Gene transfer into stem cells has been an ongoing priority as a treatment for genetic disease and cancer for more than two decades. Methods described herein, form the basis for providing the cell source to determine if osteoclast precursor cells (OcP) can be used as therapeutic gene delivery systems in vivo. Osteoclasts and tumor associated macrophages or OcP, support survival, tumor progression and osteolysis in bone cancers.
View Article and Find Full Text PDFBackground: Painful breast carcinoma metastases in bone are a common manifestation of malignant disease. Eradication of these tumors can be evasive, and as a result, skeletal morbidity increases with disease progression.
Experimental Design: The treatment potential of cytosine deaminase (CD) gene therapy combined with radiation treatment was evaluated in vitro and in vivo using a 4T1 murine breast carcinoma model.
Cytosine deaminase (CD) catalyzes the deamination of 5-fluorocytosine (5FC) to produce the highly toxic chemotherapeutic agent 5-fluorouracil (5FU). A unique feature of the CD/5FC enzyme/prodrug system is its ability to kill adjacent cells via bystander killing. Bystander killing of cancer cells can be mediated by non-cancerous accessory cells transduced with the CD gene; one type of non-cancerous accessory cell found in primary bone cancer and breast cancer metastases to bone is the osteoclast.
View Article and Find Full Text PDFIn this paper we compare two innovative models of movement-related pain: tumor-induced nociception following implantation of fibrosarcoma cells into bone and muscle inflammation-induced nociception following injection of the irritant carrageenan into muscle. Importantly, using the grip force test, an assay of movement-related hyperalgesia, both non-malignant and malignant pain are examined in parallel. Movement-related hyperalgesia, known clinically as a specific type of 'breakthrough pain', is a common feature of bone cancer and is thought to be a predictor of poor response to conventional analgesic pharmacotherapy (Bruera et al.
View Article and Find Full Text PDFThis paper describes a model of tumor-induced bone destruction and hyperalgesia produced by implantation of fibrosarcoma cells into the mouse calcaneus bone. Histological examination indicates that tumor cells adhere to the bone edge as early as post-implantation day (PID) 3, but osteolysis does not begin until PID 6, correlating with the development of hyperalgesia. C3H/He mice exhibit a reproducible hyperalgesia to mechanical and cold stimuli between PID 6 and 16.
View Article and Find Full Text PDFRecent studies indicate that the bisphosphonate pamidronate reduces skeletal complications caused by tumor osteolysis. In this investigation, the cellular mechanism through which pamidronate affects tumor-induced osteoclastogenesis is studied in osteopetrotic mice. A unique animal model is employed which studies the effect of pamidronate on a tumor (2472 sarcoma) which induces osteoclastogenesis in osteoclast-deficient mice (oplop).
View Article and Find Full Text PDFOsteoprotegerin and osteoprotegerin ligand have recently been identified as novel proteins that inhibit and stimulate, respectively, osteoclast formation. We examined the possibility that osteoprotegerin would inhibit cancer-induced osteoclastogenesis and cancer growth in bone. An experimental model was used in which osteolytic tumors are known to stimulate osteoclastogenesis and grow in femora of osteoclast-deficient mice (op/op).
View Article and Find Full Text PDFThe cellular and biochemical mechanisms that direct the destruction of bone at sites of tumor osteolysis are unknown. To better understand the mechanisms through which tumors direct bone resorption, research has focused on developing in vivo and in vitro experimental models that are useful for studying this process. In vivo experimental systems have been developed that permit study of tumor osteolysis from human and murine tumors, and that permit the study of tumors that arise from (sarcoma) or can metastasize (breast cancer) to bone.
View Article and Find Full Text PDFBone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer.
View Article and Find Full Text PDFThe cancer-related event that is most disruptive to the cancer patient's quality of life is pain. To begin to define the mechanisms that give rise to cancer pain, we examined the neurochemical changes that occur in the spinal cord and associated dorsal root ganglia in a murine model of bone cancer. Twenty-one days after intramedullary injection of osteolytic sarcoma cells into the femur, there was extensive bone destruction and invasion of the tumor into the periosteum, similar to that found in patients with osteolytic bone cancer.
View Article and Find Full Text PDFIt has been hypothesized that bone resorption during tumor osteolysis is performed by osteoclasts. Data supporting this hypothesis have been provided from analysis of human biopsy specimens obtained from sites of tumor osteolysis, as well as from experimentation with in vivo animal models. Experiments in this report take this concept one step further by testing the hypothesis that osteoclasts are required for bone tumors to grow and destroy bone.
View Article and Find Full Text PDFThe cellular mechanism or mechanisms through which tumors induce osteoclast formation at sites of tumor osteolysis is unknown. To test the hypothesis that osteoclast formation at sites of tumor osteolysis reflects influences that tumors have on proliferating osteoclast precursor cells, a novel in vivo experimental model was developed that produced mice that were deficient in osteoclasts (op/op) and were depleted (by way of total body irradiation) of proliferating osteoclast precursor cells. The femora of irradiated op/op mice were injected with tumor cells (2472 clone) that had been previously shown to form osteolytic tumors and to induce focal osteoclastogenesis, and the influence of these tumor cells on osteoclast formation was determined in op/op mice that were depleted of proliferating osteoclast precursor cells.
View Article and Find Full Text PDFThe cellular mechanism through which osseous breast cancer metastases induce the focal destruction of bone (tumor osteolysis) is unknown. An athymic mouse model designed for the study of tumor osteolysis was developed and the influence of two human breast cancer tumors on bone was studied. Tumor-induced osteolysis occurred between 7 and 10 weeks after inoculation of mouse femora with MDA-MB-231 or MDA-MB-435s breast cancer cells.
View Article and Find Full Text PDFThe cellular and biochemical mechanisms that direct destruction of bone at the site of tumor osteolysis are unknown. In order to understand this process better, a murine model designed for the study of tumor osteolysis was developed and the influence of osteolytic and nonosteolytic tumors on bone was investigated. Tumors developed following femoral intramedullary injection of sarcoma (2472) and melanoma (G3.
View Article and Find Full Text PDFDetails of the cellular and biochemical mechanisms involved in focal destruction of bone at sites of tumor osteolysis are unknown. It has been shown that tumors from sarcoma (2472) cell lines induce focal osteolysis in mice by stimulating formation and activation of osteoclasts. In this report, the influence of 2472 tumors on the skeletons of osteoclast-deficient animals (op/op) was studied.
View Article and Find Full Text PDFDihydropyrimidine dehydrogenase (DPD), the initial, rate-limiting step in pyrimidine degradation, was studied in two cell lines of murine neuroblastoma (MNB-T1 and MNB-T2) that were derived from C-1300 MNB tumor carried in A/J mice. The MNB-T2 (low malignancy) cell line was originally derived from the in situ tumor and carried in tissue culture for more than 100 passages; the MNB-T1 (high malignancy) line consisted of a new sub-culture that was also established from the in situ MNB tumor. DPD activity was determined in cytosolic preparations of MNB utilizing high performance liquid chromatography to separate the radiolabeled substrate ([2-14C]thymine) from [2-14C]dihydrothymine.
View Article and Find Full Text PDFUrinary homovanillic (HVA) and vanillylmandelic (VMA) acids were analyzed on 200 random urine samples from patients with neuroblastoma and controls, after the samples had been dried onto absorbent filter paper. The acids were determined quantitatively by gas chromatography (GC) and qualitatively by thin layer chromatography (TLC). The results were analyzed for correlation between liquid urine samples and urine dried on filter paper and between TLC and GC methods.
View Article and Find Full Text PDFThree patients with hereditary tyrosinemia type I were examined before and after liver transplantation to assess the role of extrahepatic tissues in the biochemical disorders of this disease. Before transplantation the three patients excreted excessive amounts of succinylacetoacetate (SAA), succinylacetone (SA), tyrosyl acidic compounds, and 5-aminolevulinate (ALA). The activity of 5-aminolevulinate dehydratase (ALA-D) in red blood cells was markedly inhibited (1% to 5% of control) in the three patients.
View Article and Find Full Text PDFDuring the last 3 years, random urine samples from 408 patients were tested for elevated homovanillic acid (HVA) and vanillylmandelic acid (VMA) levels to rule out the diagnosis of neuroblastoma. Thirty-seven of these patients had elevated HVA and/or VMA levels, and neuroblastoma was subsequently diagnosed. In three additional patients with negative test results (normal HVA and VMA levels), tumors were subsequently diagnosed (false-negative rate of 7.
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