Targeting the Lung: Preclinical and Comparative Evaluation of Anticancer Aerosols in Dogs with Naturally Occurring Cancers

Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Current Cancer Drug Targets (Impact Factor: 3.52). 09/2003; 3(4):265-73. DOI: 10.2174/1568009033481903
Source: PubMed


Pet dogs with naturally occurring cancers offer a novel opportunity for the study of both cancer biology and therapy. The following review will provide the rationale for the use of these spontaneous cancer models in translational research, particularly in the development of anticancer aerosols. A summary of work involving pet dogs with primary and metastatic cancers to the lung and the investigation of therapeutic chemotherapy and cytokine immunotherapy aerosols will be presented.

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    • "Chemotherapy for the dog has been largely unrewarding, with minimal responses to vindesine, cisplatin, and partial responses to vinorelbine [7,8]. No responses were seen in dogs with primary cpAC treated with the inhaled antineoplastic drugs paclitaxel or doxorubicin [9,10]. A dog with the diagnosis of primary bronchogenic carcinoma was treated with the TKI, toceranib, and was reported to have stable disease of 34+ weeks [11]. "
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    ABSTRACT: This study evaluated tyrosine kinase receptor (TKR) expression and activation in canine pulmonary adenocarcinoma (cpAC) biospecimens. As histological similarities exist between human and cpAC, we hypothesized that cpACs will have increased TKR mRNA and protein expression as well as TKR phosphorylation. The molecular profile of cpAC has not been well characterized making the selection of therapeutic targets that would potentially have relevant biological activity impossible. Therefore, the objectives of this study were to define TKR expression and their phosphorylation state in cpAC as well as to evaluate the tumors for the presence of potential epidermal growth factor receptor (EGFR) tyrosine kinase activating mutations in exons 18-21. Immunohistochemistry (IHC) for TKR expression was performed using a tissue microarray (TMA) constructed from twelve canine tumors and companion normal lung samples. Staining intensities of the IHC were quantified by a veterinary pathologist as well as by two different digitalized algorithm image analyses software programs. An antibody array was used to evaluate TKR phosphorylation of the tumor relative to the TKR phosphorylation of normal tissues with the resulting spot intensities quantified using array analysis software. Each EGFR exon PCR product from all of the tumors and non-affected lung tissues were sequenced using sequencing chemistry and the sequencing reactions were run on automated sequencer. Sequence alignments were made to the National Center for Biotechnology Information canine EGFR reference sequence. The pro-angiogenic growth factor receptor, PDGFRalpha, had increased cpAC tumor mRNA, protein expression and phosphorylation when compared to the normal lung tissue biospecimens. Similar to human pulmonary adenocarcinoma, significant increases in cpAC tumor mRNA expression and receptor phosphorylation of the anaplastic lymphoma kinase (ALK) tyrosine receptor were present when compared to the corresponding normal lung tissue. The EGFR mRNA, protein expression and phosphorylation were not increased compared to the normal lung and no activating mutations were identified in exons 18-21. Canine pulmonary adenocarcinoma TKRs are detected at both the mRNA and protein levels and are activated. Further investigation into the contribution of TKR activation in cpAC tumorigenesis is warranted.
    BMC Veterinary Research 01/2014; 10(1):19. DOI:10.1186/1746-6148-10-19 · 1.78 Impact Factor
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    • "However, post-operative limb-spare infections have been associated with improved survival in both species [3]–[5], [15]. While some evidence supports the notion that infection and/or a systemic anti-tumor immune response can inhibit growth of canine OSA [16]–[20], one clinical report noted that the majority of dogs experiencing post-operative infection were treated with FQ antibiotics [3]. We therefore questioned whether FQ's might have direct effects on canine OSA cells and set out to investigate any direct effects of commonly used FQ's on canine OSA cell lines in vitro. "
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    ABSTRACT: Despite significant advancements in osteosarcoma research, the overall survival of canine and human osteosarcoma patients has remained essentially static over the past 2 decades. Post-operative limb-spare infection has been associated with improved survival in both species, yet a mechanism for improved survival has not been clearly established. Given that the majority of canine osteosarcoma patients experiencing post-operative infections were treated with fluoroquinolone antibiotics, we hypothesized that fluoroquinolone antibiotics might directly inhibit the survival and proliferation of canine osteosarcoma cells. Ciprofloxacin or enrofloxacin were found to inhibit p21(WAF1) expression resulting in decreased proliferation and increased S-G(2)/M accumulation. Furthermore, fluoroquinolone exposure induced apoptosis of canine osteosarcoma cells as demonstrated by cleavage of caspase-3 and PARP, and activation of caspase-3/7. These results support further studies examining the potential impact of quinolones on survival and proliferation of osteosarcoma.
    PLoS ONE 08/2012; 7(8):e42960. DOI:10.1371/journal.pone.0042960 · 3.23 Impact Factor
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    ABSTRACT: Osteosarcoma (OS) is the most common bone cancer in dogs. It is biologically aggressive and <20% survive >2 years with standard therapy. Hence, new approaches must be considered. TP53 is altered in ~50% of human and canine cancers, including OS, making it a candidate for targeted suicide gene therapy strategies. Canine OS is considered to be a good model for human OS. The aims of this study were to:  examine the site incidence of canine OS retrieved from Glasgow University Veterinary School (GUVS) histology database;  perform TP53 mutational analysis in canine OS cases diagnosed at GUVS;  investigate delivery of exogenous wild-type canine TP53 into D17, CMT3, CMT7 and CMT8 canine OS cell lines;  design and construct vectors for a TP53-targeted suicide gene strategy, which can selectively target canine OS cells containing accumulated TP53, and initially analyse using Dual-Luciferase® reporter assays (DLR);  perform suicide gene/prodrug assays using nitroreductase (NTR) in combination with CB1954 or nitrofurazone (NFZ) in several canine cell lines;  replace luciferase with NTR in vectors for TP53-targeted suicide gene strategy, and with CB1954, determine if survival of CMT7 cells possessing accumulated TP53 are reduced, in comparison to D17 cells, containing wild-type TP53. OS were most commonly found in appendicular areas, followed by axial and extraskeletal sites; this agrees with published findings. No TP53 mutations were found in 7 biopsies removed from 4 dogs, 5 were OS, due to analysis of a small sample number, but still fits within published data. TP53 expression did not have a significant negative effect on canine OS cell growth. Contrasting results have been shown in canine and human OS cells. Luciferase expression levels following transfection with designed constructs were higher in CMT7 cells, than in D17 cells. Similar results were shown in NTR/CB1954 assays as reductions in cell survival only occurred in CMT7 cells but not in D17 cells. NFZ was not suitable as a prodrug for NTR in canine cells as there were no differences in cell survival with cells not expressing NTR. Hence, the TP53-targeted suicide gene therapy strategy appears to selectively reduce survival of canine OS cells possessing accumulated TP53, warranting further investigation as a treatment modality for OS, in both dogs and humans.
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