Paul J Shami

University of Utah, Salt Lake City, UT, United States

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Publications (28)115 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO) possesses antitumour activity. It induces differentiation and apoptosis in acute myeloid leukaemia (AML) cells. The NO prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate, or JS-K, has potent antileukaemic activity. JS-K is also active in vitro and in vivo against multiple myeloma, prostate cancer, non-small-cell lung cancer, glioma and liver cancer. Using the Pluronic P123 polymer, we have developed a micelle formulation for JS-K to increase its solubility and stability. The goal of the current study was to investigate the cellular distribution of JS-K in AML cells. We investigated the intracellular distribution of JS-K (free drug) and JS-K formulated in P123 micelles (P123/JS-K) using HL-60 AML cells. We also studied the S-glutathionylating effects of JS-K on proteins in the cytoplasmic and nuclear cellular fractions. Both free JS-K and P123/JS-K accumulate primarily in the nucleus. Both free JS-K and P123/JS-K induced S-glutathionylation of nuclear proteins, although the effect produced was more pronounced with P123/JS-K. Minimal S-glutathionylation of cytoplasmic proteins was observed. We conclude that a micelle formulation of JS-K increases its accumulation in the nucleus. Post-translational protein modification through S-glutathionylation may contribute to JS-K's antileukaemic properties.
    The Journal of pharmacy and pharmacology. 09/2013; 65(9):1329-36.
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    ABSTRACT: Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - were investigated in U87 glioma cells in vitro and in an orthotopic U87 xenograft model in vivo by magnetic resonance imaging (MRI). In vitro experiments showed dose-dependent antiproliferative and cytotoxic effects in U87 cells. In addition, treatment of U87 cells with JS-K resulted in a dose-dependent activation of soluble guanylate cyclase and intracellular accumulation of cyclic guanosine monophosphate (cGMP) which was irreversibly inhibited by the selective inhibitor of soluble guanylate cyclase ODQ (1H-[1,2,4]oxadiazolo(4,3a)quinoxaline-1-one). Using dynamic contrast enhanced MRI (DCE-MRI) as a minimally invasive technique, we demonstrated for the first time a significant increase in the DCE-MRI read-out initial area under the concentration curve (iAUC(60)) indicating an acute increase in blood-tumor barrier permeability after i.v. treatment with JS-K. Repeated MR imaging of animals with intracranial U87 gliomas under treatment with JS-K (3.5 ╬╝mol/kg JS-K 3x/week) and of untreated controls on day 12 and 19 after tumor inoculation revealed no significant changes in tumor growth, edema formation or tumor perfusion. Immunohistochemical workup of the brains showed a significant antiproliferative effect of JS-K in the gliomas. Taken together, in vitro and in vivo data suggest that JS-K has antiproliferative effects in U87 gliomas and opens the blood-tumor barrier by activation of the NO/cGMP signaling pathway. This might be a novel approach to facilitate entry of therapeutic drugs into brain tumors. DCE-MRI is a non-invasive, repeatable imaging modality to monitor biological effects of NO donors and other experimental therapeutics in intracranial tumor models.
    Nitric Oxide 01/2013; · 3.27 Impact Factor
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    ABSTRACT: JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.
    Bioorganic & medicinal chemistry 03/2012; 20(9):3094-9. · 2.82 Impact Factor
  • Paul J Shami
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    ABSTRACT: With the development of tyrosine kinase inhibitors (TKIs), the management and outlook for patients with chronic myelogenous leukemia (CML) have completely changed over the past 10 years. Imatinib was the first TKI approved to treat CML in the chronic phase. After their initial approval as second-line agents, dasatinib and nilotinib were compared with imatinib in the first-line setting in 2 randomized trials. Both trials showed that therapeutic milestones (complete cytogenetic remission and major molecular remission) occurred earlier with these newer agents, leading to their approval for the treatment of newly diagnosed CML. Therefore, 3 different TKIs are now available for treating CML. Long-term follow-up of patients treated with imatinib shows that the attainment of therapeutic milestones by 12 months of therapy leads to better long-term outcomes. Most patients who experience disease progression on imatinib do so within the first 3 years of therapy. Therefore, one can argue that dasatinib or nilotinib should be chosen to treat patients with newly diagnosed CML. However, these agents do not have the long-term track record of imatinib. This article summarizes the published data and reviews the rationale in choosing the appropriate TKI for first-line treatment of CML in the chronic phase.
    Journal of the National Comprehensive Cancer Network: JNCCN 01/2012; 10(1):112-8; quiz 119. · 5.11 Impact Factor
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    ABSTRACT: Promising drug candidates of the diazeniumdiolate (NONOate) chemical family include several types of thiol modification among their mechanisms of action: 1) drugs designed to release nitric oxide (NO) on reaction with the thiol group of glutathione (GSH) arylate the GSH, a step that removes reducing equivalents from the cell; (2) a similar reaction of the drug with the thiol group of a protein changes its structure, leading to potentially impaired function and cell death; (3) the NO generated as a byproduct in the above reactions can undergo oxidation, leading to S-nitrosylation and S-glutathionylation; and (4) diazeniumdiolates can also generate nitroxyl, which reacts with thiol groups to form disulfides or sulfinamides.
    Forum on immunopathological diseases and therapeutics 01/2012; 3(2):91-95.
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    ABSTRACT: Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.
    Journal of Medicinal Chemistry 11/2011; 54(22):7751-8. · 5.61 Impact Factor
  • Sujata Narayanan, Paul J Shami
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    ABSTRACT: Acute lymphoblastic leukemia (ALL) in adults is an uncommon but devastating malignant proliferation of lymphoid precursors. Treatment programs for adult patients are largely based on pediatric regimens. However, cure rates in adults have been limited to 30-40% for the past several decades as opposed to the 80% cure rate in children. Treatment of adolescents and young adults is evolving with the adoption of more aggressive "pediatric-inspired" treatment programs. The role of allogeneic stem cell transplant is first remission remains controversial in spite of recent data suggesting improved outcomes in patients younger than 35. Kinase inhibitors in combination with standard chemotherapy have significantly improved outcomes in ALL associated with the Philadelphia chromosome. The treatment of ALL in the elderly remains challenging. Promising new agents such as nelarabine and clofarabine may improve the outlook. This article reviews the current state of the art for the treatment of ALL in adults.
    Critical reviews in oncology/hematology 02/2011; 81(1):94-102. · 5.27 Impact Factor
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    ABSTRACT: Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here, we show that O(2)-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent cytotoxic agent against a subset of human non-small-cell lung cancer cell lines both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines seem to be related to their endogenous levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, which, combined with the arylating properties of the compound, was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization, and cytochrome c release. Inactivation of manganese superoxide dismutase by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy.
    Journal of Pharmacology and Experimental Therapeutics 10/2010; 336(2):313-20. · 3.89 Impact Factor
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    ABSTRACT: Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity. We studied the effect of JS-K on angiogenesis in human umbilical vein endothelial cells (HUVECs), OPM1 multiple myeloma cells, chick aortic rings and in mice. JS-K inhibited the proliferation of HUVECs with a 50% inhibitory concentration (IC50) of 0.432, 0.466 and 0.505 microm at 24, 48 and 72 h, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 microm, respectively. JS-K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 microm. In the chick aortic ring assay using VEGF or FGF-2 for vessel growth stimulation, 0.5 microm JS-K completely inhibited vessel growth. JS-K inhibited tumour angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells. JS-K is a potent inhibitor of angiogenesis in vitro and tumour vessel growth in vivo. As such, it establishes a new class of antineoplastic agent that targets the malignant cells directly as well as their microenvironment.
    The Journal of pharmacy and pharmacology. 01/2010; 62(1):145-51.
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    ABSTRACT: The selenoenzyme thioredoxin reductase 1 has a complex role relating to cell growth. It is induced as a component of the cellular response to potentially mutagenic oxidants, but also appears to provide growth advantages to transformed cells by inhibiting apoptosis. In addition, selenocysteine-deficient or alkylated forms of thioredoxin reductase 1 have also demonstrated oxidative, pro-apoptotic activity. Therefore, a greater understanding of the role of thioredoxin reductase in redox initiated apoptotic processes is warranted. The role of thioredoxin reductase 1 in RKO cells was evaluated by attenuating endogenous thioredoxin reductase 1 expression with siRNA and then either inducing a selenium-deficient thioredoxin reductase or treatment with distinct redox challenges including, hydrogen peroxide, an oxidized lipid, 4-hydroxy-2-nonenol, and a nitric oxide donating prodrug. Thioredoxin redox status, cellular viability, and effector caspase activity were measured. In cells with attenuated endogenous thioredoxin reductase 1, a stably integrated selenocysteine-deficient form of the enzyme was induced but did not alter either the thioredoxin redox status or the cellular growth kinetics. The oxidized lipid and the nitric oxide donor demonstrated enhanced cytotoxicity when thioredoxin reductase 1 was knocked-down; however, the effect was more pronounced with the nitric oxide prodrug. These results are consistent with the hypothesis that attenuation of the thioredoxin-system can promote apoptosis in a nitric oxide-dependent manner.
    PLoS ONE 01/2010; 5(1):e8786. · 3.73 Impact Factor
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    ABSTRACT: The nitric oxide (NO) prodrug JS-K is shown to have anticancer activity. To profile the molecular events associated with the anticancer effects of JS-K, HL-60 leukemia cells were treated with JS-K and subjected to microarray and real-time RT-PCR analysis. JS-K induced concentration- and time-dependent gene expression changes in HL-60 cells corresponding to the cytolethality effects. The apoptotic genes (caspases, Bax, and TNF-alpha) were induced, and differentiation-related genes (CD14, ITGAM, and VIM) were increased. For acute phase protein genes, some were increased (TP53, JUN) while others were suppressed (c-myc, cyclin E). The expression of anti-angiogenesis genes THBS1 and CD36 and genes involved in tumor cell migration such as tissue inhibitors of metalloproteinases, were also increased by JS-K. Confocal analysis confirmed key gene changes at the protein levels. Thus, multiple molecular events are associated with JS-K effects in killing HL-60, which could be molecular targets for this novel anticancer NO prodrug.
    Genomics 05/2009; 94(1):32-8. · 3.01 Impact Factor
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    ABSTRACT: Here we report a number of novel JS-K structural analogues with sub-micromolar anti-proliferative activities against human leukemia cell lines HL-60 and U937; JS-K is the anti-cancer lead compound O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. The ability of these compounds to generate intracellular nitric oxide correlated well with their observed anti-proliferative effects: analogues that had potent inhibitory activity against leukemia cells formed elevated levels of intracellular nitric oxide.
    Bioorganic & medicinal chemistry letters 04/2009; 19(10):2760-2. · 2.65 Impact Factor
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    ABSTRACT: We have designed prodrugs that release nitric oxide (NO) on metabolism by glutathione S-transferases (GST). This design exploits the upregulation of GST in acute myeloid leukemia (AML) cells. O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent anti-leukemic activity. HL-60 myeloid leukemia cells were used for in vitro studies of the combination of JS-K with daunorubicin (DAUNO), cytarabine (ARA-C) or etoposide (ETOP) using the median effect method to determine synergistic, antagonistic, or additive effects. Combinations of JS-K added simultaneously, 2h before or 2h after the other compounds were used. JS-K and DAUNO were antagonistic in all three drug sequences. JS-K and ETOP were also antagonistic but to a lesser degree. JS-K and ARA-C showed strong synergy. The combination index at the 50% fraction affected was 0.37+/-0.23, 0.24+/-0.27, and 0.15+/-0.11 for simultaneous, JS-K first and ARA-C first additions, respectively. JS-K by itself induced DNA strand breaks at relatively high concentrations. However, at submicromolar concentrations, it significantly augmented ARA-C-induced DNA strand breaks. NMR spectroscopy revealed no evidence of chemical interaction between JS-K and the other chemotherapeutic agents. We conclude that ARA-C and JS-K have synergistic anti-leukemic activity and warrant further exploration in combination.
    Leukemia research 03/2009; 33(11):1525-9. · 2.36 Impact Factor
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    ABSTRACT: Structural analogues of JS-K, an anti-cancer lead compound, were prepared and their in vitro anti-leukemic activity was determined. The rate of nitric oxide release from the corresponding diazeniumdiolate anions did not appear to affect the anti-leukemic activity of the prodrug forms. Two compounds with potent inhibitory activity and a potentially favorable toxicological profile were identified.
    Bioorganic & medicinal chemistry letters 03/2008; 18(3):950-3. · 2.65 Impact Factor
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    ABSTRACT: Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO(*)) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K-induced cytotoxicity was mediated via NO(*) in MM cells. Furthermore, JS-K induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH(2)-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM.
    Blood 08/2007; 110(2):709-18. · 9.06 Impact Factor
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    ABSTRACT: Nitric oxide (NO) induces differentiation and apoptosis in acute myelogenous leukemia (AML) cells. The NO prodrug O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate, or JS-K, has potent antileukemic activity. JS-K induces apoptosis in HL-60 cells by a caspase-dependent mechanism. The purpose of this study was to determine the pathway through which JS-K induces apoptosis. We show that JS-K alters mitochondrial membrane potential (DeltaPsim) and induces cytochrome c release from mitochondria into the cytoplasm. Treatment with JS-K resulted in activation of Caspase (Casp) 9, Casp 3 and Casp 8. JS-K constitutes a promising lead for a new class of anti-leukemic agents.
    Leukemia Research 11/2006; 30(10):1279-83. · 2.76 Impact Factor
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    ABSTRACT: The literature provides evidence that metabolic nitric oxide (NO) release mediates the cytotoxic activities (against human leukemia and prostate cancer xenografts in mice) of JS-K, a compound of structure R(2)N-N(O)=NO-Ar for which R(2)N is 4-(ethoxycarbonyl)piperazin-1-yl and Ar is 2,4-dinitrophenyl. Here we present comparative data on the potencies of JS-K and 41 other O(2)-arylated diazeniumdiolates as inhibitors of HL-60 human leukemia cell proliferation, as well as in the NCI 51-cell-line screen for six of them. The data show JS-K to be the most potent of the 42 in both screens and suggest that other features of its structure and metabolism besides NO release may contribute importantly to its activity. Results with control compounds implicate JS-K's arylating ability, and the surprisingly low IC(50) value of the N-(ethoxycarbonyl)piperazine byproduct of NO release suggests a role for the R(2)N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model.
    Journal of Medicinal Chemistry 08/2006; 49(14):4356-66. · 5.61 Impact Factor
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    ABSTRACT: PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in water. Here we report structure-based optimization efforts resulting in three analogues with improved solubility and stability in aqueous solution. We sought to explain PABA/NO's physicochemical uniqueness among these four compounds, whose aminobenzoic acid precursors differ structurally only in the presence or absence of the N-methyl group and/or the position of the carboxyl moiety (meta or para). Studies revealed that PABA/NO's N-methyl-p-aminobenzoic acid substituent is bound to the dinitrobenzene ring via its carboxyl oxygen while the other three are linked through the aniline nitrogen. This constitutes a revision of the previously published PABA/NO structure. All four analogues reacted with GSH to produce bioactive nitric oxide (NO), but PABA/NO was the most reactive. Consistent with PABA/NO's potent suppression of A2780 human ovarian cancer xenograft growth in mice, it was the most potent of the four in the OVCAR-3 cell line.
    Journal of Medicinal Chemistry 03/2006; 49(3):1157-64. · 5.61 Impact Factor
  • Nitric Oxide-biology and Chemistry - NITRIC OXIDE-BIOL CHEM. 01/2006;
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    ABSTRACT: To determine the optimal methods for pancreatic adenocarcinoma surveillance in high-risk patients with familial melanoma and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. Case report with pedigree analysis and literature review, with an emphasis on guideline development for high-risk kindreds with familial pancreatic adenocarcinoma. A university-affiliated familial melanoma research clinic. Patients The proband was referred as a participant in a research clinic protocol and was found to carry a germline CDKN2A mutation and have a history of melanoma and pancreatic adenocarcinoma. A total of 179 family members were identified through the Utah Population Database and underwent evaluation for history of melanoma and pancreatic adenocarcinoma.Intervention/ Comprehensive family history and pedigree analysis performed by means of personal interview, medical record review, and use of cancer registry and population database records. Mutation status was confirmed by results of DNA sequence analysis. Tumor identity was confirmed with immunohistochemical markers. Estimated risk for pancreatic adenocarcinoma in a high-risk family with CDKN2A-positive melanoma. Guidelines for surveillance in these families were based on review of the literature. Sequence analysis confirmed a CDKN2A mutation, and immunohistochemical evaluation confirmed the diagnoses of metastatic melanoma and metastatic pancreatic adenocarcinoma. Pedigree analysis showed an observed-expected ratio of 8.9 to 12.6 for pancreatic adenocarcinoma and 16.4 to 20.8 for melanoma in this family. Guidelines used for surveillance of kindreds at high risk for pancreatic adenocarcinoma were applied to families with CDKN2A melanoma. Conclusion Patients with melanoma and a germline CDKN2A mutation should be considered for pancreatic adenocarcinoma surveillance that is based on the most recent published studies.
    Archives of Dermatology 09/2003; 139(8):1019-25. · 4.79 Impact Factor

Publication Stats

691 Citations
115.00 Total Impact Points

Institutions

  • 2000–2013
    • University of Utah
      • • Department of Pharmaceutics and Pharmaceutical Chemistry
      • • Department of Internal Medicine
      • • Division of Oncology
      • • School of Medicine
      Salt Lake City, UT, United States
  • 2006–2012
    • National Cancer Institute (USA)
      • Chemical Biology Laboratory
      Maryland, United States
  • 2010
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States