Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease.

BACKGROUND: The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic. METHODS: We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours. RESULTS: Systemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol. CONCLUSIONS: The Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer.

Evaluation of sepramesh biosurgical composite in a rabbit hernia repair model.

BACKGROUND: In cases such as incisional hernia repair, polypropylene mesh (PPM) can be exposed to the underlying viscera and cause adhesions to the mesh. In this study, a composite prosthesis that was designed to be less susceptible to adhesion formation than PPM was evaluated in a rabbit incisional hernia repair model. MATERIALS AND METHODS: A 5 x 7-cm full-thickness defect was created in the abdominal wall of 30 female New Zealand White rabbits. Ten animals each were repaired with PPM, Bard Composix (PP/ePTFE), or Sepramesh biosurgical composite-a polypropylene mesh coated on one side with chemically modified sodium hyaluronate and carboxymethylcellulose (HA/CMC). The animals were sacrificed after 28 days and the overall performance, including adhesion formation and tissue integration by histology and mechanical testing, was evaluated. RESULTS: In the Sepramesh group, there was a significant reduction in the percentage of surface area covered by adhesions and a significant increase in the percentage of animals with no adhesions compared to standard materials. The tissue integration strength and overall cellular response were similar in all groups. A partially remesothelialized peritoneal surface was often apparent overlying the Sepramesh implant. CONCLUSIONS: Sepramesh biosurgical composite effectively repaired abdominal wall defects in rabbits and reduced adhesion development to the mesh compared to the use of a PPM and a PP/ePTFE composite.

Reversible expansion of primate mast cell populations in vivo by stem cell factor.

Mast cell development in mice is critically regulated by stem cell factor (SCF), the term used here to designate a product of fibroblasts and other cell types that is a ligand for the tyrosine kinase receptor protein encoded by the proto-oncogene c-kit. However, the factors which regulate the size of mast cell populations in primates are poorly understood. Here we report that the subcutaneous administration of recombinant human SCF (rhSCF) to baboons (Papio cynocephalus) or cynomolgus monkeys (Macaca fascicularis) produced a striking expansion of mast cell populations in many anatomical sites, with numbers of mast cells in some organs of rhSCF-treated monkeys exceeding the corresponding values in control monkeys by more than 100-fold. Animals treated with rhSCF did not exhibit clinical evidence of mast cell activation, and discontinuation of treatment with rhSCF resulted in a rapid decline of mast cell numbers nearly to baseline levels. These findings are the first to demonstrate that a specific cytokine can regulate mast cell development in primates in vivo. They also provide the first evidence, in any mammalian species, to indicate that the cytokine-dependent expansion of tissue mast cell populations can be reversed when administration of the cytokine is discontinued.

The pathobiology of salivary gland. II. Morphological evaluation of acinic cell carcinomas in the parotid gland of male transgenic (MMTV/v-Ha-ras) mice as a model for human tumours.

In the transgenic TG.SH (mouse mammary tumour virus/v-Ha-ras) mouse, designed to develop mammary tumours, occasional spontaneous salivary gland tumours have been reported, predominantly in males. The incidence and histomorphology of salivary gland tumours in 73 TG.SH mice were surveyed and in total, 21.9% developed both overt and microscopic parotid tumours. The majority developed between 73 and 150 days of age. In 31.5% of the TG.SH mice, occasional unilateral, but more frequently bilateral exophthalmos due to hyperplasia of the intraorbital (Harderian) lacrimal gland was observed. In 70% of these animals, parotid tumours developed later. Since Harderian gland hyperplasia, occurring as early as 5 weeks of age, preceded the development of palpable salivary gland lesions, this stigma is useful for the early selection of animals likely to progress to tumour formation. Before tumour-bearing transgenic mice are considered to be suitable models of human neoplastic disease, morphological characterization is necessary to ensure that the tumours are histologically representative of the human lesions for which they are potential models. In this study, all parotid tumours consisted of acinar-like glandular structures with central lumina discernible by electron microscopy. Ultrastructurally, secretory granules evident in the apical cytoplasm of the tumour cells resembled the zymogen granules of the normal parotid acinar cell, and some cells had a prominent complement of rough endoplasmic reticulum. These features, along with focal amylase expression detected immunohistochemically in some parotid tumours, identified these neoplasms as acinic cell carcinomas that mimic the human salivary gland acinic cell carcinoma faithfully.

Generation of monoclonal antibodies specific for ras p21 Glu-12 oncoproteins: detection in carcinogen-induced mammary carcinomas.

ras genes have been shown to become oncogenes by single point mutations which result in amino acid substitutions that affect either their GTPase activity (positions 12, 13, 59, 61) or their affinity for GTP and GDP. Ras oncogenes and their corresponding proteins have been described in a variety of human cancers as well as in animal tumors induced by physical and chemical carcinogens. One of these animal tumor systems involves the induction of mammary carcinomas in rats by a single dose of N-nitroso-N-methylurea (NMU), a methylating carcinogen. These NMU-induced mammary carcinomas contain transforming H-ras genes activated by G----A transitions in the second nucleotide of their 12th codon, presumably a consequence of the pre-mutagenic lesions induced by NMU. These G----A mutations result in the replacement of the normal glycine in the 12th position of the ras p21 protein by a glutamic acid residue. In this study, we report the generation of monoclonal antibodies (Mab) reactive with oncogenic ras p21 proteins containing glutamic acid at position 12 (p21 Glu-12). Mab designated E184 specifically recognized activated ras p21 Glu-12 proteins but not normal p21 (Gly-12) or p21 proteins activated by other position 12 substitutions including arginine, aspartic acid, cysteine, valine or serine residues. Western blot analysis of NMU-induced mammary carcinomas demonstrated that Mab E184 recognized p21 proteins expressed in these rat tumors but not p21 present in normal tissues nor in other carcinogen-induced tumors known to carry H-ras oncogenes activated by mutations at position 61.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial dysgenesis and lobar emphysema in an adult cat.

An adult male cat was examined because of chronic respiratory tract disease. Results of thoracic radiography indicated overinflation of the right lung, and atelectasis or agenesis of the left lung. Notable aerosol deposition (ventilation) to the right caudal lung lobe was seen by use of pulmonary ventilation scintigraphy. Postmortem findings suggested the primary pathoanatomic lesion was bronchial dysgenesis involving all but the right caudal lung lobe.

Gemistocytic astrocytoma in a one-month-old llama.

A tumor involving the caudal portion of the brainstem was detected at necropsy after euthanasia of a 1-month-old llama with clinical signs consistent with vestibular disease. Gemistocytic astrocytoma of the medullary mass was the histopathologic diagnosis. Regardless of age, neoplasia should be included in differential diagnosis in animals with signs referable to the CNS.