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ABSTRACT: Primitive neuroectodermal tumors (PNET) arising directly from the lung are very rare but particularly aggressive neoplasms. We report a case of a 31-year-old man with primary pulmonary neuroectodermal tumor. We review the clinical as well as pathological features. As typical for these tumors, the diagnosis was initially delayed in our patient and prognosis was poor despite aggressive surgical resection, postoperative chemotherapy and local irradiation. Recent biological insights have revealed unique chromosomal translocations crucial to the pathogenesis of these tumors, most notably the EWS-FLI-1 translocation. We provide an overview of the molecular features of the Ewing Sarcoma Family of Tumors (ESFT) including PNET and their potential implications for therapeutic targeting.
Cancer biology & therapy 10/2012; 14(2). · 2.64 Impact Factor
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ABSTRACT: Integrin alpha(4)beta(1) is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin alpha(4)beta(1) antagonists. We documented tumor uptake of derivatives labeled with (125)I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin alpha(4)beta(1) predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic ((18)F) or radiotherapeutic ((131)I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies.
Cancer Research 07/2010; 70(13):5448-56. · 7.86 Impact Factor
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ABSTRACT: Current cancer chemotherapeutic agents clinically deployed today are designed to be indiscriminately cytotoxic, however, achieving selective targeting of cancer malignancies would allow for improved diagnostic and chemotherapeutic tools. Integrin alpha(4)beta(1), a heterodimeric cell surface receptor, is believed to have a low-affinity conformation in resting normal lymphocytes and an activated high-affinity conformation in cancerous cells, specifically T- and B-cell lymphomas. This highly attractive yet poorly understood receptor has been selectively targeted with the bisaryl urea peptidomimetic antagonist 1. However, concerns regarding its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzothiazole moiety, resulting in an analogue with improved physicochemical properties, solubility, and kidney:tumor ratio while maintaining potency (6; IC(50) = 53 pM). The results presented herein utilized heterocyclic and solid-phase chemistry, cell adhesion assay, and in vivo optical imaging using the cyanine dye Cy5.5 conjugate.
Journal of Medicinal Chemistry 01/2009; 52(1):14-9. · 4.80 Impact Factor
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ABSTRACT: Increasing literature suggests that cell adhesion molecule alpha4beta1 integrin plays a pivotal role in autoimmune diseases and cancer development. Noninvasive visualization of alpha4beta1 integrin in vivo will facilitate the understanding of its involvement in disease progression and development of targeted therapies. Due to the lack of high-affinity targeting ligands, molecular imaging of alpha4beta1 integrin is much less explored than that of alphavbeta3 and alphavbeta5 integrins. We have recently reported using the one bead-one compound combinatorial library method to identify a peptidomimetic, LLP2A, that preferentially binds to activated alpha4beta1 integrin. Here, we described the use of LLP2A-Cy5.5 conjugate as an in vivo optical imaging probe in a human lymphoma xenograft model. This univalent LLP2A-Cy5.5 conjugate retained the binding activity and specificity to alpha4beta1 integrin as shown by cell binding assays using alpha4beta1-positive Molt-4 T-leukemia cells. The subcutaneous Molt-4 tumor was clearly visualized from 1 to 24 h after tail vein injection of the conjugate. Direct imaging and confocal microscopic examination of excised tumors and organs confirmed the accumulation of LLP2A in tumors and revealed very little or no uptake in normal organs except for lymph nodes. Kidney uptake was high when the whole organ was scanned but it was negative when examined microscopically, suggesting that LLP2A bound to the renal tubules loosely. Tumor uptake of LLP2A-Cy5.5 conjugate was blocked by excess unlabeled LLP2A. This study showed that the combinatorial chemical library-derived peptidomimetic LLP2A can be easily developed into an optical imaging probe for noninvasively monitoring of activated alpha4beta1 integrin in vivo.
Molecular Cancer Therapeutics 03/2008; 7(2):432-7. · 5.23 Impact Factor
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ABSTRACT: The cell surface receptor alpha 4 beta 1 integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety, resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC50 = 305 pM]. With exceptional solubility, this finding has the potential for improving PK to help diagnose and treat lymphomas.
Journal of Medicinal Chemistry 12/2007; 50(23):5863-7. · 5.25 Impact Factor
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ABSTRACT: The cell surface receptor α4β1 integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety, resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC50 = 305 pM]. With exceptional solubility, this finding has the potential for improving PK to help diagnose and treat lymphomas.
10/2007;
