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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinomas that originate in the ovary or from different sites in the gastrointestinal tract frequently develop metastases that involve the peritoneal and serosal surfaces. Carcinomatous involvement of the peritoneum is a significant cause of morbidity and mortality. Advances in our understanding of the immunobiology of the peritoneal cavity and the availability of technically advanced immunotherapeutic agents are providing an important opportunity for the intraperitoneal delivery of these agents. This review describes newer concepts in tumor immunology that have a bearing on the further development of intraperitoneal immunotherapy; delivery systems for and issues to be resolved in intraperitoneal immunotherapy, and results of studies with recombinant interferons alpha and gamma and interleukin (IL)-2, cellular therapies including lymphokine-activated killer cells, tumor-infiltrating lymphocytes, monoclonal antibodies, and intraperitoneal radioimmunotherapy. New trials of intraperitoneal immunotherapy employing novel agents, including IL-12 and genetically modified tumor vaccines, are discussed, as are issues related to the integration of immunotherapy with standard chemotherapy agents. A number of immunotherapy agents have been tested intraperitoneally and have shown promising clinical activity with acceptable toxicity. Complete responses have been documented at surgical restaging, and intraperitoneal treatments with these agents may soon be included in the therapeutic armamentarium for patients with peritoneal carcinomatosis.
Cytokines Cell Mol Ther 1998 Jun
PMID:Intraperitoneal immunotherapy of peritoneal carcinomatosis. 968 Dec 51

Oncolytic viral therapy is a promising new method of cancer treatment. Peritoneal dissemination of cancer is a common and fatal clinical condition seen in many malignancies, with few effective therapies available. G207, a multimutated replication-competent herpes simplex virus type-1, effectively treats disseminated peritoneal cancer. This study evaluates viral proliferation and subsequent tumoricidal effects in vitro and in vivo after regional viral delivery. In vitro studies demonstrate that G207 efficiently kills five human gastric cancer cell lines, and that permissiveness to viral replication is correlated with cytotoxicity. In a murine xenograft model of human gastric carcinomatosis, peritoneal delivery of G207 effectively kills tumor and prolongs survival. Data from quantitative PCR characterizes peritoneal clearance of virus after intraperitoneal injection, and identifies G207 replication within tumor cells in vivo, similar to in vitro proliferation. Further analysis of various organs confirms that G207 does not replicate within normal tissue after peritoneal delivery. Wild-type KOS viral replication was also demonstrated in vivo, with significant toxicity secondary to dissemination and encephalitis. In vivo viral proliferation of G207 is restricted to tumor cells, is correlated with in vitro assays, and is an important mechanism of anticancer efficacy.
J Mol Med (Berl) 2000
PMID:Antitumor efficacy of regional oncolytic viral therapy for peritoneally disseminated cancer. 1086 79

Although somatostatin-based peptide receptor imaging (sst-PRI) and peptide receptor radiotherapy (sst-PRRT) of human endocrine tumours and their metastases has become a valuable method, the experience with radiohalogenated sst-directed peptides has so far been disappointing. To extend the broad spectrum of radiohalogens with suitable radionuclide properties for sst-PRI and PRRT, new strategies in ligand development are required. The major drawbacks to be overcome include fast hepatic uptake, high abdominal background activity and low tumour uptake. Recently we introduced radiolabelled glycated octreotides as a new series of sst-binding radiotracers with excellent physicochemical characteristics. In this study we compared [(125)I]Tyr(3)-octreotide ([(125)I]TOC, ( 1)), [(125)I]Tyr(3)-octreotate ([(125)I]TOCA, ( 2)) and a carbohydrated octreotide derivative, maltotriose-[(125)I]Tyr(3)-octreotate ([(125)I]Mtr-TOCA, ( 3)) to evaluate the effect of single C-terminal oxidation and simultaneous N-terminal carbohydration. The biodistribution was compared in nude mice bearing AR42J tumour xenografts. Compared with ( 1), activity uptake of ( 2) and ( 3) at 1 h was decreased in intestine [36% ( 2), 72% ( 3)], liver [62% ( 2), 79% ( 3)] and kidney [34% ( 2), 41% ( 3)], respectively. Blood clearance was fast for all compounds investigated. Using ( 1) as reference, tumour uptake of ( 2) and ( 3) was 3.8- and 4.3-fold higher at 1 h p.i. At 1 h the tumour-to-blood ratio of ( 3) was 28.2+/-7.3, and the tumour-to-muscle ratio, 147+/-48. Specificity of tumour uptake was demonstrated in AR42J tumour-bearing mice by pretreatment with 0.8 mg TOC/kg 5 min prior to injection of ( 3). In cells transfected with sst1-sst5, the binding profile of I-Mtr-TOCA revealed a very high affinity and selectivity for sst2. In a first scintigraphic [(123)I]Mtr-TOCA study of a patient with a carcinoid of the small intestine with known peritoneal carcinomatosis and a solitary liver metastasis, all tumour tissues, including the liver metastasis, were well defined and clearly visible as soon as 30 min p.i. Based on these encouraging findings we conclude that carbohydration is a powerful strategy for the development of new radiolabelled sst-binding peptides and may represent a general method to improve pharmacokinetics of other peptide radioligands. [(123)I]Mtr-TOCA is a very promising new candidate for sst-directed PRI.
Eur J Nucl Med Mol Imaging 2002 Jan
PMID:Comparison of radioiodinated TOC, TOCA and Mtr-TOCA: the effect of carbohydration on the pharmacokinetics. 1180 4

Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.
Mol Ther 2003 Sep
PMID:Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus. 1294 18

Four cases of mixed carcinoid and adenocarcinoma of the appendix were reported. All cases presented with a dominant cecal-appendiceal tumor mass and local metastasis. Two patients had multiple peritoneal implants mimicking primary peritoneal serous adenocarcinoma or carcinomatosis. Histopathologic features of the tumors are similar, with infiltrating microglandular and cribriform patterns of tumor nests, and variable numbers of goblet cells. A literature review of "goblet cell carcinoid" that included nonlocalized cases revealed a significant percentage (>14%) of tumor-associated death, in contrast to the classic carcinoid tumor. Immunohistochemical stains were helpful to separate these tumors from carcinoid tumors and primary peritoneal serous adenocarcinoma. Mixed carcinoid and adenocarcinomas were cytokeratin (CK)-20 positive, and negative or weakly positive for chromogranin A and synaptophysin. Carcinoid tumors were CK20 negative and diffusely positive for chromogranin A and synaptophysin. Peritoneal serous adenocarcinomas were CK20 negative. These cases were clinically aggressive, and 1 patient had multiple recurrences and responded partially to chemotherapy.
Appl Immunohistochem Mol Morphol 2004 Sep
PMID:Mixed carcinoid and adenocarcinoma of the appendix: report of 4 cases with immunohistochemical studies and a review of the literature. 1555 43

The small GTP-binding protein Rho and its target Rho-associated kinase trigger an intracellular signaling cascade that controls actin cytoskeleton and plays an essential role in cell motility and adhesion. A specific Rho-associated kinase inhibitor, Y-27632, has been reported to inhibit cancer invasion. Clinically, disseminated tumor cells in the cerebrospinal fluid invade the intraparenchymal region, damaging the brain and nerves, resulting in fatal brain stem dysfunction, despite intrathecal chemotherapy. To expand therapeutic options for this devastating neoplastic meningitis, we evaluated the potential use of intrathecal Y-27632 administration by employing Walker 256 cells, a rat mammary cancer cell line. Y-27632 dose-dependently inhibited chemotactic and invasive activity of Walker 256 cells. Y-27632 also inhibited the phosphorylation level of regulatory myosin light chain in vitro, but the effect was temporary and was considerably diminished within 16 hours. Y-27632 induced striking morphologic changes in Walker 256 cells, as evidenced by decreased cell-matrix adhesion in culture dishes and three-dimensional collagen I gels, and slightly inhibited colony formation in soft agar. Nevertheless, this drug treatment did not affect Walker 256 cell growth rate. We were able to administer continuous delivery of this inhibitor using an osmotic pump and maintaining drug concentration of 10 mumol/L within the brain. Importantly, this concentration of Y-27632 showed minimal neurotoxicity both in vitro and in vivo. We found that an intrathecal therapy, combining 5-fluoro-2'-deoxyuridine with Y-27632, significantly increased the survival time of rats bearing meningeal carcinomatosis in comparison with animals treated with 5-fluoro-2'-deoxyuridine alone. Taken together, our findings indicate that continuous intrathecal administration of Y-27632 could be a promising therapeutic method when combined with chemotherapy for treating human neoplastic meningitis.
Mol Cancer Res 2005 Aug
PMID:Intrathecal administration of Y-27632, a specific rho-associated kinase inhibitor, for rat neoplastic meningitis. 1612 38

We have previously generated antihuman HER2/neu-humanized IgG3 fused to interleukin-2 (IL-2), IL-12, or granulocyte macrophage colony-stimulating factor (GM-CSF) [monofunctional fusion proteins (mono-AbFP)] or fused to IL-2 and IL-12 or IL-12 and GM-CSF [bifunctional fusion proteins (bi-AbFP)]. These AbFPs retained cytokine and antigen-binding activities. We have now further characterized the AbFPs and determined the heparin-binding activity of the fused cytokines, their ability to trigger IFN-gamma secretion and natural killer (NK) activation, and their direct antitumor efficacy. Flow cytometry revealed heparin-binding activity in the AbFPs containing IL-12 and IL-2, although this activity seems to be decreased in the bi-AbFPs. However, both bi-AbFPs retained the capacity to stimulate IL-12-dependent IFN-gamma secretion in the NK cell line KY-1, and IL-12/IL-2 bi-AbFP induced NK activity in splenocytes. The antitumor effectiveness of bi-AbFPs and mono-AbFP combinations was studied in mice challenged i.p. with three different human HER2/neu murine syngeneic models (D2F2/E2, CT26-HER2/neu, and MC38-HER2/neu). Although a significant variability in the profile of antitumor response was observed in the different tumor models, the combination of IL-12 and GM-CSF mono-AbFPs protected 100% of D2F2/E2-challenged and 75% of CT26-HER2/neu-challenged mice. In contrast, bi-AbFPs protected less than the combination of mono-AbFPs and, in some models, even less than mono-AbFPs alone. However, in all cases, most of long-term survivors showed protection after s.c. rechallenge with the tumors and later with the parental tumors not expressing HER2/neu. These results show that, although the pattern of protection is tumor model dependent, treatments with AbFPs can effectively generate high levels of protection against peritoneal tumors expressing HER2/neu, which may be relevant in patients with primary or metastatic peritoneal carcinomatosis that may be observed in ovarian, colon, stomach, bladder, lung, and breast cancers.
Mol Cancer Ther 2006 Apr
PMID:Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors. 1664 75

We have developed and validated a new tumor-targeting gene therapy strategy based upon the targeting and replacement of human telomerase reverse transcriptase (hTERT) RNA, using a trans-splicing ribozyme. By constructing novel adenoviral vectors harboring the hTERT-targeting trans-splicing ribozymes with the downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by the cytomegalovirus (CMV) promoter, we demonstrated that this viral system selectively marks tumor cells expressing hTERT or sensitizes tumor cells to prodrug treatments. We confirmed that Ad-Ribo-LacZ successfully and selectively delivered a ribozyme that performed a highly specific trans-splicing reaction into hTERT-expressing cancer cells, both in vitro and in a peritoneal carcinomatosis nude mouse model. We also determined that the hTERT-specific expression of the suicide gene in the Ad-Ribo-HSVtk, and treatment with the corresponding prodrug, reduced tumor progression with almost the same efficacy as the strong constitutive CMV promoter-driven adenovirus, both in cancer cell lines and in nude mouse HT-29 xenografts. These observations provide the basis for a novel approach to cancer gene therapy, and demonstrate that trans-splicing ribozymes can be employed as targeting anti-cancer agents which recognize cancer-specific transcripts and reprogram them, thereby combating cancerous cells.
Mol Ther 2008 Jan
PMID:In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cells. 1770 May 43

Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP(-/-) mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid-enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of alpha(v) and beta(1) integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP(+/+), SP(-/-) ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP(-/-) ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F(2)alpha) that were positively correlated with extensive infiltration of SP(-/-) ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation.
Mol Cancer Res 2007 Oct
PMID:Normalization of the ovarian cancer microenvironment by SPARC. 1795 2

Ovarian cancer is the leading cause of death from gynecologic cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes ascites. Whereas mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and metastasis, vascular endothelial growth factor promotes tumor angiogenesis, ascites formation, and metastasis in ovarian cancer. In this study, an i.p. model of human ovarian cancer was used to determine the antitumor activity of rapamycin, bevacizumab, and rapamycin plus bevacizumab (BEV/RAPA). We report that administration of rapamycin, bevacizumab, and BEV/RAPA in mice bearing peritoneal OV-90 ovarian carcinoma resulted in 74.6%, 82.4%, and 93.3% reduction in i.p. tumor burden, respectively. BEV/RAPA-induced reduction in microvessel density and inhibition of cell proliferation were associated with significant reduction in hypoxia-inducible factor-1alpha and cyclin D1 and inactivation of downstream targets of mTOR, p70S6 kinase, S6R, and 4E-binding protein 1. BEV/RAPA treatment was not only able to prolong life of i.p. mice but also more effective than rapamycin and bevacizumab to prevent the development of peritoneal carcinomatosis in adjuvant setting and reverse ascites accumulation in heavy peritoneal disease. Our data indicate that simultaneous inhibition of the vascular endothelial growth factor receptor and mTOR pathways with BEV/RAPA or their analogues may represent a novel approach for prevention of metastasis, recurrence, and treatment of ovarian cancer.
Mol Cancer Ther 2007 Nov
PMID:Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer. 1802 80


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