Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study was carried out to evaluate the clinical validity and usefulness of serum tartrate-resistant acid phosphatase (TRAP) activity determined using an improved spectrophotometric assay. Enzyme activity was measured in 84 normal subjects and in 109 patients with common metabolic bone diseases. Mean values of serum TRAP activity in male subjects (n = 19; 10.4 +/- 2.15 U l-1) were not significantly different from those found in female subjects (n = 65; 10.8 +/- 1.8 U l-1). In the latter group mean values were significantly raised in post-menopausal subjects (10.5 +/- 2.0 U l-1; p less than 0.01) compared with mean values in pre-menopausal women (8.45 +/- 1.8 U l-1). We found a significant inverse correlation between serum TRAP activity values and bone mineral density (BMD) measured both at an ultradistal radial point (n = 33, r = -0.506; p less than 0.01), and at the lumbar spine (n = 57, r = -0.261; p less than 0.05). Mean serum TRAP activity values in patients with metabolic bone diseases were: primary hyperparathyroidism, n = 30: 14.2 +/- 4.89 U l-1, p less than 0.001 vs normal subjects; chronic maintenance haemodialysis, n = 19: 17.4 +/- 6.7, p less than 0.001; metastatic cancer, n = 13: 21.2 +/- 6.3, p less than 0.001; post-surgical hypoparathyroidism, n = 10: 9.9 +/- 1.8, NS; involutional osteoporosis, n = 20: 12.5 +/- 2.3 p less than 0.001; Paget's disease, n = 10: 16.8 +/- 3.5, p less than 0.001; osteomalacia, n = 7: 19.5 +/- 3.31, p less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical usefulness of serum tartrate-resistant acid phosphatase activity determination to evaluate bone turnover. 176 45

Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits bone metastasis. We examined the effects of TNP-470 in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-MB-231 (MDA-231) produced osteolytic bone metastasis. After inoculation of MDA-231 cells into the left heart ventricle, TNP-470 (30 mg/kg, three times a week) or PBS was s.c. administrated for 4 weeks. After this period, the TNP-470 had reduced not only the number and area of osteolytic bone metastases (approximately 60 and 70%, respectively) but also their radiolucency. Histological examination of the femurs of the untreated group revealed that most of the cancellous bone had been replaced by the metastatic cancer. Numerous active osteoclasts were present along the trabecular bone surface surrounded by the metastatic MDA-231 cancer cells aggressively invading the bone marrow. In contrast, in the bone from TNP-470-treated mice, bone destruction was markedly inhibited, and there were much fewer osteoclasts. In a murine bone marrow culture under 1,25-dihydroxyvitamin D3 in which mature functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells. And also, TNP-470 suppressed the in vivo bone resorption in calvaria treated with interleukin-1beta, an osteoclast stimulator. These data suggested that TNP-470 inhibited bone metastasis through not only antitumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.
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PMID:Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. 945 90

Since bone markers may reflect different aspects of bone disorders and cell function, and osteolytic and osteoblastic activities may be individually or concomitantly altered, determination of more than one marker type is generally appropriate. Also, the individual markers of a particular type do not necessarily show parallelism. For example, in osteomalacia from vitamin D deficiency, bone-specific alkaline phosphatase may be grossly elevated because of enhanced osteoblastic activity, whereas the vitamin D dependent osteocalcin may be decreased. With the exception of measurement of the bone enzymes, bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase, bone marker measurements require complex and expensive immunoassays. As a general rule, the simple enzyme measurements can precede other investigation in most bone disorder> Bone-specific alkaline phosphatase measurement alone is generally adequate for the investigation of osteomalacia, Paget's disease and hyperparathyroidism but should be combined with measurement of tartrate-resistant acid phosphatase in suspected metastatic disease, and in multiple myeloma. Determination of both enzymes together may also be of value in the investigation of osteoporosis but in this disorder added benefit may be obtained by the addition of other bone markers, particularly urine deoxypyridinoline and possibly serum collagen telopeptide.
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PMID:Biochemical markers of bone turnover. 974 51

An autopsy case of cardiac leiomyosarcoma and its pulmonary metastasis, both with osteoclast-like multinucleated giant cells (OMGC) mimicking the so-called giant cell variant of malignant fibrous histiocytoma (MFH), is reported. The patient, a 70-year-old male, was admitted for sudden dyspnea. Extensive work-up established only a left atrial tumor mass. Three months after admission, the patient developed multiple intracranial and pulmonary metastases, followed by a worsening clinical course characterized by semicoma and dyspnea, and subsequently died 6 months after the onset of his symptoms. At subsequent autopsy, the left atrial polypoid tumor was found to have invaded destructively to the left half of the cardiac wall. Histology of the cardiac tumor revealed a bimorphic sarcoma in which a poorly differentiated leiomyosarcoma comfirmed by histologic and immunohistochemical findings was juxtaposed to a small nodule with features closely mimicking giant cell MFH. The pulmonary metastatic nodules exhibited features that were entirely indistinguishable from giant cell MFH except for the fact that a minority of polymorphic cells manifested myogenic differentiation. We believe that such a MFH-like pattern represents a pleomorphic form of leiomyosarcoma rather than a dedifferentiated one. The OMGC within the MFH-like component coexpressed CD68 and tartrate-resistant acid phosphatase activity.
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PMID:Leiomyosarcoma of the heart and its pulmonary metastasis, both with prominent osteoclast-like multinucleated giant cells expressing tartrate-resistant acid phosphatase activity. 1022 28

Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells at metastatic sites also may lead to fractures or bone instability. Misinterpretation of new periosteal bone due to bone instability as tumor-cell osteo-induction is another disadvantage of the osteolytic models. To circumvent these problems, we have developed a model system of new bone formation in the calvaria of nude mice stimulated by normal canine prostate tissue. Collagenase-digested normal prostate tissue was implanted adjacent to the calvaria of nude mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone microenvironment by histology, calcein uptake at sites of bone mineralization, and tartrate-resistant acid phosphatase staining for osteoclasts. The prostate tissue remained viable and induced abundant new woven bone formation on the adjacent periosteal surface. In some cases new bone formation also was induced on the distant or concave calvarial periosteum. The new bone stained intensely with calcein, which demonstrated mineralization of the bone matrix. The new bone formation on prostate-implanted calvaria significantly increased (1.7-fold) the thickness of the calvaria compared with control calvaria. New bone formation was not induced in calvaria of mice implanted with normal canine kidney, urinary bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced disruption of the periosteum. Osteoclast numbers in the medullary spaces and periosteum of calvaria were mildly increased (61%) in mice with implanted prostate tissue. In conclusion, this animal model will be useful for investigating the roles of prostate-derived growth factors on new bone formation in vivo.
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PMID:New bone formation in nude mouse calvaria induced by canine prostate tissue. 1243 20

Recent data have implicated macrophage inflammatory protein-1alpha (MIP-1alpha) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1alpha requires other factors such as receptor activator of nuclear factor-kappaB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1alpha antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1alpha on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1alpha (CHO/MIP-1alpha) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1alpha tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1alpha tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1alpha tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1alpha over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1alpha had no effect in RANK-/- mice. Together, these results establish that MIP-1alpha is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1alpha exerts a dual effect in myeloma, on osteoclasts, and tumor cells.
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PMID:Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. 1264 40

Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n = 39; pN1M0, n = 34; M1, n = 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin (OC)], bone resorption markers [bone sialoprotein (BSP), cross-linked C-terminal (CTX) and cross-linked N-terminal (NTX) telopeptides of type I collagen, tartrate-resistant acid phosphatase isoenzyme 5b (TRAP)] and osteoclastogenesis markers [osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL)] were measured. tALP, bALP, BSP, P1NP, TRAP, NTX and OPG were significantly increased in PCa patients with bone metastases compared to patients without metastases. OPG showed the best discriminatory power to differentiate between these patients. Logistic regression analysis resulted in a model with OPG and TRAP as variables that predicted bone metastasis with an overall correct classification of 93%. Patients with concentrations of OPG, P1NP, tALP, bALP, BSP, NTX, TRAP and CTX above cut-off levels showed significantly shorter survival than patients with low marker concentrations. Multivariate Cox proportional hazards regression revealed that only OPG and BSP were independent prognostic factors for PCa-related death. Thus, the importance of serum OPG in detecting bone metastatic spread, alone or in combination with other bone markers, and predicting survival in PCa patients has been clearly demonstrated.
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PMID:Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. 1525 51

This study was designed to evaluate the utility of the bone markers total alkaline phosphatase (TAP), bone-specific alkaline phosphatase (BAP), aminoterminal propeptide of type I collagen (PINP), carboxyterminal propeptide of type I collagen (PICP), pyridinoline crosslinks (PYD), deoxypyridinoline crosslinks (DPD), cross-linked carboxyterminal telopeptide of type I collagen (ICTP), cross-linked carboxyterminal telopeptide of type I collagen (CTx, beta-CrossLaps) and tartrate-resistant acid phosphatase 5b (TRAP 5b) in comparison with bone scintigraphy for the diagnosis of bone metastasis in lung carcinoma patients. The study population consisted of 49 patients with bone metastasis confirmed by plain radiography and/or computed tomography, 89 patients without bone metastasis, 12 patients with benign lung diseases and 18 healthy persons. All patients were of male gender. The bone markers were measured using commercially available tests. Serum and urine were collected from fasting patients at the time of bone scan between 7.00 and 8.00 a.m. The sensitivity of bone scintigraphy was 100%, its specificity 76.4%, resulting in a diagnostic efficiency of 84.8%. The positive predictive value was calculated to be 70% and the negative one to be 100%. The concentrations of the bone markers TAP, BAP, PINP, PYD, DPD and ICTP were significantly higher in patients with bone metastasis than in those without bone metastasis (p<0.01). The levels of PICP and CTx only tended to be higher in the patients with bone metastasis compared to those without bone metastasis. There was no significant difference in the TRAP 5b levels between the two groups. There was also no difference in the marker levels between osteoblastic, osteolytic and mixed osteoblastic-osteolytic lesions. Contrary to BAP, PICP, CTx and TRAP 5b, the markers TAP, PINP, PYD, DPD and ICTP were found to be higher (p<0.01-0.05) in patients with bone metastasis than in patients with benign lung diseases. In addition, PYD, DPD and ICTP differentiated patients with benign lung diseases from the healthy controls. Based on cut-off values that correspond to 95% specificity in the group of healthy persons, the sensitivity of the marker assays were as follows (specificity in brackets): TAP 33.3% (97.5%), BAP 22% (100%), PINP 18.4% (97.5%), PICP 2.1% (95.2%), PYD 91.8% (24.1%), DPD 83.7% (34.5%), ICTP 75.5% (44.6%), CTx 45.8% (77.5%) and TRAP 5b 14% (84%). The corresponding data for the diagnostic efficiency were as follows: TAP 73.6%, BAP 77.1%, PINP 67.7%, PICP 61.1%, PYD 48.5%, DPD 55.2%, ICTP 56.1%, CTx 65.6% and TRAP 5b 58.7%, respectively. The positive predictive values ranged from 20% (PICP) to 100% (BAP) and the negative values from 62.7% (PICP) to 84% (PYD). In the ROC analysis, TAP, followed by RAP, PINP and PYD, showed the best performance. The levels of TAP, BAP, PINP, PYD, DPD and ICTP were found to be higher in the patients with bone metastasis compared to those with metastastic lesions in other sites (p<0.01, except for ICTP having a p value of < 0.05). The levels of TAP, BAP, PYD, DPD and ICTP increased significantly with the number of metastases. There was also a steady increase in T scores of the markers PINP, PYD, DPD and ICTP with the extent of the metastatic bone disease. It is concluded that the currently available bone markers cannot replace bone scintigraphy, either for screening or in the diagnosis of bone metastasis, in lung carcinoma patients. However, a panel consisting of TAP, BAP, PINP, PYD, DPD and ICTP may be of some value as an adjunct tool to bone scintigraphy for this purpose.
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PMID:Comparison of bone scintigraphy with bone markers in the diagnosis of bone metastasis in lung carcinoma patients. 1551 Jun 10

Serum activity of tartrate-resistant acid phosphatase 5b (TRAP 5b) in patients with breast cancer and prostate cancer having bone metastases was much higher than in healthy donors and patients without skeletal injuries. TRAP 5b activity in patients with breast cancer and multiple bone metastases surpassed that in patients with single bone metastases. The mean activity of TRAP 5b and range of enzyme activity in women treated with bisphosphonates were significantly lower than in patients not receiving antiresorptive therapy. Diagnostic sensitivity and specificity of TRAP 5b as a marker of skeletal metastases in patients with breast cancer were 82 and 87%, respectively. In patients with prostate cancer these indexes were 71 and 83.4%, respectively. Detection of this marker in tumor patients holds much promise for early diagnostics of bone metastases, estimation of the severity of skeletal metastases, and monitoring of the efficiency of bisphosphonate therapy.
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PMID:Tartrate-resistant acid phosphatase as a marker of bone metastases in patients with breast cancer and prostate cancer. 1551 30

Bone metastasis is a common untreatable complication associated with prostate cancer. Metastatic cells seed in skeletal sites under active turnover containing dense marrow cellularity. We hypothesized that differences in these skeletal-specific processes are among the critical factors that facilitate the preferential localization of metastatic prostate cancer in bone. To test this, athymic mice were administered PTH to induce bone turnover and increase marrow cellularity daily 1 wk before and after intracardiac inoculation of luciferase-tagged PC-3 cells. Tumor localization was monitored by bioluminescence imaging weekly for 5 wk. At the time of tumor inoculation, PTH-treated mice demonstrated significant increases in serum levels of bone turnover markers such as osteocalcin and tartrate-resistant acid phosphatase 5b and in the number of tartrate-resistant acid phosphatase-positive osteoclasts per millimeter of bone when compared with the other groups. Likewise, PTH treatment stimulated a qualitative increase in marrow cellular proliferation as determined by 5-bromo-2'-deoxyuridine immunostaining. Skeletal metastases formed in the hind limb and craniofacial regions of young mice with no difference between groups. In adult mice, however, bioluminescent signals in the hind limb and craniofacial regions were 3-fold higher in PTH-treated mice vs. controls. Fluorochrome labeling revealed increased bone formation activity in trabecular bone adjacent to tumors. When zoledronic acid, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered concurrently with PTH, a significant reduction in the incidence of bone tumors was observed. Overall, these studies provide new evidence that skeletal sites rich in marrow cellularity under active turnover offer a more congenial microenvironment to facilitate cancer localization in the skeleton.
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PMID:Bone turnover mediates preferential localization of prostate cancer in the skeleton. 1563 91


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