In the current study, we examined whether the combination of tumor vasculature-targeted gene therapy with adeno-associated virus bacteriophage-tumor necrosis factor-α (AAVP-TNF-α) and/or the orally administered LCL161, an antagonist of inhibitors of apoptosis proteins (IAPs), enhanced antitumor efficacy without systemic toxicity. M21 human melanoma xenografts were grown subcutaneously in nude mice. Mice were treated according to one of four treatment regimens: AAVP-TNF-α alone (AAVP-TNF-α plus sodium acetate-acetic acid (NaAc) buffer) via tail vein injection; LCL161 alone (phosphate-buffered saline (PBS) plus LCL161) via oral gavage; AAVP-TNF-α plus LCL161; and PBS plus NaAc Buffer as a control group. Tumor volume, survival and toxicity were analyzed. AAVP trafficking and TNF-α production in vivo were detected on days 7 and 21 by real-time PCR, enzyme-linked immunosorbent assay and immunofluorescence. The levels of apoptosis and activation of caspases were assessed on days 7 and 21 by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) and immunofluorescence assays. Our results showed that the combination of AAVP-TNF-α and LCL161 significantly inhibited tumor growth and prolonged survival in mice with melanoma xenografts. The combination of AAVP-TNF-α and LCL161 was also significantly more effective than either agent alone, showing a synergistic effect without systemic toxicity.
Background Pasireotide (SOM230), a long acting somatostatin analogue (LAR) has improved agonist activity at somatostatin receptors. We tested the effect of SOM230 on insulin secretion, glucose levels, tumor growth, and survival using an MEN1 transgenic mouse model. Methods Eight 12 month-old conditional Men1 knockout mice with insulinoma were assessed. The treatment (N=4) and control groups (N=4) received monthly subcutaneous injections of SOM230 or PBS. Serum insulin and glucose levels were determined by ELISA and enzymatic colorimetric assay, respectively. Tumor activity, growth, and apoptosis were determined by microPET/CT scan and histological analysis. Results On day 7, there was a significant decrease in serum insulin from 1.060μg/L±0.2769 to 0.3653μg/L±0.1676 (p=0.0128) and a significant increase in serum glucose from 4.246mmol/L±0.4536 to 7.122mmol/L±1.058 (p=0.0075) in the treatment group, but no change in the control group. Tumor size was significantly smaller in the treatment group (2098μm2±388) compared with the control group (7067μm2±955) (p=0.0024). Furthermore, apoptosis was significantly increased in the treatment group (6.92%±1.23) compared with the control group (0.299%±0.103). Conclusions SOM230 demonstrates antisecretory, antiproliferative, and proapoptotic activity in our MEN1 model of insulinoma. Further studies of the effects of SOM230 in PNET patients with MEN1 mutations are warranted.
Glial cells missing homolog 2 (GCM2) is a transcription factor that is expressed predominately in the pharyngeal pouches and, at later stages, in the developing and mature parathyroid glands. In humans, loss of GCM2 function, either through recessive apomorphic mutations or dominant inhibitor mutations in the human GCM2 gene, leads to isolated hypoparathyroidism. In mice, homozygous disruption of Gcm2 by conventional gene targeting results in parathyroid aplasia and hypoparathyroidism. In this study, we report the generation and functional characterization of mice encoding a conditional null allele of Gcm2. We demonstrate the functional integrity of the conditional Gcm2 allele and report successful in vivo deletion of exon 2 using Cre recombinase. The mice with conditional deletion of Gcm2 displayed phenotypes similar to those previously described for a conventional Gcm2 knockout, including perinatal lethality, hypocalemia, low or undetectable serum levels of parathyroid hormone (PTH), and absent parathyroid glands. The production of a conditional mutant allele for Gcm2 represents a valuable resource for the study of the temporal- and spatial-specific roles for Gcm2, and for understanding the postnatal activities of GCM2 protein.
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