Melanoma: Bailly C

Saiag P, Bosquet L, Guillot B, Verola O, Avril MF, Bailly C, Cupissol D, Dalac S, Danino A, Dréno B, Grob JJ, Leccia MT, Renaud-Vilmer C, Négrier S, Anonymous00110. · Hôpital Ambroise Paré, 92104 Boulogne, Université Versailles-Saint Quentin, France. · Eur J Dermatol. · Pubmed #17540641 links to  free full text

This publication has no abstract.

Négrier S, Saiag P, Guillot B, Verola O, Avril MF, Bailly C, Cupissol D, Dalac S, Danino A, Dreno B, Grob JJ, Leccia MT, Renaud-Vilmer C, Bosquet L, Anonymous00209, Anonymous00210, Anonymous00211, Anonymous00212, Anonymous00213, Anonymous00214, Anonymous00215, Anonymous00216. · Centre Léon-Bérard, Lyon. · Bull Cancer. · Pubmed #16714227 links to  free full text

Abstract: CONTEXT: The National French federation of comprehensive cancer centres (FNCLCC) and the French society of dermatology (SFD) initiated together the update of clinical practice guideline for the management of patients with cutaneous melanoma in collaboration with the French national cancer institute and with specialists from French public universities, general hospitals and private clinics. This work is based on the methodology developed in the "Standards, Options and Recommendations" (SOR) project. OBJECTIVES: To update SOR guidelines for the management of patients with cutaneous melanoma previously validated in 1998 and French melanoma consensus conference published by SFD and ANAES in 1995. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines have been developed, they are reviewed by independent reviewers. RESULTS: This article is a summary version of the updated clinical practice guidelines with algorithms. The main questions addressed by the expert group in this update concerned (1) The new AJCC-UICC classification (2) Excision margins (3) Sentinel node biopsy (4) Adjuvant treatments (5) Initial staging and follow up of operated patients.

Négrier S, Saiag P, Guillot B, Verola O, Avril MF, Bailly C, Cupissol D, Dalac S, Danino A, Dreno B, Grob JJ, Leccia MT, Renaud-Vilmer C, Bosquet L, Anonymous00273, Anonymous00274. · Centre Léon-Bérard, Lyon. · Ann Dermatol Venereol. · Pubmed #16521904 No free full text.

This publication has no abstract.

Négrier S, Fervers B, Bailly C, Beckendorf V, Cupissol D, Doré JF, Dorval T, Garbay JR, Vilmer C, Anonymous00212. · Centre Léon Bérard, Lyon, France. · Br J Cancer. · Pubmed #11355977 links to  free full text

This publication has no abstract.

Négrier S, Fervers B, Bailly C, Beckendorf V, Cupissol D, Doré JF, Dorval T, Garbay JR, Vilmer C. · No affiliation provided · Presse Med. · Pubmed #10923143 No free full text.

This publication has no abstract.

Négrier S, Fervers B, Bailly C, Beckendorf V, Cupissol D, Doré JF, Dorval T, Garbay JR, Vilmer C. · FNCLCC, Standards, Options, Recommandations, 101, rue de Tolbiac, 75654 Paris Cedex 13. · Bull Cancer. · Pubmed #10705288 links to  free full text

Abstract: 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 systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the management of patients with cutaneous melanoma. METHODS: Data have been identified by literature search using Medline - until December 1998 - and the personal reference lists of the expert group. Once the guidelines were defined, the document was submitted for review to national and international independent reviewers and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the management of cutaneous melanoma (CM) are: 1) The primary prevention of melanoma is based on a reduction in exposure to ultraviolet rays (solar or artificial). 2) The diagnosis of CM requires the surgical removal and histological examination of the lesion (standard). 3) The pathological report must include the diagnosis of primary malignant melanoma, the maximum thickness of the tumour in millimeters (Breslow), the clearance of surgical margins, the level of invasion (Clark), the presence and extension of regression and the presence of any ulceration (standard). 4) The standard treatment of a primary melanoma without lymph node involvement is based on surgery that must ensure adequate margins depending on the thickness of the tumour (standard, level of evidence B). 5) After surgery of a stage I melanoma, there is no indication for additional treatment outside a prospective therapeutic study (standard, level of evidence B, French Consensus Conference). 6) For a local recurrence without node involvement, in the absence of other metastases, surgical excision is the standard treatment. 7) In the case of metastatic regional lymph nodes, a complete regional lymphadenectomy is required. There is no indication for additional treatment outside a prospective therapeutic study (standard, level of evidence B). The inclusion of these patients in controlled studies of immunotherapy is recommended. 8) There is no standard therapeutic strategy for metastatic melanoma. Conventional palliative treatment is chemotherapy with dacarbazine (level of evidence B). 9) Follow-up is based on physical examination (standard). Patient information must encourage self-surveillance. Clinical surveillance and self-detection are indicated in all cases throughout life (standard).

Baudet C, Shell M, Bergeron C, Mollard P, Dijoud F, Bailly C, Stephan JL. · Unité d'Hématologie et de Cancérologie Pédiatrique, CHU Saint-Etienne, France. · Prog Urol. · Pubmed #15822396 No free full text.

Abstract: Melanomas are very rare in children. The authors report an original case of bladder melanoma in a 7-year-old girl. The initial staging assessment and complete remission 7 years after partial cystectomy with healthy resection margins confirmed the primary nature of this tumour Bladder melanomas are exceptional in adults, as only about 20 cases have been published. To the best of our knowledge, this is the first published case in a child.

Cochran AJ, Bailly C, Paul E. · Department of Pathology, Center for the Health Sciences, University of California-Los Angeles Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA. · Facial Plast Surg Clin North Am. · Pubmed #15062284 No free full text.

This publication has no abstract.

Kluza J, Mazinghien R, Degardin K, Lansiaux A, Bailly C. · INSERM U-524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, 1 Place de Verdun, 59045 Lille, France. · Eur J Pharmacol. · Pubmed #16289142 No free full text.

Abstract: Sampangine is a plant-derived copyrine alkaloid extracted from the stem bark of Cananga odorata. This azaoxoaporphine alkaloid primarily exhibits antifungal and antimycobacterial activities but also displays in vitro antimalarial activity against Plasmodium falciparum and it is cytotoxic to human malignant melanoma cells. Recently, sampangine was described as a pro-apoptotic agent, but the biochemical pathway leading to cell death remained unclear. Considering that sampangine possesses an iminoquinone moiety, potentially functioning as an oxidizing agent, we have investigated the implication of an oxidant stress on sampangine-induced cytotoxicity. We show that the treatment of human HL-60 leukemia cells for 48 h with sampangine induced an important oxidative burst. Real time flow cytometry measurements indicated that the production of oxidative species is very rapid, within minutes following the drug addition. Quenching of reactive oxygen species by the antioxidants N-acetyl cystein, vitamin C and vitamin E abolishes the pro-apoptotic activity of sampangine. The drug-induced production of reactive oxygen species is associated with cell cycle perturbations and mitochondrial alterations. This study shed light on the mechanism of action of sampangine and provides novel opportunities to use azaoxoaporphine alkaloids as lead compounds for the design of pro-apoptotic anticancer agents.

Kluza J, Clark AM, Bailly C. · INSERM U-524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, 59045 Lille Cedex, France. · Ann N Y Acad Sci. · Pubmed #15033745 No free full text.

Abstract: Sampangine, a plant-derived copyrine alkaloid extracted from the stem bark of Cananga odorata, primarily exhibits antifungal and antimycobacterial activities, but it also displays in vitro antimalarial activity against Plasmodium falciparum and is cytotoxic to human malignant melanoma cells. It inhibits cell aggregation, but no molecular target has yet been identified. We investigated the biochemical pathway involved in sampangine-induced cytotoxicity toward HL-60 cells. These leukemia cells are prone to enter apoptosis after treatment with various stimuli, including genotoxic compounds structurally close to sampangine, such as ascididemin.

Vincent-Naulleau S, Le Chalony C, Leplat JJ, Bouet S, Bailly C, Spatz A, Vielh P, Avril MF, Tricaud Y, Gruand J, Horak V, Frelat G, Geffrotin C. · Laboratoire de Radiobiologie et Etude du Génome, CEA INRA, Jouy-en-Josas Cedex, France. · Pigment Cell Res. · Pubmed #14717842 No free full text.

Abstract: Spontaneous animal tumors appear to be highly suitable models to study human oncology and cancer therapy. The aim of this study was to characterize the clinical and histological features of hereditary melanocytic lesions found in the French herd of melanoblastoma-bearing Libechov minipigs (MeLiM) and their Duroc crossbreeds. Clinically, we discriminated between three types of melanocytic skin lesions, which offer a lesion continuum from lentigo to metastatic melanomas. More than 70% of these lesions appear on piglets before they are 3 months old and preferentially on homogeneous black coat piglets. The incidence of melanoma reaches 50% in MeLiM. Most of the highly invasive melanomas regressed spontaneously in the first year of the piglet's life and the regression was followed by hair, skin and iris depigmentation. A histopathological study was conducted according to the human melanoma classification. Except for lentigo maligna, we observed the three main types of human melanoma in swine [superficial spreading melanoma (SSM), nodular or unclassified melanoma] with an excess of SSM (59-67%). The histological events leading to total spontaneous regression are chronologically described. The genetic predisposition, the high incidence of melanoma, the clinical and histopathological features similar to the human disease and the high rate of spontaneous regression offer an opportunity to use this model for studying genetic events controlling melanoma development and regression and the biological mechanisms involved in oncogenesis and anti-cancerous self-defense.

Lefevre M, Vergier B, Balme B, Thiebault R, Delaunay M, Thomas L, Beylot-Barry M, Machet L, De Muret A, Bioulac-Sage P, Bailly C. · Department of Pathology, University Hospital, Bordeaux, France. · Am J Surg Pathol. · Pubmed #12766575 No free full text.

Abstract: Thin (<or=0.76 mm) level II cutaneous superficial spreading melanomas (SSMs) are known to be of excellent prognosis and very few recur, metastasize, or are lethal. Although many prognostic features at this stage have been studied, none appears to be statistically significant. The concept of tumor growth phase is correlated with Clark's level except for level II. SSM level II show either an invasive vertical growth phase or an invasive radial growth phase. The aim of our study (retrospective, multicenter, and case-control type) was to investigate the prognostic impact of vertical growth phase in thin level II cutaneous SSM. We identified 12 patients of poor outcome with complete initial excision. Each case was matched with three controls for gender, age, location, tumor thickness, and follow-up period since diagnosis. Independent pathologists studied all cases and controls. Univariate analyses were performed with a conditional logistic regression method. A kappa test was used to assess reproducibility between pathologists. Our study is the first and largest that shows that vertical growth phase is the only statistically significant prognostic factor for thin level II cutaneous SSM. We propose that growth phase evaluation (a minimum of eight serial sections being mandatory not to underdiagnose vertical growth phase) should be added to the recommendations for melanoma histologic report, at least for level II SSM.

Lansiaux A, Tanious F, Mishal Z, Dassonneville L, Kumar A, Stephens CE, Hu Q, Wilson WD, Boykin DW, Bailly C. · Institut National de la Santé et de la Recherche Médicale U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, 59045 Lille, France. · Cancer Res. · Pubmed #12499262 links to  free full text

Abstract: Diphenylfuran diamidines represent an important class of DNA minor groove binders of high therapeutic interest as antiparasitic or antitumor agents depending on the compounds structures. To exert their cytotoxic action, the compounds must first get into the cell and reach the nuclear compartment where the main target, DNA, is located. The forces that drive the drugs into cell nuclei, as well as the influence of the molecular structures on the cell distribution, are not known. To address these issues, we took advantage of the fluorescence of the molecules to analyze their intracellular distribution profiles in tumor cells of different origins (B16 melanoma, MCF7 mammary adenocarcinoma, A549 lung carcinoma, HT29 colon carcinoma, LNCaP, and PC3 prostatic carcinoma) by epifluorescence and confocal microscopy. A homogeneous series of synthetic bis-substituted alkyl or phenyl amidine and reverse amidine derivatives of furamidine was used to dissect the molecular mechanisms that control the distribution of the drugs into the cytoplasm or the nucleus of the cells. The amidine (DB75) and the various N-alkyl derivatives were found to accumulate selectively in the cell nuclei. This is also the case for a guanidine derivative but not for the phenyl-substituted compound DB569, which essentially localizes in cytoplasmic granules. Similar cytoplasmic patterns were observed with a reverse amidine analogue and a pyridine-substituted compound indicating that the presence of aromatic rings on the terminal side chain is the limiting factor that restricts the uptake of the compounds in the nuclear compartment. The use of different organelle-selective fluorescent probes, such as JC-1 and chloromethyl-X-rosamine, both specific to mitochondria and neutral red considered as a lysosome-selective probe, suggests that DB569 preferentially accumulates in mitochondria. Competition experiments with the antitumor drug daunomycin reveal that the diphenylfurans are attracted into the nuclei by the DNA. The DNA minor groove-drug interactions provide the driving force that permits massive accumulation of the fluorescent molecules in the nuclei. The DNA binding properties of the diphenylfuran derivatives were investigated by DNase I footprinting and surface plasmon resonance biosensor experiments to measure sequence selectivity and binding affinities, respectively. Furamidine and its phenyl-substituted analogue that accumulate in the cell nuclei and mitochondria, respectively, share a common selectivity for AT sites and bind equally tightly to these sites. Therefore, it is possible to modulate the intracellular distribution of the furamidine derivatives without affecting their DNA binding and sequence recognition properties. The introduction of aromatic substituents on diphenylfuran diamidines represents a novel strategy to control the intracellular compartmentalization of these DNA binding agents and directs them to mitochondria. This drug design strategy may prove useful to trigger drug-induced apoptosis.

David-Cordonnier MH, Laine W, Lansiaux A, Kouach M, Briand G, Pierré A, Hickman JA, Bailly C. · INSERM U-524, Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, Institut de Recherches sur le Cancer, 1 Place de Verdun, Lille 59045, France. · Biochemistry. · Pubmed #12146956 No free full text.

Abstract: The discovery of a new DNA-targeted antitumor agent is a challenging enterprise, and the elucidation of its mechanism of action is an essential first step in investigating the structural and biological consequences of DNA modification and to guide the rational design of analogues. Here, we have dissected the mode of action of the newly discovered antitumor agent S23906-1. Gel retardation experiments reveal that the diacetate compound S23906-1 and its monoacetate analogue S28687 form highly stable covalent adducts with DNA. The covalent adducts formed between S23906-1 and a 7-bp hairpin oligonucleotide duplex were identified by spectrometry. In contrast, the inactive compound S23907, lacking the two acetate groups of S23906-1, fails to yield covalent DNA adducts, indicating that the C1-C2 functionality is the DNA reactive moiety. DNase I footprinting and DNA alkylation experiments indicate that S23906-1 reacts primarily with guanine residues. A 30-mer oligonucleotide containing only G.C bp forms highly stable complexes with S23906-1 and S28687, whereas the equivalent A.T oligonucleotide is not a good substrate for these two drugs. The use of an oligonucleotide duplex containing inosines instead of guanosines identifies the guanine 2-amino group exposed in the minor groove of DNA as the potential reactive site. The reactivity of S23906-1 toward the guanine-N2 group was independently confirmed by fluorescence spectroscopy. Covalent DNA adducts were also identified in the genomic DNA of B16 melanoma cells exposed to S23906-1, and the specific accumulation of the drug in the nucleus of the cells was visualized by confocal microscopy. The elucidation of the mechanism of action of this highly potent anticancer agent opens a new field for future drug design.

Wechsler J, Bastuji-Garin S, Spatz A, Bailly C, Cribier B, Andrac-Meyer L, Vergier B, Fraitag S, Verola O, Wolkenstein P, Anonymous00243. · Department of Pathology, Henri-Mondor Hospital, F-94010 Créteil CEDEX, France. · Arch Dermatol. · Pubmed #12020223 links to  free full text

Abstract: 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. Category 1 was considered the gold standard. Four pairs of expert dermatopathologists reviewed the slides and classified them into melanoma, nevus (including Spitz nevus), or ambiguous tumors. INTERVENTION: None. MAIN OUTCOME MEASURE: Concordance between pairs of experts. RESULTS: For category 1 slides (n = 20), the concordance was weak to moderate. For category 2 slides (n = 47), the concordance was weak. For category 3 slides (n = 18), the concordance was poor to moderate. CONCLUSION: This study demonstrates that the reliability of diagnosis of melanoma in childhood is poor, even when submitted to experts.

Kluza J, Lansiaux A, Wattez N, Hildebrand MP, Léonce S, Pierré A, Hickman JA, Bailly C. · INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France. · Biochem Pharmacol. · Pubmed #11996885 No free full text.

Abstract: 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. With both cell lines, the drug induces cell cycle perturbations (G2/M arrest) and triggers apoptosis as revealed by the externalization of Annexin V-targeted PS residues at the periphery of the cells. But the biochemical pathways leading to apoptosis are different for the two cancer cell lines. In HL-60 cells, the drug induces significant variations of the Delta Psi(mt), measured by flow cytometry using the fluorochromes JC-1 and cm-X-ros. Activation of caspase-3 and chromatin condensation in HL-60 cells exposed to submicromolar concentrations of S23906-1 for 24hr were also clearly seen by flow cytometry and confocal microscopy experiments. In contrast, the extent of apoptosis induced by S23906-1 was found to be much more limited in B16 cells. No significant variations of Delta Psi(mt) and no cleavage of the fluorescent caspase-3 substrate GDEVDGI (PhiPhiLux-G(1)D(2) probe) could be detected by cytometry in B16 cells exposed to S23906-1. In addition, we characterized the mitochondrial production of reactive oxygen species (ROS) using the probe dihydroethidine (HE) and the variations of the mitochondrial mass using the cardiolipin-interacting probe nonyl acridine orange (NAO). S23906-1 stimulates the production of ROS in both cell lines but the number of mitochondria seems to increase only in drug-treated B16 cells. Collectively these findings identify S23906-1 as a potent inducer of cell apoptosis in the leukemia cells and to a lower extent in the melanoma cells. The results help to understand the downstream cytotoxic actions of this new anticancer agent which is currently undergoing preclinical development.

Lansiaux A, Dassonneville L, Facompré M, Kumar A, Stephens CE, Bajic M, Tanious F, Wilson WD, Boykin DW, Bailly C. · INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France. · J Med Chem. · Pubmed #11985467 No free full text.

Abstract: 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. The B16 melanoma cell line was used to compare the capacities of mono-, bis-, and tetracations to enter the cell and nuclei. The high-resolution fluorescence pictures show that in the furamidine series, the compounds with two or four positive charges selectively accumulate in the cell nuclei whereas, in most cases, those bearing only one positive charge show reduced cell uptake capacities. One of the monocationic compounds, DB607, distributes in the cytoplasm, possibly in mitochondria, with no distinct nuclear accumulation. In sharp contrast, furamidine and benzimidazole analogues, including the drug DB293 that forms DNA minor groove dimers, efficiently accumulate in the cell nuclei and the intranuclear distribution of these DNA minor groove binders is significantly different from that seen with the DNA intercalating drug propidium iodide. The results suggest that the presence of two amidine terminal groups plays a role in facilitating nuclear accumulation into cells, probably as a result of nucleic acid binding. The determination of DNA melting temperature increases on addition of these compounds supports the importance of DNA binding in nuclear uptake.

Fazaa B, Zghal M, Bailly C, Zeglaoui F, Goucha S, Mokhtar I, Kharfi M, Ezzine N, Kamoun MR. · Service de Dermatologie, Hôpital Charles Nicolle, Tunis, Tunisie. · Ann Dermatol Venereol. · Pubmed #11395647 links to  free full text

Abstract: BACKGROUND: Xeroderma pigmentosum is a rare genodermatosis, with a defect affecting recovery of ultraviolet-induced damages and characterized by a high rate of malignancies of the exposed skin areas. We studied melanoma features of patients with xeroderma pigmentosum. PATIENTS AND METHODS: A retrospective study of xeroderma pigmentosum patients admitted to the Charles Nicolle Hospital of Tunis between 1973 and 1998. RESULTS: Two hundred sixteen patients with xeroderma pigmentosum were registered. Melanoma was present in 12 patients, 7 females and 5 males. Two patients were sisters. Cutaneous melanoma was found in 8 patients. Four patients presented with metastatic melanoma. The median age for development of the first melanoma was 17.5 years. All of the cutaneous melanomas were found on the face. Lentigo malignant melanoma was reported in 3 cases. The tumors were treated with surgical excision. Except for a melanoma affecting the orbit, characterized by a fatal outcome, no metastases were detected at the different investigations. DISCUSSION: Melanoma occurs frequently in patients with xeroderma pigmentosum, it has been reported in 5.5 p. 100 of cases and 11.3 p. 100 of patients with cutaneous carcinoma. The age of onset was low: 17.5 years. It appeared later than the carcinoma. The location of cutaneous melanoma in face in xeroderma pigmentosum patients indicates that they were caused mainly by sunlight exposure. Lentigo malignant melanoma was the most frequent type. Prognosis is difficult to define owing to the large number of other cutaneous malignancies. Apart from one case of rapidly fatal orbital melanoma, we recorded long survivals even in cases of melanoma revealed by metastases.

Bailly C, Laine W, Baldeyrou B, De Pauw-Gillet MC, Colson P, Houssier C, Cimanga K, Van Miert S, Vlietinck AJ, Pieters L. · INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, Lille, France. · Anticancer Drug Des. · Pubmed #11049087 No free full text.

Abstract: Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II. In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety. The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine. The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer. The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug.

Bailly C, Lansiaux A. · Laboratoire de pharmacologie antitumorale, Centre Oscar-Lambret, et U. 524 Inserm, place de Verdun, 59045 Lille Cedex. · Bull Cancer. · Pubmed #10903786 links to  free full text

This publication has no abstract.

Ah-Hot P, Rivet J, Saliou C, Bailly C, Bruneval P. · Service d'Anatomie Pathologique, Hôpital Broussais, 96, rue Didot 75676 Paris cedex 14. · Ann Pathol. · Pubmed #10891718 No free full text.

Abstract: We report a new case of a cellular blue nevus with clinicopathologic atypia. It was a large lesion presenting clinically as a vascular tumor located in the middle of the back. It grew for 2 years without skin ulceration. The pathological study suggested a cellular blue nevus with moderate nuclear atypia, without any atypical mitosis and necrosis. The differential diagnosis such as malignant blue nevus and melanoma are discussed in search of a better definition of these rare lesions.

Dassonneville L, Wattez N, Mahieu C, Colson P, Houssier C, Frederich M, Tits M, Angenot L, Bailly C. · INSERM U-524, IRCL, Lille, France. · Anticancer Res. · Pubmed #10697543 No free full text.

Abstract: Usambarensine is a plant alkaloid isolated from the roots of Strychnos usambarensis collected in Central Africa. This bis-indole compound displays potent antiamoebic activities and shows antigardial, antimalarial and cytotoxic effects. Usambarensine is highly toxic to B16 melanoma cells and inhibits the growth of leukemia and carcinoma cells. To date, the molecular basis for its diverse biological effects remains totally unknown. However, its capacity to inhibit nucleic acids synthesis in melanoma cells, on the one hand, and its structural analogy with DNA-binding pyridoindole plant alkaloids recently studied (cryptolepine and matadine), on the other hand, suggested that usambarensine could also bind to DNA. Consequently, we studied the strength and mode of binding to DNA of usambarensine by means of absorption, circular and linear dichroism. The results of the optical measurements indicate that the alkaloid effectively binds to DNA and behaves as a typical intercalating agent. Biochemical experiments indicated that, in contrast to cryptolepine and matadine, usambarensine does not interfere with the catalytic activity of topoisomerase II. Human HL60 leukemia cells were used to assess the cytotoxicity of the alkaloid and its effect on the cell cycle. Usambarensine treatment is associated with a loss of cells in the G1 phase accompanied with a large increase in the sub-G1 region which is characteristic of apoptotic cells. The DNA of usambarensine-treated cells was severely fragmented and the proteolytic activity of DEVD-caspases is enhanced. Usambarensine is thus characterized as DNA intercalator inducing apoptosis in leukemia cells.

Goossens JF, Hénichart JP, Anizon F, Prudhomme M, Dugave C, Riou J, Bailly C. · Laboratoire de Chimie Analytique, Faculté de Pharmacie, 59006, Lille, France. · Eur J Pharmacol. · Pubmed #10688977 No free full text.

Abstract: Rebeccamycin is an antitumor antibiotic possessing a DNA-intercalating indolocarbazole chromophore linked to a glycosyl residue. The carbohydrate moiety of rebeccamycin and related synthetic analogues, such as the potent antitumor drug NB-506 (6-N-formylamino-12,13-dihydro-1, 11-dihydroxy-13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo- [3,4-c]carbazole-5,7-(6H)-dione), is a key element for both DNA-binding and inhibition of DNA topoisomerase I. In this study, we have investigated the cellular uptake of rebeccamycin derivatives and their interaction with purified membranes. The transport of radiolabeled [3H]dechlorinated rebeccamycin was studied using the human leukemia HL60 and melanoma B16 cell lines as well as two murine leukemia cell lines sensitive (P388) or resistant (P388CPT5) to camptothecin. In all cases, the uptake is rapid but limited to about 6% of the drug molecules. In HL60 cells, the uptake entered a steady-state phase of intracellular accumulation of about 0.26+/-0.05 pmol/10(6) cells, which persisted to at least 90 min. The efflux of exchangeable radiolabeled molecules was relatively weak. Fluorescence studies were performed to compare the interaction of a rebeccamycin derivative and its aglycone with membranes purified from HL60 cells. The glycosylated drug molecules bound to the cell membranes can be extracted upon washing with buffer or by adding an excess of DNA. In contrast, the indolocarbazole drug lacking the carbohydrate domain remains tightly bound to the membranes with very little or no exchange upon the addition of DNA. The membrane transport and binding properties of indolocarbazole drugs related to rebeccamycin are reminiscent to those of other DNA-intercalating antitumor agents. The uptake most likely occurs via a passive diffusion through the plasma membranes and the glycosyl residue of the drug plays an essential role for the translocation of the drug from the membranes to the internal cell components, such as DNA.

Dassonneville L, Bonjean K, De Pauw-Gillet MC, Colson P, Houssier C, Quetin-Leclercq J, Angenot L, Bailly C. · INSERM U524, Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Lille, France. · Biochemistry. · Pubmed #10387011 No free full text.

Abstract: Cryptolepine, matadine, and serpentine are three indoloquinoline alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina, respectively. For a long time, these alkaloids have been used in African folk medicine in the form of plant extracts for the treatment of multiple diseases, in particular as antimalarial drugs. To date, the molecular basis for their diverse biological effects remains poorly understood. To elucidate their mechanism of action, we studied their interaction with DNA and their effects on topoisomerase II. The strength and mode of binding to DNA of the three alkaloids were investigated by spectroscopy. The alkaloids bind tightly to DNA and behave as typical intercalating agents. All three compounds stabilize the topoisomerase II-DNA covalent complex and stimulate the cutting of DNA by topoisomerase II. The poisoning effect is more pronounced with cryptolepine than with matadine and serpentine, but none of the drugs exhibit a preference for cutting at a specific base. Cryptolepine which binds 10-fold more tightly to DNA than the two related alkaloids proves to be much more cytotoxic toward B16 melanoma cells than matadine and serpentine. The cellular consequences of the inhibition of topoisomerase II by cryptolepine were investigated using the HL60 leukemia cell line. The flow cytometry analysis shows that the drug alters the cell cycle distribution, but no sign of drug-induced apoptosis was detected when evaluating the internucleosomal fragmentation of DNA in cells. Cryptolepine-treated cells probably die via necrosis rather than via apoptosis. The results provide evidence that DNA and topoisomerase II are the primary targets of cryptolepine, matadine, and serpentine.

Cochran AJ, Wen DR, Berthier-Vergnes O, Bailly C, Doré JF, Bérard F, Moulin G, Thomas L. · Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1732, USA. · Hum Pathol. · Pubmed #10333227 No free full text.

Abstract: In an experimental model, human melanoma cell lines enriched for cells that express the glycoconjugate B-D galactose N-acetyl-D-galactosamine, which reacts with the peanut agglutinin lectin (PNA), are associated with an increase in the frequency of metastases. We previously showed that this glycoconjugate is expressed on the cells of some primary melanomas in humans and that such cells are found selectively in melanomas with a high risk for developing metastases and causing death. Using fixed archival tissues from 99 primary melanomas and lectin histochemistry, we found 65 tumors that contained melanoma cells that were PNA-positive. PNA-reactive cells were not identified in normal melanocytes or in the nevocytes of 24 nevi. PNA-reactive material accumulates adjacent to the nucleus in the area of the Golgi apparatus, initially as a tiny dot, but later in quantities sufficient to displace and indent the nucleus, producing a signet ring cell-like appearance. Tumor cells containing PNA-reactive material were associated with more evolved, deeper, and thicker tumors. Two melanomas up to Clark level II were PNA positive (20%), compared with 60% of level III, 76% of level IV, and 100% of level V. Five of 13 tumors less than 0.76 mm thick (39%) were positive, compared with 50% of tumors 0.76 to 1.49 mm thick, 64% of tumors 1.5 to 2.99 mm thick, and 85% of tumors 3 mm thick or thicker. PNA-reactivity was negatively correlated with disease-free survival (PNA-negative, 49.2+/-23 months; PNA-positive grade 1, 41.6+/-26 months and PNA-positive grade 2, 24.4+/-23 months), survival rate 5 years after initial treatment (PNA-negative, 84.8%; PNA-positive grade 1, 63.8%; and PNA-positive grade 2, 31.3%) and disease-free survival at 5 years after initial treatment (PNA-negative, 69.7%; PNA-positive grade 1, 53.2%; and PNA-positive grade 2, 25%).