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

CNS relapse after PCI may reflect either suboptimal radiation dose schedules or reseeding from other sites of active disease. A retrospective study has been undertaken to investigate these alternative mechanisms of treatment failure. Between August 1981 and December 1983, 30 patients with SCLC treated by induction chemotherapy, followed by high-dose cyclophosphamide (7 Gm/m2), were selected for PCI on the basis of clinical, radiological, and bronchoscopic CR. Pretreatment CT brain scans were normal in all patients, and 20 Gy mid-plane dose in 5 daily fractions were delivered by lateral fields to whole brain using megavoltage X rays and localizing check films. Progressive focal neurological signs of cranial metastases developed in 7/30 (23%) patients 3-11 months after PCI, confirmed on CT scanning in 4 patients. Relapse at other sites, predominantly the thorax, occurred in all seven patients at intervals of 1-6 months prior to CNS relapse. Published clinical data of tumor volume doubling times in SCLC predict longer CNS relapse-free intervals after PCI than those observed in our patients if reseeding was responsible for relapse. This suggests that incomplete eradication of intracranial disease is the main cause of CNS relapse after PCI. Higher equivalent radiation doses may improve the results of PCI.
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PMID:CNS relapse despite prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC). 302 95

Previous studies using dynamic scintigraphy have shown that the measurement of changes in hepatic perfusion may be exploited to detect liver metastases. Similar hepatic haemodynamic changes also occur in cirrhosis, however, thereby reducing the diagnostic power of the technique. The ability of duplex colour Doppler sonography (DCDS) to differentiate between the changes in liver perfusion in patients with cirrhosis and those with hepatic metastases was assessed. Hepatic arterial and portal venous blood flows were measured in 30 control subjects, 20 patients with cirrhosis, and 55 patients with overt liver metastases. The Doppler perfusion index (DPI) (the rate of hepatic arterial to total liver blood flow) and the congestive index (ratio of the cross sectional area of the vessel to time averaged velocity of blood flow in the vessel) of the hepatic artery (HCI) and portal vein (PCI) were calculated. The hepatic arterial blood flow of the cirrhotic and metastatic groups was significantly raised compared with that of controls, and the portal venous blood flow of the former groups were reduced (p < 0.0001). The DPIs of the cirrhotic and metastatic groups were therefore significantly raised compared with those of controls (p < 0.0001). No significant difference was noted in HCI values between the three groups. The PCI values of the cirrhotic group, however, were significantly raised compared with those of controls and patients with metastases (p < 0.0001). The data suggest that DCDS measurement of PCI may be of value in differentiating between the hepatic perfusion changes caused by cirrhosis and those resulting from hepatic metastases, thereby increasing the diagnostic power of this technique.
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PMID:Hepatic perfusion changes in patients with liver metastases: comparison with those patients with cirrhosis. 849 6

Brain metastases are one of the important causes of failure in the treatment of SCLC patients. Intracranial metastases are reported in 10% of the newly diagnosed SCLC pts. Further 20% brain metastases develop during therapy. Autopsy studies showed that 40%-60% of pts had evidence of intracranial spread at the time of death. The frequency of brain metastases increases with the duration of survival, reaching a probability of 80% after 2 years of observation. The high risk of brain metastases which developed in spite of chemotherapy was the reason of introducing PCI to the treatment. PCI reduces the risk of brain metastases to less than 10%, but unfortunately, does not prolong median survival. Probably this is due to the fact, that in the majority of cases the brain is one of many sites of metastases at the time of progression. In addition, in some pts brain metastases developed in spite of PCI and/or brain toxicity may develop after this treatment. Thus, up till now the role of PCI in the treatment of SCLC pts remains controversial. The indication for this treatment could improve if we have more exact information which pts have the greatest probability do develop metastases restricted to the brain only. This question was the main aim of our study.
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PMID:[Indications for prophylactic cranial irradiation in patients with small cell lung cancer]. 863 Apr 63

Metastasis to the liver often occurs in patients during the natural course of pancreatic cancer. Using carcinoma cell lines established from 9 such patients, we examined phenotypes of cell lines to search for correlations with their potential to metastasize to the liver. Anti-asialo GMI-treated nude mice were used. PCI-43, -55, -24 and -6, in this order, had frequent metastases, while PCI-10, -19, -35, -64, and -66 did not. In vitro doubling time, surface expression of sialyl Lewis(a) (SLe(a)), VLA-4/6, LFA-I/3, CEA, E-selectin, VCAM-I, NCAM, Mac-I, HLA-ABC/ DR/DQ, ICAM-I/2, production of interleukin-I alpha, tumor necrosis factor-alpha, and matrix metalloproteinase, as well as susceptibility to cytotoxicity by natural killer cells, were all examined. Expression of surface SLea was significantly associated with metastasis; numbers of metastatic colonies of SLe(a)-positive and -negative cell lines were 21.6 +/- 33.9 and 6.5 +/- 14.3 (p < 0.01), respectively. Moreover, the intensity of surface SLe(a) expression of each PCI line correlated with the number of metastatic colonies in the liver. When anti-SLe(a) monoclonal antibody (MAb) was administered, the development of liver metastasis by PCI-43 cells was significantly repressed, as compared with a control MAb. Although a reverse correlation between surface ICAM-I expression and liver metastasis was noted, the species-restricted function of ICAM-I makes interpretation difficult. Collective evidence indicates that expression of SLe(a) is an important positive mediator in the hematogenous metastasis of pancreas carcinoma.
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PMID:Phenotypes correlating to metastatic properties of pancreas adenocarcinoma in vivo: the importance of surface sialyl Lewis(a) antigen. 879 70

Effects on the liver of the antiangiogenesis agent O-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on hematogenous metastasis of a human pancreatic carcinoma cell line were examined. One million PCI-43 cells, a human pancreas carcinoma cell line, were injected into the spleen of SCID beige mice, then TNP-470 at 30 mg/kg was administered subcutaneously every other day. The mice were killed 6 or 10 weeks thereafter and metastatic nodules in the liver were counted and measured microscopically. Metastases were inhibited and an approximately 10% loss of weight was evident in the TNP-470-administered mice. There was no suppression in maximal size of metastatic colonies in mice given the agent for 6 weeks, while inhibition was apparent in mice given the drug for 10 weeks. Suppression of proliferation and an increase in apoptosis were evident in metastatic nodules in the TNP-470-administered groups, following stainings for proliferative cell nuclear antigen and terminal deoxytransferase-mediated dUTP-biotin nick end-labeling, respectively. TNP-470 inhibited the proliferation of human umbilical vein endothelial cells but not PCI-43 in vitro. TNP-470 did not suppress production of vascular endothelial growth factor by PCI-43 cells. Neovascularization in vivo induced by PCI-43 cells was suppressed in the TNP-470-administered mice, using a diffusion chamber placed in subcutaneous tissues of SCID beige mice. These observations suggest that inhibition of angiogenesis is effective in suppressing establishment and subsequent growth of hematogenous micrometastases of pancreatic adenocarcinoma to the liver.
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PMID:Inhibitory effects of the antiangiogenic agent TNP-470 on establishment and growth of hematogenous metastasis of human pancreatic carcinoma in SCID beige mice in vivo. 933 88

Production of interleukin-6 (IL-6) by human pancreatic carcinoma cells inversely correlates with potentials for blood-borne metastasis to the liver in nude mice. IL-6 cDNA was transfected to PCI-43, one of our cultured pancreatic carcinoma cell lines that does not produce IL-6 and generates numerous metastases to the liver. An IL-6 high-producer clone (PCI-43h) generated few metastases; IL-6 production thus has a direct effect on metastasis, whereas other transfectants (PCI-43l and PCI-43n), which are IL-6 low-, and IL-6 non-producers, respectively, did generate metastases. Tumor-reactive IgG, which mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, was detected in sera from recipient nude mice inoculated with PCI-43h but not in sera from mice given PCI-43l, PCI-43n or parent PCI-43. Tumor-reactive IgM was detected in sera from all mice, irrespective of inoculated PCI-43 species, with a slight augmentation being noted in PCI-43h-inoculated nude mice. Severe combined immunodeficiency (SCID) beige mice were then used as recipients for PCI-43 species, and tumorigeneity was examined by s.c. inoculation of a suboptimal number of PCI-43 transfectants (1 x 10(6)/0.1 ml). Only PCI-43h formed palpable masses in SCID beige mice, whereas it first grew to be palpable but subsequently became not palpable in nude mice, thereby revealing a dual action of tumor-derived IL-6. Thus, tumor-derived IL-6 confers growth promotion in SCID beige mice, while the same cytokine exhibits anti-tumorigenic functions, presumably through humoral immune responses, in nude mice.
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PMID:Interleukin-6 produced by pancreatic carcinoma cells enhances humoral immune responses against tumor cells: a possible event in tumor regression. 946 20

We assessed a regimen of alternating regional and systemic therapy in patients with gastrointestinal malignancies with liver-dominant metastases for feasibility, toxicity, response rate, response duration, patterns of progression, and progression-free and overall survival. Regional therapy comprised selective hepatic transcatheter arterial chemoembolization (TACE) using a suspension of cisplatin and particulate polyvinyl alcohol. This procedure was delivered between cycles of protracted continuous infusion 5-fluorouracil (PCI-5FU) as systemic chemotherapy. Patient eligibility criteria included: (a) having histologically documented adenocarcinoma arising from a gastrointestinal primary site with unresectable liver metastases bidimensionally measurable on computerized tomography scan; (b) age greater than 18 years; and (c) performance status 0-2 (Zubrod). PCI-5FU (250 mg/m2/day) was administered i.v. for 28 days, followed by the first TACE (TACE 1) delivered to the hepatic artery supplying the lobe with the greatest tumor burden. Restaging was performed before TACE 2 and TACE 3, which followed at monthly intervals. PCI-5FU for 21 days was sandwiched between each of the TACE treatments. After the final TACE, maintenance PCI-5FU was given for 28 days of each 35-day cycle until toxicity or progression. Between December 23, 1991, and January 19, 1995, 32 patients were registered in this trial, of whom 27 were eligible; 20 completed one or more treatment cycles and were evaluable for radiographic response. Patients with colorectal liver metastases predominated (74%). Twelve (44%) of 27 patients had failed one or more prior treatment regimens. There were no treatment-related deaths, and hematological and hepatic toxicities were generally manageable and reversible. Two patients, however, developed hepatic abscesses requiring drainage, and one patient developed an infarcted gallbladder, which necessitated cholecystectomy. There were no patients with complete responses; there were 8 (40%) with partial responses, 4 (20%) with minor responses, 2 (10%) with stable disease, and 6 (30%) who progressed on the treatment. The median duration of response for partial responders was 4.2 months (127 days; range, 56-245 days). The median reduction in carcinoembryonic antigen for responders was 87.5%. Two patients underwent subsequent resection of residual metastases; one of them is still alive at 58.4 months follow-up. The predominant site of disease progression was the liver; 25% of the patients progressed in extrahepatic sites. The median overall survival for the whole group is 14.3 months (95% confidence interval, 7.2-16.2). Actuarial overall survival for the whole group at 1 year and 2 years is 57 and 19%, respectively. Alternating systemic PCI-5FU and regional TACE (cisplatin/polyvinyl alcohol) is an active and feasible regimen with manageable toxicities in patients with metastatic gastrointestinal malignancies with liver-dominant disease and merits further investigation. The complications seen were in line with those reported at other specialized centers.
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PMID:Hepatic transcatheter arterial chemoembolization alternating with systemic protracted continuous infusion 5-fluorouracil for gastrointestinal malignancies metastatic to liver: a phase II trial of the Puget Sound Oncology Consortium (PSOC 1104). 991 7

Human glandular kallikrein 2 (hK2) is a serine protease expressed by the prostate gland with 80% identity in primary structure to prostate-specific antigen (PSA). Recently, hK2 was shown to activate the zymogen form of PSA (proPSA) in vitro and is likely to be the physiological activator of PSA in the prostate. hK2 is also able to activate urokinase and effectively cleave fibronectin. We studied the substrate specificity of hK2 and regulation of its activity by zinc and extracellular protease inhibitors present in the prostate and seminal plasma. The enzymatic activity and substrate specificity was studied by determining hK2 cleavage sites in the major gel proteins in semen, semenogelin I and II, and by measuring hydrolysis of various tripeptide aminomethylcoumarin substrates. HK2 cleaves substrates C-terminal of single or double arginines. Basic amino acids were also occasionally found at several other positions N-terminal of the cleavage site. Therefore, the substrate specificity of hK2 fits in well with that of a processor of protein precursors. Possible regulation mechanisms were studied by testing the ability of Zn2+ and different protease inhibitors to inhibit hK2 by kinetic measurements. Inhibitory constants were determined for the most effective inhibitors PCI and Zn2+. The high affinity of PCI for hK2 (kass = 2.0 x 10(5) M-1 x s-1) and the high concentrations of PCI (4 microM) and hK2 (0.2 microM) in seminal plasma make hK2 a very likely physiological target protease for PCI. hK2 is inhibited by Zn2+ at micromolar concentrations well below the 9 mM zinc concentration found in the prostate. The enzymatic activity of hK2 is likely to be reversibly regulated by Zn2+ in prostatic fluid. This regulation may be impaired in CAP and advanced metastatic cancer resulting in lack of control of the hK2 activity and a need for other means of control.
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PMID:Enzymatic action of human glandular kallikrein 2 (hK2). Substrate specificity and regulation by Zn2+ and extracellular protease inhibitors. 1041 40

Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.
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PMID:Motexafin gadolinium: gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120. 1472 95

To improve the prognosis of limited stage small cell lung cancer (LS-SCLC) the addition of concurrent thoracic radiotherapy to a platinum-containing regimen is important. In the Netherlands, we initiated a multicenter, phase II study, of the combination of four cycles of carboplatin (AUC 5), paclitaxel (200 mg m(-2)) and etoposide (2 x 50 mg orally for 5 days) combined with 45 Gy (daily fractions of 1.8 Gy). The radiation was given to the involved field and concurrently with the second and third chemotherapy cycle. Patients with a partial or complete response received prophylactic cranial irradiation to a dose of 30 Gy. From January 1999 to December 2001, 37 of the 38 patients with LS-SCLC entered were eligible for toxicity analysis and response. Grade 3 and 4 haematological toxicity occurred in 57% (21/37) with febrile neutropenia in 24% (9/37). There were no treatment-related deaths or other grade 4 toxicity. Grade 3 toxicities were oesophagitis (27%), radiation pneumonitis (6%), anorexia (14%), nausea (16%), dyspnea (19%) and lethargy (22%). The objective response rate was 92% (95% confidence interval (CI) 80-98%) with a median survival time of 19.5 months (95% CI 12.8-29.2). The 1-, 2- and 5-year survival rate was 70, 47 and 27%, respectively. In field local recurrences occurred in six patients. Distant metastases were observed in 19 patients of which 13 in the brain. This study indicates that combination chemotherapy with concurrent involved-field radiation therapy is an effective treatment for LS-SCLC. Despite PCI, the brain remained the most important site of recurrence.
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PMID:Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study. 1759 61


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