd.112.047480] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The pharmacokinetics of pegylated liposomal doxorubicin (PLD) were investigated in 17 women undergoing intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian cancer and peritoneal carcinomatosis. HIPEC was performed immediately after completing debulking surgery, which included a number of peritonectomy procedures. PLD was injected and allowed to equilibrate in peritoneal cavity filled with 4 liters of physiological solution and stabilized at 42°C; next, the outflow line was opened and perfusion proceeded for 1 h. PLD was stable in peritoneal perfusate and plasma. During HIPEC, PLD peritoneal perfusate/plasma gradients averaged ∼600 or ≥1000 for peak concentration or area under the curve. After HIPEC, PLD plasma levels remained stable or decreased. Biopsy samples of residual normal peritoneum or ovarian carcinomatosis were collected at the end of HIPEC and were shown to contain free doxorubicin. Correlating PLD decrements in peritoneal perfusate with plasma exposure to PLD or peritoneal deposition of free doxorubicin showed that the former occurred during preperfusional equilibration of PLD in peritoneal cavity, whereas the latter occurred during 1 h of perfusion. Plasma exposure to PLD correlated negatively with the number of peritonectomy procedures performed during surgery, whereas peritoneal deposition of free doxorubicin correlated positively. Taken together, these results show that PLD administered by intraoperative HIPEC undergoes limited systemic diffusion and releases active free doxorubicin in peritoneum exposed to ovarian carcinomatosis. PLD pharmacokinetics seem to be influenced by peritonectomy procedures.
Collapse
Affiliation(s)
- Emanuela Salvatorelli
- CIR and Drug Sciences, University Campus Bio-Medico, Via Alvaro del Portillo 21, 00128 Rome, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models. Br J Cancer 2012; 107:360-9. [PMID: 22713663 PMCID: PMC3394985 DOI: 10.1038/bjc.2012.261] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background: Bevacizumab is being incorporated as first-line therapy with standard-of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models. Methods: Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models. Results: Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft. Conclusion: Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression.
Collapse
|
|
21
|
Emoto S, Yamaguchi H, Kishikawa J, Yamashita H, Ishigami H, Kitayama J. Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination. Cancer Sci 2012; 103:1304-10. [PMID: 22429777 DOI: 10.1111/j.1349-7006.2012.02274.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/01/2012] [Accepted: 03/13/2012] [Indexed: 12/26/2022] Open
Abstract
The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX-Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24 100 ± 3560 vs 108 ± 25 ng/mL, respectively; P < 0.001), as was the area under the concentration-time curve from 0 to 48 h (191 000 ± 32 100 vs 1500 ± 108 ng·h/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation.
Collapse
Affiliation(s)
- Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
| | | | | | | | | | | |
Collapse
|
|
22
|
Wu F, Tamhane M, Morris ME. Pharmacokinetics, lymph node uptake, and mechanistic PK model of near-infrared dye-labeled bevacizumab after IV and SC administration in mice. AAPS JOURNAL 2012; 14:252-61. [PMID: 22391791 DOI: 10.1208/s12248-012-9342-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Accepted: 02/21/2012] [Indexed: 12/31/2022]
Abstract
Our objective was to determine the pharmacokinetics, bioavailability and lymph node uptake of the monoclonal antibody bevacizumab, labeled with the near-infrared (IR) dye 800CW, after intravenous (IV) and subcutaneous (SC) administration in mice. Fluorescence imaging and enzyme-linked immunosorbent assay (ELISA) assays were developed and validated to measure the concentration of bevacizumab in plasma. The bevacizumab-IRDye conjugate remained predominantly intact in plasma and in lymph node homogenate samples over a 24-h period, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and size exclusion chromatography. The plasma concentration vs. time plots obtained by fluorescence and ELISA measurements were similar; however, unlike ELISA, fluorescent imaging was only able to quantitate concentrations for 24 h after administration. At a low dose of 0.45 mg/kg, the plasma clearance of bevacizumab was 6.96 mL/h/kg after IV administration; this clearance is higher than that reported after higher doses. Half-lives of bevacizumab after SC and IV administration were 4.6 and 3.9 days, respectively. After SC administration, bevacizumab-IRDye800CW was present in the axillary lymph nodes that drain the SC site; lymph node uptake of bevacizumab-IRDye 800CW was negligible after IV administration. Bevacizumab exhibited complete bioavailability after SC administration. Using a compartmental pharmacokinetic model, the fraction absorbed through the lymphatics after SC administration was estimated to be about 1%. This is the first report evaluating the use of fluorescent imaging to determine the pharmacokinetics, lymphatic uptake, and bioavailability of a near-infrared dye-labeled antibody conjugate.
Collapse
Affiliation(s)
- Fang Wu
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, USA
| | | | | |
Collapse
|
|
23
|
Kasuya K, Nagakawa Y, Suzuki M, Suzuki Y, Kyo B, Suzuki S, Matsudo T, Itoi T, Tsuchida A, Aoki T. Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma. Exp Ther Med 2012; 3:599-602. [PMID: 22969935 DOI: 10.3892/etm.2012.456] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 01/09/2012] [Indexed: 11/06/2022] Open
Abstract
We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors.
Collapse
Affiliation(s)
- Kazuhiko Kasuya
- Department of Digestive Surgery, Tokyo Medical University, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Rein DT, Volkmer AK, Volkmer J, Beyer IM, Janni W, Fleisch MC, Welter AK, Bauerschlag D, Schöndorf T, Breidenbach M. Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pre-treated ovarian cancer. Oncol Lett 2012; 3:530-534. [PMID: 22740945 DOI: 10.3892/ol.2012.553] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 12/21/2011] [Indexed: 12/26/2022] Open
Abstract
Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment.
Collapse
Affiliation(s)
- Daniel T Rein
- Department of Obstetrics and Gynaecology, University of Düsseldorf Medical Centre, D-40225 Düsseldorf, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Hurwitz SJ, Zhang H, Yun S, Batuwangala TD, Steward M, Holmes SD, Rycroft D, Pan L, Tighiouart M, Shin HJC, Koenig L, Wang Y, Chen Z, Shin DM. Pharmacodynamics of DT-IgG, a dual-targeting antibody against VEGF-EGFR, in tumor xenografted mice. Cancer Chemother Pharmacol 2011; 69:577-90. [DOI: 10.1007/s00280-011-1713-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 07/15/2011] [Indexed: 02/07/2023]
|