Synthesis, cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neocryptolepine derivatives.

On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides.

Allogeneic hematopoietic stem cell transplantation in ovarian carcinoma: results of five patients.

Allogeneic hematopoietic stem cell transplantation is often used to treat hematologic malignancies. The efficacy of this procedure is due to both myeloablative conditioning and graft-versus-leukemia (GVL). However, the disadvantages of allogeneic transplantation include graft-versus-host disease (GVHD), relapse from the original tumor, and patient susceptibility to opportunistic infections.

Modelling, synthesis and biological evaluation of an ethidium-arginine conjugate linked to a ribonuclease mimic directed against TAR RNA of HIV-1.

Using molecular modelling studies, an active anti-HIV ethidium-arginine conjugate targeted against the viral TAR RNA sequence has been linked to an artificial ribonuclease, with the aim to obtain an irreversible inhibitor. The ribonuclease moiety consists of an N-[N-(3-aminopropyl)-3-aminopropyl] glycine and has been constructed via two successive N-alkylations following the Fukuyama procedure.

Pancreatic Neuroendocrine Carcinoma Metastatic to the Breast as Part of the Multiple Endocrine Neoplasia Type 1 Syndrome.

Breast metastases from nonmammary tumors are rare. We report here the first case of pancreatic neuroendocrine carcinoma metastatic to the breast in a patient with possible multiple endocrine neoplasia type 1. The diagnosis was supported by histological examination, immunohistochemistry, and ultrastructural analysis.

DNA sequence recognition by the antitumor drug ditercalinium.

The antitumor drug ditercalinium is a rare example of a noncovalent DNA-binding ligand that forms bisintercalation complexes via the major groove of the double helix. Previous structural studies have revealed that the two connected pyridocarbazolium chromophores intercalate into DNA with the positively charged bis(ethylpiperidinium) linking chain oriented to the wide groove side of the helix. Although the interaction of ditercalinium with short oligonucleotides containing 4-6 contiguous GC base pairs has been examined in detail by biophysical and theoretical approaches, the sequence preference for ditercalinium binding to long DNA fragments that offer a wide variety of binding sites has been investigated only superficially.

Reliability of the histopathologic diagnosis of malignant melanoma in childhood.

Objective: To assess interrater reliability in the diagnosis of malignant melanoma in children.

Design, Setting, And Participants: We collected 85 slides of melanomas diagnosed in patients younger than 17 years through a network of dermatopathologists and dermatologists. The slides were classified into 3 categories: (1) slides from children with metastatic melanoma; (2) slides from disease-free children with a follow-up of less than 5 years; (3) slides from disease-free children with a follow-up of 5 years or longer.

Dimers from dechlorinated rebeccamycin: synthesis, interaction with DNA, and antiproliferative activities.

In the course of structure-activity relationships on rebeccamycin analogues, two dimers of dechlorinated rebeccamycin were synthesised with the aim to improve the interaction with DNA and in vitro antiproliferative activities. The synthesis of two dimeric compounds obtained by joining two molecules of dechlorinated rebeccamycin via the imide nitrogen is described. Melting temperature and DNase I footprinting studies were performed to investigate their interaction with DNA.

Induction of apoptosis in HL-60 leukemia and B16 melanoma cells by the acronycine derivative S23906-1.

The benzoacronycine derivative S23906-1 is a highly potent antitumor agent with a broad spectrum of activity against different human solid tumor xenografts. The marked cytotoxic potential of this drug may be the result of its interaction with DNA but the precise mechanism of action remains unclear at present. We have investigated the induction of apoptosis in human promyelocytic leukemia HL-60 and murine melanoma B16 cells treated with S23906-1.

Distribution of furamidine analogues in tumor cells: influence of the number of positive charges.

Fluorescence microscopy has been used to study the cellular distribution properties of a series of DNA binding cationic compounds related to the potent antiparasitic drug furamidine (DB75). The compounds tested bear a diphenylfuran or a phenylfuranbenzimidazole unfused aromatic core substituted with one or two amidine or imidazoline groups. The synthesis of five new compounds is reported.

DNA binding properties of the indolocarbazole antitumor drug NB-506.

Indolocarbazoles derived from the antibiotic rebeccamycin represent an important group of antitumor agents. Several indolocarbazoles are currently undergoing clinical trials. These compounds inhibit topoisomerase 1 to produce DNA breaks that are responsible for cell death.

Synthesis and DNA interaction of a mixed proflavine-phenanthroline Tröger base.

We report the synthesis of an asymmetric Tröger base containing the two well characterised DNA binding chromophores, proflavine and phenanthroline. The mode of interaction of the hybrid molecule was investigated by circular and linear dichroism experiments and a biochemical assay using DNA topoisomerase I. The data are compatible with a model in which the proflavine moiety intercalates between DNA base pairs and the phenanthroline ring occupies the DNA groove.

DNA sequence recognition by the indolocarbazole antitumor antibiotic AT2433-B1 and its diastereoisomer.

The antibiotic AT2433-B1 belongs to a therapeutically important class of antitumor agents. This natural product contains an indolocarbazole aglycone connected to a unique disaccharide consisting of a methoxyglucose and an amino sugar subunit, 2,4-dideoxy-4-methylamino-L-xylose. The configuration of the amino sugar distinguishes AT2433-B1 from its diastereoisomer iso-AT2433-B1.

Comparative thermodynamics for monomer and dimer sequence-dependent binding of a heterocyclic dication in the DNA minor groove.

Phenylamidine cationic groups linked by a furan ring (furamidine) and related symmetric diamidine compounds bind as monomers in the minor groove of AT sequences of DNA. DB293, an unsymmetric derivative with one of the phenyl rings of furamidine replaced with a benzimidazole, can bind to AT sequences as a monomer but binds more strongly to GC-containing minor-groove DNA sites as a stacked dimer. The dimer-binding mode has high affinity, is highly cooperative and sequence selective.

A pilot survey of social work services in pediatric primary care programs in urban teaching hospitals.

Objective: To determine the current status of social work presence in pediatric primary care clinics in urban teaching hospitals.

Design: Survey instrument mailed to the medical directors of outpatient pediatrics in the major pediatric teaching hospital of approved residency programs in the 100 largest metropolitan areas in the United States.

Results: Sixty responses (60%) were received.

Influence of compound structure on affinity, sequence selectivity, and mode of binding to DNA for unfused aromatic dications related to furamidine.

In the course of a program aimed at developing sequence-specific gene-regulatory small organic molecules, we have investigated the DNA interactions of a new series of nine diphenylfuran dications related to the antiparasitic drug furamidine (DB75). Two types of structural modifications were tested: the terminal amidine groups of DB75 were shifted from the para to the meta position, and the amidines were replaced with imidazoline or dimethyl-imidazoline groups, to test the importance of both the position and nature of positively charged groups on DNA interactions. The interactions of these compounds with DNA and oligonucleotides were studied by a combination of biochemical and biophysical techniques.

Novel dications with unfused aromatic systems: trithiophene and trifuran derivatives of furimidazoline.

We report the synthesis, interaction with DNA, topoisomerase II inhibition, and cytotoxicity of two novel unfused aromatic dications derived from the antimicrobial agent furimidazoline. The central diphenylfuran core of furimidazoline has been replaced with a trithiophene (DB358) or a trifuran (DB669) unit and the terminal imidazoline groups were preserved. The strength and mode of binding of the drugs to nucleic acids were investigated by complementary spectroscopic techniques including spectrophotometric, surface plasmon resonance, circular and linear dichroism measurements.

A novel B-ring modified homocamptothecin, 12-Cl-hCPT, showing antiproliferative and topoisomerase I inhibitory activities superior to SN-38.

We report the synthesis and pharmacological evaluation of a novel homocamptothecin (hCPT) derivative, 12-Cl-hCPT, which contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone found in camptothecin (CPT) and bears a chloro substituent at position 12. The capacity of 12-Cl-hCPT to inhibit DNA topoisomerase I was compared with that of SN-38, the active metabolite of the clinically used antitumour prodrug CPT-11. In the DNA relaxation assay, 12-Cl-hCPT proved to be slightly more potent than SN-38 at stimulating the formation of nicked plasmid DNA molecules.

Synthesis and biological activities of indolocarbazoles bearing amino acid residues.

Three indolocarbazole compounds bearing a tripeptide or a lysine group attached to one of the indole nitrogens via a propylamino chain and two rebeccamycin derivatives bearing a lysine residue on the sugar moiety were synthesised with the aim of improving the binding to DNA and the antiproliferative activities. Four tumour cell lines, from murine L1210 leukemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells and their antimicrobial properties against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also investigated.

Active site mutations in DNA topoisomerase I distinguish the cytotoxic activities of camptothecin and the indolocarbazole, rebeccamycin.

DNA topoisomerase I (Top1p) catalyzes topological changes in DNA and is the cellular target of the antitumor agent camptothecin (CPT). Non-CPT drugs that target Top1p, such as indolocarbazoles, are under clinical development. However, whether the cytotoxicity of indolocarbazoles derives from Top1p poisoning remains unclear.

Design and optimization of camptothecin conjugates of triple helix-forming oligonucleotides for sequence-specific DNA cleavage by topoisomerase I.

To achieve a sequence-specific DNA cleavage by topoisomerase I, derivatives of the antitumor drug camptothecin have been covalently linked to triple helix-forming oligonucleotides that bind in a sequence-specific manner to the major groove of double-helical DNA. Triplex formation at the target sequence positions the drug selectively at the triplex site, thereby stimulating topoisomerase I-mediated DNA cleavage at this site. In a continuous effort to optimize this strategy, a broad set of conjugates consisting of (i) 16-20-base-long oligonucleotides, (ii) alkyl linkers of variable length, and (iii) camptothecin derivatives substituted on the A or B quinoline ring were designed and synthesized.

Design of two etoposide-amsacrine conjugates: topoisomerase II and tubuline polymerization inhibition and relation to cytotoxicity.

Topoisomerase II represents the main target for the antitumour drugs etoposide and amsacrine, which are both used clinically. Previous studies have shown that the glycoside moiety of etoposide is not necessary for cytotoxicity or DNA topoisomerase II inhibition. For this reason, we designed two epipodophyllotoxin derivatives for which the dispensable sugar moiety of etoposide has been replaced by a m-methoxy-methane-sulfonamide-anilino group analogous to the topoisomerase II-targeted domain of amsacrine.

DNA interaction and cytotoxicity of a new series of indolo[2,3-b]quinoxaline and pyridopyrazino[2,3-b]indole derivatives.

Absorption, melting temperature and linear dichroism measurements were performed to investigate the interaction with DNA of a series of 16 tricyclic and tetracyclic compounds related to the antiviral agent B-220. The relative DNA affinity of the test compounds containing an indolo[2,3-b]quinoxaline, pyridopyrazino[2,3-b]indoles or pyrazino[2,3-b]indole planar chromophore varies significantly depending on the nature of the side chain grafted onto the indole nitrogen. Compounds with a dimethylaminoethyl chain strongly bind to DNA and exhibit a preference for GC-rich DNA sequences, as revealed by DNase I footprinting.

Tris-benzimidazole derivatives: design, synthesis and DNA sequence recognition.

Two tris-benzimidazole derivatives have been designed and synthesized based on the known structures of the bis-benzimidazole stain Hoechst 33258 complexed to short oligonucleotide duplexes derived from single crystal X-ray studies and from NMR. In both derivatives the phenol group has been replaced by a methoxy-phenyl substituent. Whereas one tris-benzimidazole carries a N-methyl-piperazine at the 6-position, the other one has this group replaced by a 2-amino-pyrrolidine ring.

[Standards, options and recommendations: practice guidelines for difficult diagnosis in surgical pathology or cytopathology in cancer patients].

Context: The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.