Person: Adelstein, Stanley
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Adelstein
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Stanley
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Adelstein, Stanley
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Publication Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors(American Association for Cancer Research (AACR), 2007-03-01) Pospisil, Pavel; Wang, Ketai; Al Aowad, Ayman F.; Iyer, Lakshmanan K.; Adelstein, Stanley; Kassis, Amin I.We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ(2-P)) was docked in silico into the X-ray structure of PAP. The data indicate that IQ(2-P) docked into the PAP active site with a calculated inhibition constant (K-i) more favorable than that of the PAP inhibitor alpha-benzylaminobenzylphosphonic acid. When (125)IQ(2-P), the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2'-hydroxyphenyl)-6-[I-125] iodo-4-(3H)-quinazolinone ((125)IQ(2-OH))- Similarly, the incubation of IQ(2-P) with human LNCaP, PC-3, and 22110 prostate tumor cells resulted in the formation of large fluorescent IQ(2-OH) crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with (125)IQ(2-P) showed accumulation of radioactive grains ((125)IQ(2-OH)) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radio-therapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases.Publication DMSO Increases Radioiodination Yield of Radiopharmaceuticals(Elsevier BV, 2008-01) Wang, Ketai; Adelstein, Stanley; Kassis, AminA high-yield radioiodination method for various types of molecules is described. The approach employs DMSO as precursor solvent, a reaction ratio of 2-5 precursor molecules per iodine atom, 5-10 mu g oxidant, and a 10-25 mu l reaction volume. The solution is vortexed at room temperature for 1-5 min and progress of the reaction is assessed by HPLC. Radioiodinated products are obtained in >= 95% yield and meet the requirements for radiotracer imaging, biodistribution studies, and molecular and cellular biology research.Publication Novel Method for Quantifying Radiation-Induced Single-Strand-Break Yields in Plasmid DNA Highlights 10-Fold Discrepancy(Elsevier BV, 2011-10) Balagurumoorthy, Pichumani; Adelstein, Stanley; Kassis, AminThe widely used agarose gel electrophoresis method for assessing radiation-induced single-strand-break (SSB) yield in plasmid DNA involves measurement of the fraction of relaxed-circular (C) form that migrates independently from the intact supercoiled (SC) form. We rationalized that this method may underestimate the SSB yield since the position of the relaxed-circular form is not altered when the number of SSB per DNA molecule is >1. To overcome this limitation, we have developed a novel method that directly probes and quantifies SSBs. Supercoiled (3)H-pUC19 plasmid samples were irradiated with gamma-rays, alkali-denatured, dephosphorylated, and kinated with gamma-[(32)P]ATP, and the DNA-incorporated (33)P activities were used to quantify the SSB yields per DNA molecule, employing a standard curve generated using DNA molecules containing a known number of SSBs. The same irradiated samples were analyzed by agarose gel and SSB yields were determined by conventional methods. Comparison of the data demonstrated that the mean SSB yield per plasmid DNA molecule of [21.2 +/- 0.59] x 10(-2) Gy(-1) as measured by direct probing is similar to 10-fold higher than that obtained from conventional gel-based methods. These findings imply that the SSB yields inferred from agarose gels need reevaluation, especially when they were utilized in the determination of radiation risk.Publication Integrative Genomic Data Mining for Discovery of Potential Blood-Borne Biomarkers for Early Diagnosis of Cancer(Public Library of Science, 2008) Yang, Yongliang; Iyer, Lakshmanan K.; Adelstein, Stanley; Kassis, Amin; Hofmann, Oliver; Pospisil, PavelBackground: With the arrival of the postgenomic era, there is increasing interest in the discovery of biomarkers for the accurate diagnosis, prognosis, and early detection of cancer. Blood-borne cancer markers are favored by clinicians, because blood samples can be obtained and analyzed with relative ease. We have used a combined mining strategy based on an integrated cancer microarray platform, Oncomine, and the biomarker module of the Ingenuity Pathways Analysis (IPA) program to identify potential blood-based markers for six common human cancer types. Methodology/Principal Findings: In the Oncomine platform, the genes overexpressed in cancer tissues relative to their corresponding normal tissues were filtered by Gene Ontology keywords, with the extracellular environment stipulated and a corrected Q value (false discovery rate) cut-off implemented. The identified genes were imported to the IPA biomarker module to separate out those genes encoding putative secreted or cell-surface proteins as blood-borne (blood/serum/plasma) cancer markers. The filtered potential indicators were ranked and prioritized according to normalized absolute Student t values. The retrieval of numerous marker genes that are already clinically useful or under active investigation confirmed the effectiveness of our mining strategy. To identify the biomarkers that are unique for each cancer type, the upregulated marker genes that are in common between each two tumor types across the six human tumors were also analyzed by the IPA biomarker comparison function. Conclusion/Significance: The upregulated marker genes shared among the six cancer types may serve as a molecular tool to complement histopathologic examination, and the combination of the commonly upregulated and unique biomarkers may serve as differentiating markers for a specific cancer. This approach will be increasingly useful to discover diagnostic signatures as the mass of microarray data continues to grow in the ‘omics’ era.Publication Radionuclide Therapy with Iodine-125 and Other Auger–Electron-Emitting Radionuclides: Experimental Models and Clinical Applications(Mary Ann Liebert Inc, 2003-12) Bodei, Lisa; Kassis, Amin I.; Adelstein, Stanley; Mariani, GiulianoAuger-electron emitters represent an attractive alternative to beta-particle emitters for cancer therapy if they can be placed intracellularly, especially in close proximity to (or within) nuclear DNA. Based on investigations in animal tumor models, including those for ovarian cancer, bladder cancer, and brain and spinal cord tumors, in which the thymidine analog 5-radioiodo-2'-deoxyuridine (*IUdR) has been shown to be therapeutically efficacious, it is hypothesized that iodine-125 and other Auger-electron-emitting radionuclides might be valuable in the treatment of certain malignant diseases, assuming that uptake of the radiopharmaceutical by tumor cells exceeds that by normal dividing cells. Preliminary patient studies have shown that this requirement can be met partially by the locoregional administration of the radiopharmaceutical and metabolic modulation of its uptake by tumor cells. Investigators continue to seek molecules that can carry Auger-electron emitters to nuclear DNA, especially those radionuclides with higher Auger-electron yields and varying half-lives.Publication Specific Uptake of the Auger Electron-emitting Thymidine Analogue 5-[123I/125I]Iodo-2′-deoxyuridine in Rat Brain Tumors: Diagnostic and Therapeutic Implications in Humans(1990) Adelstein, StanleyGlial neoplasms of the human central nervous system are malignancies that have defied treatment. Part of the problem lies in the limitations of current diagnostic techniques which are unable to identify small collections of neoplastic glia within normal parenchyma and in the difficulty of sterilizing these tumors because of limited selectivity of the cytotoxic agents available. The thymidine analogue 5-iodo-2'-deoxyuridine (IdUrd) radiolabeled with 123I and 125I was injected directly into an intracerebral rat 9L gliosarcoma and found to be a sensitive and specific agent for the detection of this neoplasm in rats. External gamma camera imaging (123I) visualized tumors as small as 0.5 mm in diameter. Autoradiography (125I) indicated that IdUrd was incorporated into the DNA of neoplastic glia only. Since 123I emits gamma-photons suitable for scintigraphy, [123I]IdUrd holds promise for the diagnosis of brain tumors in humans as well. Furthermore, since 123I and 125I are Auger electron emitters that have demonstrated antineoplastic effects, direct administration of [123I]IdUrd or [125I]IdUrd into tumors may also have potential for the treatment of central nervous system malignancies.Publication A Combined Approach to Data Mining of Textual and Structured Data to Identify Cancer-Related Targets(Springer Nature, 2006) Pospisil, Pavel; Iyer, Lakshmanan K; Adelstein, Stanley; Kassis, AminBackground: We present an effective, rapid, systematic data mining approach for identifying genes or proteins related to a particular interest. A selected combination of programs exploring PubMed abstracts, universal gene/protein knowledge bases (LSGraph and Ingenuity Pathway Analysis) was assembled to distinguish enzymes with hydrolytic activities that are expressed in the extracellular space of cancer cells. Proteins were identified with respect to six types of cancer occurring in the prostate, breast, lung, colon, ovary, and pancreas.Results: The data mining method identified previously undetected targets. Our combined strategy applied to each cancer type identified a minimum of 375 proteins expressed within the extracellular space and/or attached to the plasma membrane. The method led to the recognition of human cancer-related hydrolases (on average, similar to 35 per cancer type), among which were prostatic acid phosphatase, prostate-specific antigen, and sulfatase 1.Conclusion: The combined data mining of several databases overcame many of the limitations of querying a single database and enabled the facile identification of gene products. In the case of cancer-related targets, it produced a list of putative extracellular, hydrolytic enzymes that merit additional study as candidates for cancer radioimaging and radiotherapy. The proposed data mining strategy is of a general nature and can be applied to other biological databases for understanding biological functions and diseases.