Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTH-related peptide (PTHrP) has been shown to be the major mediator of hypercalcemia of malignancy, but may also exert effects on cell growth and differentiation. The Leydig cell tumor H-500, when implanted in Fischer rats, produces abundant PTHrP and eventually causes the death of the host animal. In the present study we have used antisense RNA technology to block the effects of PTHrP in H-500 Leydig tumor cells in vivo. The full-length rat PTHrP complementary DNA encoding amino acid -36-->141 was subcloned as an EcoRI-BglII insert in the antisense orientation into the mammalian expression vector pRc/CMV to produce the plasmid pRc-PAS. This plasmid was then stably transfected into the H-500 Leydig tumor cells with a Lipofectin reagent. After selection with the neomycin derivative G-418, a stable cell line, H-500-PTHrP-AS, was obtained which showed 80% inhibition of endogenous PTHrP messenger RNA compared to wild-type or vector-only transfected H-500 cells. Conditioned culture medium from these experimental cells showed a marked decrease in PTHrP immunoreactivity and in the ability of the medium to stimulate adenylate cyclase in UMR-106 rat osteosarcoma cells. Furthermore, inhibition of PTHrP production resulted in a significant increase in the doubling time of the H-500 cells. Transfection of the experimental plasmid into Rat-2 fibroblasts, which do not produce PTHrP, had no effect on cell growth. Control and experimental cells were then implanted sc into male Fischer rats. Animals were killed at timed intervals, and their tumor volumes were determined. Experimental animals receiving cells transfected with antisense PTHrP plasmid showed near-normal levels of plasma calcium and decreased expression of tumoral PTHrP messenger RNA. These animals also showed a 30-70% lower tumor volume during the course of the experiment compared to control animals. These studies have demonstrated that PTHrP can play a role as a promoter of tumor growth in vitro and in vivo.
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PMID:Regulation in vivo of the growth of Leydig cell tumors by antisense ribonucleic acid for parathyroid hormone-related peptide. 758 90

Humoral hypercalcemia of malignancy is a paraneoplastic syndrome believed to be due to production by the tumor of substances that stimulate osteoclastic bone resorption primarily. The human renal cell carcinoma cell line RC-8, grown in nude mice, was investigated for factors involved in renal cancer-induced hypercalcemia. At a tumor load of 200 to 400 mm.3 the mice developed hypercalcemia and hypophosphatemia associated with a rise in serum 1,25-dihydroxyvitamin D concentration and cachexia. The tumor released 1) significant amounts of human interleukin-6 (IL-6) and 2) parathyroid hormone-related peptide (PTHrP) into the circulation. Cancer cells further expressed mRNA for both human IL-6 and PTHrP. No secretion of human tumor necrosis factor-alpha or interleukin-1 beta could be demonstrated in the circulation of the host. Antibodies to IL-6 caused a significant (p = 0.043) inhibition of tumor growth and decreased serum calcium concentrations compared with control animals. Our data suggest that IL-6 is involved, either directly or indirectly, in the development of hypercalcemia in renal cell carcinoma.
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PMID:Hypercalcemia and cosecretion of interleukin-6 and parathyroid hormone related peptide by a human renal cell carcinoma implanted into nude mice. 786 50

Hypercalcemia is a common paraneoplastic syndrome. Tumors induce hypercalcemia by a local mechanism associated with the tumor's production of various cytokines increasing bone osteolysis. In addition, many tumors release humoral factors, mainly parathyroid hormone (PTH)-related protein (PTHrP), which stimulates bone resorption and/or tubular calcium reabsorption leading to hypercalcemia. Interaction of PTHrP with other tumor-elaborated cytokines might explain some nonPTH-like features associated with the hypercalcemia of malignancy syndrome. Using assays recognizing various PTHrP epitopes, the majority of hypercalcemic cancer patients have higher immunoreactive PTHrP levels in either plasma or urine than normal subjects. Present data support the concept that PTHrP might also be a factor which promotes tumor growth and also the development of osteolytic metastasis. A variety of therapeutic approaches are available to lower serum calcium in hypercalcemic cancer patients. The pathophysiological mechanisms of hypercalcemia appear to be a determinant of the efficacy of different antihypercalcemic treatments.
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PMID:Hypercalcemia of malignancy--new insights into an old syndrome. 1121 25

We report the case of a 34 year old male presenting with symptomatic hypercalcemia due to excessive PTHrP secretion from a pancreatic neuroendocrine carcinoma with extensive hypervascularization and without any evidence for metastatic disease. In the early phase of the disease conventional chemotherapy with streptozocin and doxorubicin was able to control functional activity as well as tumor growth. However, after 2 years tumor escape was indicated by severe therapy-resistant hypercalcemia. Therapeutic options were reduced due to the excessive tumor vascularization and the patient died from his disease after a short period of intensified therapy. The role of PTHrP in hypercalcemia of malignancy (HHM) and its association with neuroendocrine pancreatic tumors as well as possible therapeutic options are reviewed.
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PMID:Pancreatic neuroendocrine tumor with extensive vascularisation and parathyroid hormone-related protein (PTHrP)--associated hypercalcemia of malignancy. 1157 50

Bone metastases are one of the most common problematic complications of advanced cancers. In addition to causing significant pain, bone metastases often result in fractures and debilitation. Stimulation of osteoclast activity by factors secreted by tumor cells is believed be the primary mechanism of bone destruction. Bisphosphonates inhibit osteoclast-related bone resorption, and have become standard therapy in the treatment of hypercalcemia of malignancy and postmenopausal osteoporosis. More recently, bisphosphonates have been shown to decrease pain and skeletal fractures associated with bone metastases. Structural changes in bisphosphonates influence their relative potency as well as other potentially beneficial effects such as inhibition of tumor growth factors, alteration of adhesion molecules, and apoptosis of tumor cells.
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PMID:Bisphosphonates in the treatment of bone metastases. 1189 24

Bone metastases commonly occur in the course of malignant tumor disease. For many years, attempts have been made to identify factors for the management of cancer-induced skeletal complications. Nowadays, synthetic antiresorptive agents are considered to be indispensable for the treatment of cancer-related skeletal events, such as bone metastasis. The most common of these drugs are the bisphosphonates, which represent one of the most significant advances over the last 10 years in the field of supportive care and cancer. They are used for the treatment of cancer-induced hypercalcemia, for the prevention and treatment of postmenopausal osteoporosis, for patients with bone metastases secondary to breast cancer and multiple myeloma. A third-generation bisphosphonate, zolendronate, has been shown to minimize the destructive consequences of bone metastases and to exert a profound effect on tumor-induced osteolysis and tumor growth in bone. Zoledronate is already used for the treatment of hypercalcemia of malignancy, multiple myeloma-related osteolytic events and for patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy. The structure-function activity of the three generations of bisphosphonates developed to date, the in vitro models used for studying their effects on osteoclasts and osteoblasts, as well as the results of clinical trials obtained by the third generation bisphosphonate, zoledronic acid, are presented.
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PMID:In vitro and in vivo antiresorptive effects of bisphosphonates in metastatic bone disease. 1579 91

Interferon-gamma (IFN-gamma) has been shown to enhance anti-tumor immunity and inhibit the formation of bone-resorbing osteoclasts. We evaluated the role of IFN-gamma in bone metastases, tumor-associated bone destruction, and hypercalcemia in human T cell lymphotrophic virus type 1-Tax transgenic mice. Compared with Tax(+)IFN-gamma(+/+) mice, Tax(+)IFN-gamma(-/-) mice developed increased osteolytic bone lesions and soft tissue tumors, as well as increased osteoclast formation and activity. In vivo administration of IFN-gamma to tumor-bearing Tax(+)IFN-gamma(-/-) mice prevented new tumor development and resulted in decreased bromodeoxyuridine uptake by established tumors. In vitro, IFN-gamma directly decreased the viability of Tax(+) tumor cells through inhibition of proliferation, suppression of ERK phosphorylation, and induction of apoptosis and caspase 3 cleavage. IFN-gamma also inhibited macrophage colonystimulating factor-mediated proliferation and survival of osteoclast progenitors in vitro. Administration of IFN-gamma to C57BL/6 mice decreased Tax(+) tumor growth and prevented tumor-associated bone loss and hypercalcemia. In contrast, IFN-gamma treatment failed to protect IFN-gammaR1(-/-) mice from Tax(+) tumor-induced skeletal complications, despite decreasing tumor growth. These data demonstrate that IFN-gamma suppressed tumor-induced bone loss and hypercalcemia in Tax(+) mice by inhibiting both Tax(+) tumor cell growth and host-induced osteolysis. These data suggest a protective role for IFN-gamma in patients with bone metastases and hypercalcemia of malignancy.
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PMID:Interferon-gamma targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases. 1905 14

Bone metastases add to the burden of breast cancer, with patients experiencing severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy. Nitrogen-containing bisphosphonates have become the standard treatment for skeletal-related events and bone pain, as well as for bone loss associated with chemotherapy and aromatase inhibitors. Emerging preclinical and clinical evidence indicates that bisphosphonates negatively affect multiple processes that support tumor growth and proliferation and formation of metastases. Several small clinical trials suggest that bisphosphonates can modify angiogenic factors, immune surveillance, and disseminated tumor cells detected in bone marrow. Emerging data suggest that bisphosphonates used for osteoporosis prevention may inhibit breast cancer development. Three large prospective studies have shown improved outcomes with the addition of zoledronic acid to conventional neoadjuvant or adjuvant therapy. This article focuses on current clinical trials examining the use of bisphosphonates in patients with breast cancer.
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PMID:Bisphosphonates in breast cancer: antitumor effects. 2155 88