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)

We report on a 26-year old female patient with thoracic pain and dyspnea, in whom a large tumorous mass in the anterior mediastinum with a pleural effusion was diagnosed by computed tomography and magnetic resonance imaging. After rapid progression of tumor growth and detection of malignant cells within the pleural effusion operative intervention including resection of the tumor was performed. Histologic examination of the tumor revealed the typical morphology of a large mediastinal choriocarcinoma. The excessively high hCG-levels returned to normal values post-operatively. A thorough history making revealed an ectopic pregnancy which had made unilateral salpingectomy necessary. Although primary histologic examination of the tubarian tissue had shown no malignancy, a secondary look revealed a choriocarcinoma with identical histological features compared to the mediastinal tumor. Thus, final diagnosis of a mediastinal metastasis of a tubarian choriocarcinoma in ectopic pregnancy was made. We discuss this extremely rare disease and provide a short overview of the literature.
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PMID:[Mediastinal metastasis of a tubal choriocarcinoma following ectopic pregnancy as a rare cause of thoracic pain]. 1667 52

Ibuprofen belongs to the 2-aryl propionic-acid derivatives and consists of two enantiomers, of which S-ibuprofen is a potent cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitor whereas the R-enantiomer is two to three orders of magnitude less potent to inhibit cyclooxygenases. Beside its positive effects on inflammation and pain several animal studies have shown that ibuprofen also inhibits tumor initiation and proliferation but the molecular mechanisms are not fully understood. To investigate to which extent the antiproliferative effect of ibuprofen depends on COX-inhibition we tested both enantiomers in different human colon carcinoma cell lines (HCA-7 express COX-1, COX-2 and produce high prostaglandin E2 level; HCT-15 express only COX-1 and produce nearly no prostaglandin E2). S- and R-ibuprofen reduced concentration dependently cell survival in both cell lines to a similar extent and caused a G0/G1 phase block as well as apoptosis. The cell cycle block was accompanied by a down regulation of cyclin A and B and an increase of the cell cycle inhibitory protein p27Kip-1. HCA-7 cells were less sensitive against the antiproliferative effects of ibuprofen enantiomers which was probably due to lower ibuprofen concentrations in this cell type. Also in the nude mice model both enantiomers inhibited tumor growth of HCA-7 and HCT-15 xenografts to a similar extent. However, in mice about 54% of R-ibuprofen was unidirectionally inverted to S-ibuprofen, thus the observed antitumorigenic effect of R-ibuprofen in vivo cannot solely be assigned to this enantiomer. In conclusion our data indicate that S- and R-ibuprofen show similar antiproliferative effects in human colon carcinoma cell lines irrespective of its COX-inhibiting potencies.
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PMID:Evidence of COX-2 independent induction of apoptosis and cell cycle block in human colon carcinoma cells after S- or R-ibuprofen treatment. 1673 Jul 2

The endogenous cannabinoid system has revealed potential avenues to treat many disease states. Medicinal indications of cannabinoid drugs including compounds that result in enhanced endocannabinoid responses (EER) have expanded markedly in recent years. The wide range of indications covers chemotherapy complications, tumor growth, addiction, pain, multiple sclerosis, glaucoma, inflammation, eating disorders, age-related neurodegenerative disorders, as well as epileptic seizures, traumatic brain injury, cerebral ischemia, and other excitotoxic insults. Indeed, a great effort has led to the discovery of agents that selectively activate the cannabinoid system or that enhance the endogenous pathways of cannabinergic signaling. The endocannabinoid system is comprised of three primary components: (i) cannabinoid receptors, (ii) endocannabinoid transport system, and (iii) hydrolysis enzymes that break down the endogenous ligands. Two known endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are lipid molecules that are greatly elevated in response to a variety of pathological events. This increase in endocannabinoid levels is suggested to be part of an on-demand compensatory response. Furthermore, activation of signaling pathways mediated by the endogenous cannabinoid system promotes repair and cell survival. Similar cell maintenance effects are elicited by EER through inhibitors of the endocannabinoid deactivation processes (i.e., internalization and hydrolysis). The therapeutic potential of the endocannabinoid system has yet to be fully determined, and the number of medical maladies that may be treated will likely continue to grow. This review will underline studies that demonstrate medicinal applications for agents that influence the endocannabinoid system.
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PMID:Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states. 1702 37

Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and a high risk of fractures due to tumor-driven bone loss (osteolysis), which is caused by increased osteoclast activity. Osteolysis releases bone-bound growth factors including transforming growth factor beta (TGF-beta). The widely accepted model of osteolytic bone metastasis in breast cancer is based on the hypothesis that the TGF-beta released during osteolytic lesion development stimulates tumor cell parathyroid hormone related protein (PTHrP), causing stromal cells to secrete receptor activator of NFkappaB ligand (RANKL), thus increasing osteoclast differentiation. Elevated osteoclast numbers results in increased bone resorption, leading to more TGF-beta being released from bone. This interaction between tumor cells and the bone microenvironment results in a vicious cycle of bone destruction and tumor growth. Bisphosphonates are commonly prescribed small molecule therapeutics that target tumor-driven osteoclastic activity in osteolytic breast cancers. In addition to bisphosphonate therapies, steroidal and non-steroidal antiestrogen and adjuvant therapies with aromatase inhibitors are additional small molecule therapies that may add to the arsenal for treatment of osteolytic breast cancer. This review focuses on a brief discussion of tumor-driven osteolysis and the effects of small molecule therapies in reducing osteolytic tumor progression.
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PMID:Breast cancer bone metastasis and current small therapeutics. 1716 Jul 9

The medicinal properties of extracts from the hemp plant Cannabis sativa have been known for centuries but only in the 90s membrane receptors for the Cannabis major principle were discovered in mammalian cells. Later on the endogenous ligands for the cannabinoid receptors were identified and the term 'endocannabinoid system' was coined to indicate the complex signaling system of cannabinoid receptors, endogenous ligands and the enzymes responsible for their biosynthesis and inactivation. The 'endocannabinoid system' is involved in a broad range of functions and in a growing number of pathological conditions. There is increasing evidence that endocannabinoids are able to inhibit cancer cell growth in culture as well as in animal models. Most work has focused on the role of endocannabinoids in regulating tumor cell growth and apoptosis and ongoing research is addressed to further dissect the precise mechanisms of cannabinoid antitumor action. However, endocannabinoids are now emerging as suppressors of angiogenesis and tumor spreading since they have been reported to inhibit angiogenesis, cell migration and metastasis in different types of cancer, pointing to a potential role of the endocannabinoid system as a target for a therapeutic approach of such malignant diseases. The potential use of cannabinoids to retard tumor growth and spreading is even more appealing considering that they show a good safety profile, regarding toxicity, and are already used in cancer patients as palliatives to stimulate appetite and to prevent devastating effects such as nausea, vomiting and pain.
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PMID:Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review). 1734 20

The management of pain and morbidity due to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the alphavbeta3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that alphavbeta3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional alphavbeta3 enabled tumor growth in bone (incidence: 4/4), whereas alphavbeta3 (-), inactive or constitutively active mutants of alphavbeta3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated alphavbeta3 (either inactive of constitutively active), but not those lacking beta3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for beta3 integrin, we next demonstrated that alphavbeta3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated alphavbeta3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development.
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PMID:Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. 1736 40

Chronic inflammation often acts as a tumor promoter, resulting in aggressive cancerous growth and spread. Many of the same inflammatory factors that promote tumor growth also are responsible for cancer cachexia/anorexia, pain, debilitation, and shortened survival. A compelling case may be made for mounting an attack on inflammation with other anticancer measures at initial diagnosis, with the consequent probability of improving both patient quality of life and survival. High serum levels of the inflammatory marker C-reactive protein or fibrinogen and an elevated white blood cell count correlate with poor prognosis and may be used as a prognostic index to establish the need for nutritional/metabolic intervention. At the author's institution, a concerted effort is being made to screen all newly diagnosed patients with non-small cell lung cancer for the presence of nutritional problems, inflammatory markers, and related symptoms. Interventions include dietary counseling; nutritional and, if warranted, vitamin supplementation; exercise concordant with the patient's physical condition; a prescription for omega 3 fatty acids if inflammation is present, and general symptom management. To establish the value of early nutritional/metabolic intervention, clinical trials are needed that combine measures that combat cachexia and inflammation with first-line chemotherapy in patients who present with weight loss, fatigue, and deteriorating function.
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PMID:Cancer cachexia and targeting chronic inflammation: a unified approach to cancer treatment and palliative/supportive care. 1750 May 3

Chronic pain resulting from metastasis into skeleton of certain neoplastic diseases remains poorly understood and relatively resistant to analgesic treatment. Opioids are the principal axis in drug therapy for this type of pain, especially at the end stage of cancer. Our aim was to examine whether, fentanyl as well as morphine, two potent analgesic opioids commonly used to treat cancer pain, would inhibit pain and bone lesion-related responses in a murine model of bone cancer pain. Repeated administration of equianalgesic doses of fentanyl (0.16 mg/kg s.c. once a day) and morphine (20 mg/kg s.c. once a day) initiated at day 1 (prophylactic treatment) or at day 7 (curative treatment) after tumor cell inoculation in the femoral cavity consistently decreased bone pain symptoms and tumor growth-induced bone destruction (micro-CT bone structure parameters). Both fentanyl and morphine treatments resulted in clear antinociceptive properties as well as reductions in cancer cell-induced bone lesions. The present results demonstrate that fentanyl, and to some lesser degree morphine, has potential benefits in the treatment and development of bone cancer pain. As such, chronic administration of high doses of certain opioids like fentanyl may have clinical utility in the management of bone cancer pain.
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PMID:The impact of the opioids fentanyl and morphine on nociception and bone destruction in a murine model of bone cancer pain. 1752 15

Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcoma-induced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity and upregulated IL-1 beta within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma-induced osteolysis. These results indicate that sustained morphine increases pain, osteolysis, bone loss, and spontaneous fracture, as well as markers of neuronal damage in DRG cells and expression of pro-inflammatory cytokines. Morphine treatment may result in "add-on" mechanisms of pain beyond those engaged by sarcoma alone. While it is not known whether the present findings in this model of osteolytic sarcoma will generalize to other cancers or opioids, the data suggest a need for increased understanding of neurobiological consequences of prolonged opioid exposure which may allow improvements in the use of opiates in the effective management of cancer pain.
Pain 2007 Nov
PMID:Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer. 1785 96

Radiation therapy is a widely used treatment for metastatic bone cancer, but the rapid onset of tumor radioresistance is a major problem. We investigated the radiosensitizing effect of enzastaurin, a protein kinase Cbeta (PKCbeta) inhibitor, on bone tumor growth and tumor-related pain. We found that enzastaurin enhanced the effect of ionizing radiation on cultured murine 4T1 breast cancer and murine endothelial cells, suppressing their proliferation and colony formation. Enzastaurin and ionizing radiation also induced caspase-mediated apoptosis of 4T1 cells to a greater degree than radiation alone. Enzastaurin treatment of 4T1 cells blocked the phosphorylation of PKCbeta, as well as Ras and two of its downstream effectors ERK1/2 and RAL-GTP. Using an orthotopic model of bone metastasis, we observed that a combination of enzastaurin and localized radiation treatment reduced tumor blood vessel density, bone destruction and pain compared to single modality treatment. In conclusion, we demonstrate that inhibition of PKCbeta in combination with localized radiation treatment suppresses tumor growth and alleviates pain as compared to radiation-only treatment. We also show that the radiosensitizing effect of enzastaurin is associated with suppression of tumor cell proliferation and tumor-induced angiogenesis possibly through inhibition of the Ras pathway.
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PMID:Protein kinase C-beta inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis. 1780 85


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