Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nitrosoureas (BCNU, CCNU, methyl CCNU) represent a new class of antineoplastic agents with a broad spectrum of antitumor activity. They are cell-cycle nonspecific cytotoxic agents. Postulated modes of action and pharmacology of these nitrosoureas are reviewed. Their therapeutic effectiveness as single agents and in combinations have been recognized in malignant lymphomas, multiple myeloma, melanoma, glioblastoma multiforme, gastric and colorectal carcionma, and small-cell carcinoma of the lung. The nitrosoureas are administered on an intermittent 6--8-week schedule because of delayed and frequently severe bone marrow toxicity which may be cumulative in nature.
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PMID:Nitrosoureas: a reappraisal of clinical trials. 39 66

Tumor perfusion and oxygenation status have been suggested as factors which may influence treatment outcome in cancer patients. Nuclear medicine assays of tumor perfusion [99mTc-hexamethylpropylenamine oxime (HMPAO)] and tumor hypoxia [123I-iodoazomycin arabinoside (IAZA)] have recently been developed and described. We report on measurements of perfusion and oxygenation status of 27 tumors in 22 patients using these probes. An inverse correlation between tumor uptake of HMPAO and IAZA was measured (p < 0.05), with severe perfusion deficit usually associated with an increased uptake of the hypoxic marker. This trend was observed for limited stage small-cell lung carcinoma, squamous-cell carcinoma of the head and neck, soft-tissue sarcoma, brain metastases from small-cell lung carcinoma and adenocarcinoma of the prostate as a group, but not for glioblastoma multiforme. Whereas each imaging agent can yield information about the physiological status of tumor and normal tissue, the information resulting from their combined use could be important in cancer therapy.
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PMID:Imaging tumor hypoxia and tumor perfusion. 838 42

Two novel porphyrin-bisacridine conjugates (1 and 2) were designed as bifunctional antitumour agents to combine the DNA-binding character of the acridines and the photosensitizing capacity of porphyrin, and have been subjected to biophysical and biological evaluation. The interactions of the conjugates with calf thymus DNA were evaluated using viscometric, spectrophotometric and stopped-flow sodium dodecyl sulphate (SDS) sequestration methods. Both conjugates acted as bis-intercalators via the two acridine chromophores and displayed a longer residence time on DNA relative to the parent acridine ligand. Their biological activity in vitro was studied against the C6 rat glioma, MCF-7, GBM and A431 cell lines. Both conjugates were cytotoxic to all four cell lines. The ID50 (C6 glioma) was essentially the same as that of the parent acridine for one conjugate, but was increased 20-fold for the other, while both conjugates were approximately 10-fold more cytotoxic than the parent porphyrin component. The tissue distribution of the two conjugates was assessed in nude mice xenografted with a human small cell lung carcinoma (POVD). There were large differences in the tissue distribution of the two conjugates, with conjugate 2 localizing 8-fold more in the tumour than conjugate 1.
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PMID:Biophysical and biological evaluation of porphyrin-bisacridine conjugates. 866 8

This retrospective immunohistochemical study compares the expression of five stress-response (heat-shock) proteins (srp's) [srp 90, srp 72, srp 27, alpha B-crystallin and ubiquitin], p53 protein and proliferating cell nuclear antigen (PCNA) in 118 primary brain tumors and 21 carcinoma metastases to the central nervous system. Serial sections of formalin-fixed, paraffin-embedded tissues were used. Most astrocytomas (9/13), ependymomas (5/5), glioblastoma multiforme (GBM) (11/12), schwannomas (19/21), meningiomas (22/23) and breast carcinoma metastases (Br-Mt) (9/10), and some medulloblastomas (5/15), primitive neuroectodermal tumors (PNETs) (5/11), pituitary adenomas (4/7) and lung carcinoma metastases (6/11), but none of 10 oligodendrogliomas had tumor cells that expressed one or more (up to five) srp's. The percentage of tumors with p53-positive cells was variable; the proportion was highest among srp-expressing GBMs (mean: 16.1%) and Br-Mts (mean: 15.3%). The mean PCNA-labeling index (LI) also varied, ranging from 1.2% in the group of pituitary adenomas to 24.5% in Br-Mts, with GBMs (20.4%) and medulloblastomas (18.4%) approaching the latter value. PCNA-LI was higher in the astrocytomas, GBMs, medulloblastomas and PNETs that expressed srp's than in those did not. A high proportion of p53-positive cells (31.3 to 59.0%) and the highest PCNA-LIs (41.0 to 49.0%) were seen in two GBMs and one Br-Mt that expressed all five srp's. We conclude that primary and metastatic tumors of the brain produce one or more stress-related proteins, and that a variable proportion of the tumor cells have immunohistochemically-detectable p53, the expression of which may depend, at least in part, on the growth potential of a given tumor.
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PMID:Brain tumor: immunohistochemical studies on the stress-response proteins, p53 protein and proliferating cell nuclear antigen. 886 93

Using the technique of DD-PCR (differential display-polymerase chain reaction) we isolated a novel gene (D2-2) that is overexpressed in glioblastoma multiforme tissue (GMT) as compared to normal brain tissue (NBT). D2-2 is also highly expressed in recurrent glioma, colon tumor metastatic to brain, breast tumors, prostate tumors and a prostate tumor cell line (LNCaP). Northern blot analysis showed that D2-2 is highly expressed in several tumor cell lines (MOLT lymphoblastic leukemia, SW480 colorectal adrenocarcinoma, A549 lung carcinoma, HL-60 promyelocytic leukemia, S3 HeLa cells, K-562 chronic myelogeneous leukemia and G361 melanoma) as compared to NBT. Additionally, D2-2 is very highly expressed in cell lines derived from glioblastomas, grade IV astrocytomas, normal human fetal astrocytes (NHFA) and glioma. D2-2 is moderately expressed in neuroblastoma, neuroectodermal and medulloblastoma tumor cell lines. D2-2 expression is localized to the frontal lobe, occipital lobe and the cerebellum in the normal brain. Normal tissues such as thyroid, stomach, adrenal cortex, small intestine and pancreas show high expression of D2-2. We also show that D2-2 is expressed 28-fold higher in fetal brain (20 weeks) than in adult brain. Sequence analysis of a 2.0-kb fragment for D2-2 shows no homology to known sequences in the data base.
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PMID:Isolation and characterization of a novel gene from human glioblastoma multiforme tumor tissue. 917 9

Prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that was initially characterized by the monoclonal antibody (mAb) 7E11. PSMA is highly expressed in prostate secretory-acinar epithelium and prostate cancer as well as in several extraprostatic tissues. Recent evidence suggests that PSMA is also expressed in tumor-associated neovasculature. We examined the immunohistochemical characteristics of 7E11 and those of four recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and PM2J004.5), each of which binds a distinct epitope of PSMA. Using the streptavidin-biotin method, we evaluated these mAbs in viable prostate cancer cell lines and various fresh-frozen benign and malignant tissue specimens. In the latter, we compared the localization of the anti-PSMA mAbs to that of the anti-endothelial cell mAb CD34. With rare exceptions, all five anti-PSMA mAbs reacted strongly with the neovasculature of a wide spectrum of malignant neoplasms: conventional (clear cell) renal carcinoma (11 of 11 cases), transitional cell carcinoma of the urinary bladder (6 of 6 cases), testicular embryonal carcinoma (1 of 1 case), colonic adenocarcinoma (5 of 5 cases), neuroendocrine carcinoma (5 of 5 cases), glioblastoma multiforme (1 of 1 cases), malignant melanoma (5 of 5 cases), pancreatic duct carcinoma (4 of 4 cases), non-small cell lung carcinoma (5 of 5 cases), soft tissue sarcoma (5 of 6 cases), breast carcinoma (5 of 6 cases), and prostatic adenocarcinoma (2 of 12 cases). Localization of the anti-PSMA mAbs to tumor-associated neovasculature was confirmed by CD34 immunohistochemistry in sequential tissue sections. Normal vascular endothelium in non-cancer-bearing tissue was consistently PSMA negative. The anti-PSMA mAbs reacted with the neoplastic cells of prostatic adenocarcinoma (12 of 12 cases) but not with the neoplastic cells of any other tumor type, including those of benign and malignant vascular tumors (0 of 3 hemangiomas, 0 of 1 hemangioendothelioma, and 0 of 1 angiosarcoma). The mAbs to the extracellular PSMA domain (J591, J415, and Hybritech PEQ226.5) bound viable prostate cancer cells (LNCaP and PC3-PIP), whereas the mAbs to the intracellular domain (7E11 and Hybritech PM2J004.5) did not. All five anti-PSMA mAbs reacted with fresh-frozen benign prostate secretory-acinar epithelium (28 of 28 cases), duodenal columnar (brush border) epithelium (11 of 11 cases), proximal renal tubular epithelium (5 of 5 cases), colonic ganglion cells (1 of 12 cases), and benign breast epithelium (8 of 8 cases). A subset of skeletal muscle cells was positive with 7E11 (7 of 7 cases) and negative with the other four anti-PSMA mAbs. PSMA was consistently expressed in the neovasculature of a wide variety of malignant neoplasms and may be an effective target for mAb-based antineovasculature therapy.
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PMID:Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. 1039 65

The macrocyclic bisindolylmaleimide, LY333531, selectively inhibits protein kinase C beta 1 and beta 2 isoforms with an approximate IC50 of 5 nanomolar. The efficacy of LY333531 administered alone and in combination with cytotoxic cancer therapies in models of non-small cell lung carcinoma and brain tumors was determined in vivo. In the Lewis lung carcinoma, administration of LY333531 enhanced the activity of paclitaxel and fractionated radiation and, to a lesser degree, carboplatin and gemcitabine. In the human T98G glioblastoma multiforme xenograft, the addition of LY333531 to treatment with carmustine (BCNU) resulted in enhanced tumor response in a nodule grown subcutaneously and increased life-span in animals bearing an intracranial tumor from 37 days in the control animals to 64 days in the BCNU treated animals, and to 104 days in the LY333531 plus BCNU treated animals with 4 out of 5 animals being long-term survivors.
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PMID:Enzymatic rationale and preclinical support for a potent protein kinase C beta inhibitor in cancer therapy. 1047 Mar 81

Antiangiogenic therapy can enhance radiation-induced tumor growth inhibition. However, the effects of combined antiangiogenic and radiation therapy on long-term tumor control and normal tissue response have not been reported. We treated mice bearing two different human tumor xenografts with anti-vascular endothelial growth factor receptor-2 antibody (DC101) and five dose fractions of local radiation and followed them for at least 6 months. DC101 significantly decreased the dose of radiation necessary to control 50% of tumors locally. The decrease was 1.7- and 1.3-fold for the moderately radiosensitive small cell lung carcinoma 54A and the highly radioresistant glioblastoma multiforme U87, respectively. In contrast to tumors, no increase in skin radiation reaction by the antibody was detected. Surprisingly, 44% of mice bearing 54A tumor developed clear ascites after DC101 treatment at its highest dose; this was fatal to 20% of mice. This adverse effect was seen only in mice that received whole-body irradiation 1 day before tumor implantation. The encouraging results on two human tumor xenografts suggest that vascular endothelial growth factor receptor-2 blockade merits further investigation to assess its potential as an enhancer of radiation therapy in the clinic.
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PMID:Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. 1119 92

CP-673,451 is a potent inhibitor of platelet-derived growth factor beta-receptor (PDGFR-beta) kinase- and PDGF-BB-stimulated autophosphorylation of PDGFR-beta in cells (IC(50) = 1 nmol/L) being more than 450-fold selective for PDGFR-beta versus other angiogenic receptors (e.g., vascular endothelial growth factor receptor 2, TIE-2, and fibroblast growth factor receptor 2). Multiple models have been used to evaluate in vivo activity of CP-673,451 and to understand the pharmacology of PDGFR-beta inhibition and the effect on tumor growth. These models include an ex vivo measure of PDGFR-beta phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition. Inhibition of PDGFR-beta phosphorylation in tumors correlates with plasma and tumor levels of CP-673,451. A dose of 33 mg/kg was adequate to provide >50% inhibition of receptor for 4 hours corresponding to an EC(50) of 120 ng/mL in plasma at C(max). In a sponge angiogenesis model, CP-673,451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. x 5, p.o., corresponding to 5.5 ng/mL at C(max)). The compound did not inhibit vascular endothelial growth factor- or basic fibroblast growth factor-induced angiogenesis at concentrations which inhibited tumor growth. The antitumor efficacy of CP-673,451 was evaluated in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. Once-daily p.o. x 10 days dosing routinely inhibited tumor growth (ED(50) < or = 33 mg/kg). These data show that CP-673,451 is a pharmacologically selective PDGFR inhibitor, inhibits tumor PDGFR-beta phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.
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PMID:Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. 1570 96

NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily x 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.
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PMID:Phase I trial of intravenous IL-4 pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor. 1600 Sep 56


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