Repeated immunization with plasmid DNA formulated in poly(lactide-co-glycolide) microparticles is well tolerated and stimulates durable T cell responses to the tumor-associated antigen cytochrome P450 1B1

Luby, Thomas M.; Cole, Gerald A.; Baker, Lisa; Kornher, J.Steven; Ramstedt, Urban; Hedley, Mary Lynne

doi:10.1016/j.clim.2004.04.002

Cited by 41 publications

(17 citation statements)

References 21 publications

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“…CYP1B1 showed a highly significant overexpression in ovarian cancer, and of the P450s that are overexpressed in tumors its exploitation as a therapeutic target is the most advanced with an anticytochrome P450 vaccine about to enter phase 2 clinical trials having completed a successful phase 1 trial (29). Although the P450s are located intracellularly, proteolytic processing of the P450s results in peptides being presented on the cell surface that are available to be recognized as tumor antigens (30,31).…”

Section: Discussionmentioning

confidence: 99%

Profiling Cytochrome P450 Expression in Ovarian Cancer: Identification of Prognostic Markers

Downie

McFadyen

Rooney

et al. 2005

Clinical Cancer Research

154

124

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Purpose: The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. Experimental Design: Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. Results: In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/ negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1were also independent markers of prognosis. Conclusions: The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1in primary ovarian cancer were independent markers of prognosis.Ovarian cancer is the most common gynecological malignancy worldwide; yet, the 5-year survival rate for this disease has remained low at f30% for the last 20 years and with relatively little recent improvement (1, 2). Poor prognosis is generally considered to be the result of late presentation when ovarian cancer is of advanced stage and the unpredictable and generally very limited response of this type of cancer to current cancer therapies (3, 4). Improved survival in ovarian cancer is, therefore, dependent on the development of new paradigms in treatment.The cytochrome P450 (P450) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that metabolize many lipophilic, biologically active endogenous and xenobiotic substrates, including a large number of therapeutic drugs and toxic environmental chemicals (5 -8). Currently, the human P450 superfamily is classified into 18 distinct families based on nucleic acid homology (5). Some P450s, especially the major xenobiotic metabolizing forms of P450, have been very well characterized, whereas very little is known about the biology of some of the more recently identified P450s. Individual P450s show characteristic cell type -and tissue-spe...

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Section: Discussionmentioning

confidence: 99%

Profiling Cytochrome P450 Expression in Ovarian Cancer: Identification of Prognostic Markers

Downie

McFadyen

Rooney

et al. 2005

Clinical Cancer Research

154

124

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“…Several cancer therapy approaches under development are focusing on CYP1B1. One of them, ZYC300, is an immunotherapy approach promoting the immune system to react toward the CYP1B1 overexpressing tumor cells (Luby et al 2004;Maecker et al 2003). One Phase I trial was successfully completed a few years ago (Gribben et al 2005) and…”

Section: Cyp1b1mentioning

confidence: 99%

Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment

et al. 2009

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The cytochromes P450 (CYPs) are very efficient catalysts of foreign compound metabolism and are responsible for the major part of metabolism of clinically important drugs. The enzymes are important in cancer since they (a) activate dietary and environmental components to ultimate carcinogens, (b) activate or inactivate drugs used for cancer treatment, and (c) are potential targets for anticancer therapy. The genes encoding the CYP enzymes active in drug metabolism are highly polymorphic, whereas those encoding metabolism of precarcinogens are relatively conserved. A vast amount of literature is present where investigators have tried to link genetic polymorphism in CYPs to cancer susceptibility, although not much conclusive data have hitherto been obtained, with exception of CYP2A6 polymorphism and tobacco induced cancer, to a great extent because of lack of important functional polymorphisms in the genes studied. With respect to anticancer treatment, the genetic CYP polymorphism is of greater importance, where treatment with tamoxifen, but also with cyclophosphamide and maybe thalidomide is influenced by CYP genetic variants. In the present review we present updates on CYP genetics, cancer risk and treatment and also epigenetic aspects of interindividual variability in CYP expression and the use of these enzymes as targets for cancer therapy. We conclude that the CYP polymorphism does not predict cancer susceptibility to any large extent but that this polymorphism might be an important factor for optimal cancer therapy using selected anticancer agents.

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“…Lipid complexes can include varying combinations of cationic lipids and cholesterol (40). Microparticulates include DNA adsorbed to or entrapped in biodegradable microparticles such as poly-lactide-co-glycolide or chitosan, or complexed with nonionic block copolymers or polycations such as polyethyleneimine (39,41,42). Among the classical adjuvants, aluminum phosphate is noteworthy for its effectiveness and simplicity of preparation (43).…”

Section: Formulations and Targetingmentioning

confidence: 99%

DNA Vaccines: Progress and Challenges

Donnelly

Wahrén²,

Liu³

2005

The Journal of Immunology

403

245

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In the years following the publication of the initial in vivo demonstration of the ability of plasmid DNA to generate protective immune responses, DNA vaccines have entered into a variety of human clinical trials for vaccines against various infectious diseases and for therapies against cancer, and are in development for therapies against autoimmune diseases and allergy. They also have become a widely used laboratory tool for a variety of applications ranging from proteomics to understanding Ag presentation and cross-priming. Despite their rapid and widespread development and the commonplace usage of the term “DNA vaccines,” however, the disappointing potency of the DNA vaccines in humans underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the varied immunological mechanisms that play a role in their ability to generate immune responses.

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Repeated immunization with plasmid DNA formulated in poly(lactide-co-glycolide) microparticles is well tolerated and stimulates durable T cell responses to the tumor-associated antigen cytochrome P450 1B1

Cited by 41 publications

References 21 publications

Profiling Cytochrome P450 Expression in Ovarian Cancer: Identification of Prognostic Markers

Profiling Cytochrome P450 Expression in Ovarian Cancer: Identification of Prognostic Markers

Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment

DNA Vaccines: Progress and Challenges

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