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Biomedical subjects

C Bailly

Publications and source records attributed to C Bailly.

At least 37 records · Page 2Linked to original sources
PubMed2001

Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site.

NB-506 is a topoisomerase I (top1) inhibitor in clinical trials. In this study, we used a series of camptothecin (CPT)-resistant cell lines with known top1 alterations. We show that three mutations in different domains of the top1 enzyme that confer CPT resistance also confer cross-resistance to NB-506. The CPT-resistant cell lines and corresponding mutations were: human prostate carcinoma cells DU-145/RC1 (mutation R364H), Chinese hamster fibroblasts DC3F/C10 (mutation G503S), and human leukemia CEM/C2 cells (N722S). This result suggests that NB-506 and CPT share a common binding site in the top1-DNA complex. We next used these three cell lines and their parental cells to study the relationship between top1 poisoning by NB-506 and antiproliferative activity. We found that the CPT-resistant cells were only 2-10-fold resistant to NB-506, which suggests that NB-506 targets other cellular processes/pathways besides top1. This conclusion was further supported by the limited cross-resistance of top1-deficient murine leukemia P388/CPT45 cells (2-fold). Cross-resistance was also limited for J-109,382, an isomer of NB-506 that does not intercalate into DNA, indicating that the non-top1-mediated antiproliferative activity of NB-506 is not attributable to DNA intercalation. Together, these data indicate that NB-506 and indolocarbazoles are promising agents to overcome CPT resistance.

Antineoplastic Agents↗
PubMed2001

Directing topoisomerase I mediated DNA cleavage to specific sites by camptothecin tethered to minor- and major-groove ligands.

The covalent linkage of a hairpin polyamide, which binds in the minor groove, to camptothecin provides an efficient system to direct topoisomerase I mediated DNA cleavage to specific sites. These conjugates are equally as potent at targeting the enzyme to a single site in a DNA fragment as camptothecin conjugates of ligands that bind in the major groove (triplex-forming oligonucleotides).

DNA cleavage↗
PubMed2001

Rebeccamycin analogues from indolo[2,3-c]carbazole.

Glycosylated indolocarbazoles related to the antibiotic rebeccamycin represent an important series of antitumor drugs. In the course of structure-activity relationship studies, we report the synthesis of two new derivatives containing an indolo[2,3-c]carbazole chromophore instead of the conventional indolo[2,3-a]carbazole unit found in the natural metabolites. The N-methylated compound 8 containing one glucose residue behaves as a typical DNA intercalating agent, as judged from circular and electric linear dichroism measurements with purified DNA. In contrast, the bis-glycosylated derivative 7 containing a glucose residue on each indole nitrogen has lost its capacity to form stable complexes with DNA. DNA relaxation experiments reveal that the two drugs 7 and 8 have weak effects on human DNA topoisomerase I. The modified conformation of the indolocarbazole chromophore is detrimental to the stabilization of topoisomerase I-DNA complexes. The lack of potent topoisomerase I inhibition leads to decreased cytotoxicity but, however, we observed that the DNA-intercalating mono-glycosyl derivative 8 is about 5 times more cytoxic than the bis-glycosyl analogue 7. The study suggests that the naturally-occurring indolo[2,3-a]carbazole skeleton should be preserved to maintain the topoisomerase I inhibitory and cytotoxic activities.

Aminoglycosides↗
PubMed2001

Synthesis, cytotoxicity, DNA interaction and topoisomerase II inhibition properties of tetrahydropyrrolo[3,4-a]carbazole-1,3-dione and tetrahydropyrido-[3,2-b]pyrrolo[3,4-g]indole-1,3-dione derivatives.

Three tetrahydropyrrolo[3,4-a]carbazole-1,3-diones (6--8) and two tetrahydropyrido[3,2-b]pyrrolo[3,4-g]indole-1,3-diones (11--12) have been synthesized. Their interaction with DNA was probed by absorption and thermal melting studies. Compounds 8 and 12 both equipped with a hydroxyethyl-aminoethyl side-chain demonstrated higher affinities for poly(dA-dT)(2) than compounds 6, 7 and 11 bearing a dimethylaminoethyl side-chain. Circular and electric linear dichroism measurements showed that all five drugs behave as typical DNA intercalating agents. A plasmid cleavage assay was used to evaluate the capacity of the drugs to inhibit human topoisomerase II. Compounds 8 and 12 which bind strongly to DNA were found to stabilize DNA-topoisomerase II covalent complexes but their topoisomerase II inhibitory properties do not correlate with their cytotoxic potential. Compounds 6 and 7 are essentially inactive whereas compounds 8, 11 and 12 exhibit a high toxicity to P388 murine leukemia cells and provoke a marked accumulation in the G2/M phase of the cell cycle. These compounds form a new class of DNA-targeted antitumor agents.

Animals↗
PubMed2001

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. This latter substituent results in stronger DNA binding. The optimized synthesis of the drugs is described. The two tris-benzimidazoles exhibit high AT-base pair (bp) selectivity evident in footprinting experiments which show that five to six base pairs are protected by the tris-benzimidazoles as compared to four to five protected by the bis-benzimidazoles. The tris-benzimidazoles bind well to sequences like 5'-TAAAC, 5'-TTTAC and 5'-TTTAT, but it is also evident that they can bind weakly to sequences such as 5'-TATGTT-3' where the continuity of an AT stretch is interrupted by a single G*C base pair.

Base Sequence↗
PubMed2001

DNA topoisomerase II inhibition by peroxisomicine A(1) and its radical metabolite induces apoptotic cell death of HL-60 and HL-60/MX2 human leukemia cells.

Peroxisomicine A(1) (T-514) is a dimeric anthracenone first isolated from the plant Karwinskia humboldtiana. The compound presents a high and selective toxicity toward liver and skin cell cultures and is currently the subject of preclinical studies as an antitumor drug. To date, the molecular basis for its diverse biological effects remains poorly understood. To elucidate its mechanism of action, we studied its interaction with DNA and its effects on human DNA topoisomerases. Practically no interaction with DNA was detected. Peroxisomicine was found to inhibit topoisomerase II but not topoisomerase I. DNA relaxation and decatenation assays indicated that the drug interferes with the catalytic activity of topoisomerase II but does not stimulate DNA cleavage, in contrast to conventional topoisomerase poisons such as etoposide. Two human leukemia cell lines sensitive or resistant to mitoxantrone were used to assess the cytotoxicity of the toxin and its effect on the cell cycle. In both cases, peroxisomicine treatment was associated with a loss of cells from every phase of the cell cycle and was accompanied by a large increase in the sub-G1 region which is characteristic of apoptotic cells. The cell cycle changes were more pronounced with the sensitive HL-60 cells than with the resistant HL-60/MX2 cells (with reduced topoisomerase II activity), in agreement with the cytotoxicity measurements. Treatment of HL-60 cells with T-514 stimulated the cleavage of the poly(ADP-ribose) polymerase by intracellular proteases such as caspase-3. The cytometry and Western blot analyses reveal that peroxisomicine induces apoptosis in leukemia cells. In addition, we characterized a catabolite of peroxisomicine, named T-510R, in the form of a highly stable radical metabolite. The electron spin resonance and mass spectrometry data are consistent with the formation of an anionic semiquinonic radical. The oxidized product T-510R inhibits topoisomerase II with a reduced efficiency compared to the parent toxin and was found to be about 3-4 times less toxic to both the sensitive and resistant leukemia cell lines than T-514. Collectively, the results suggest that topoisomerase II inhibition plays a role in the cytotoxicity of the plant toxin peroxisomicine. Inhibition of topoisomerase II may serve as an inducing signal triggering the apoptotic cell death of leukemia cells exposed to the toxin. The dihydroxyanthracenone unit may represent a useful chemotype for the preparation of topoisomerase II-targeted anticancer agents.

Anthracenes↗
PubMed2001

Sequence-dependent binding of bis-amidine carbazole dications to DNA.

The conventional wisdom argues that DNA intercalators possess a condensed polyaromatic ring whereas DNA minor groove binders generally contain unfused aromatic heterocycles, frequently separated by amide bonds. Recently, this view has been challenged with the discovery of powerful intercalating agents formed by unfused aromatic molecules and groove binders containing a polyaromatic nucleus. Bis-amidinocarbazoles belong to this later category of drugs having a planar chromophore and capable of reading the genetic information accessible within the minor groove of AT-rich sequences [Tanious, F.A., Ding, D., Patrick, D.A., Bailly, C., Tidwell, R.R. & Wilson, W.D. (2000) Biochemistry 39, 12091-12101]. But in addition to the tight binding to AT sites, we show here that bis-amidinocarbazoles can also interact with GC sites. The extent and mode of binding of 2,7 and 3,6 substituted amidinocarbazoles to AT and GC sequences were investigated by complementary biochemical and biophysical methods. Absorption, fluorescence, melting temperature and surface plasmon resonance (SPR) measurements indicate that the position of the two amidine groups on the carbazole ring influences significantly the drug-DNA interaction. SPR and DNase I footprinting data confirm the AT-preference of the compounds and provide useful information on their additional interaction with GC sequences. The 3,6-carbazole binds approximately twice as strongly to the GC-containing hairpin oligomer than the 2,7-regioisomer. The high tendency of the 3,6 compound to intercalate into different types of DNA containing G.C base pairs is shown by electric linear dichroism. This work completes our understanding of the sequence-dependent DNA binding properties of carbazole dications.

Amidines↗
PubMed2001

Changes in oligosaccharide content and antioxidant enzyme activities in developing bean seeds as related to acquisition of drying tolerance and seed quality.

Seeds of bean (Phaseolus vulgaris cv. Vernel) were collected throughout their development on the plant and dried at 15 degrees C and 75% relative humidity to a final moisture content of about 16% (fresh weight basis) to determine whether the onset of tolerance to this drying condition was related to changes in soluble sugars or the activities of the main antioxidant enzymes, namely superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR). Measurements of soluble sugars and enzyme activities were made after drying the seeds, and drying tolerance was evaluated by the ability of dried seeds to germinate and to produce normal seedlings. Seeds became tolerant to drying at 45 d after anthesis, a time marking physiological maturity. At physiological maturity, the moisture content of seeds was about 50-55% (fresh weight basis) and seed dry matter reached about 190 mg per seed. Seed vigour, evaluated by controlled deterioration and conductivity measurements, continued to increase after seed mass maturity, but decreased when seeds remained thereafter for more than 7 d on the plant. Acquisition of drying tolerance was coincident with an accumulation of raffinose and stachyose. Dried-tolerant seeds were also characterized by a high amount of sucrose, the most abundant sugar, and by a low content of monosaccharides. The (raffinose+stachyose)/sucrose ratio increased during seed filling, reaching a value close to 1 when all the seeds became tolerant to drying, and maintaining this proportion during the final stages of maturation. Acquisition of drying tolerance was also related to a reorientation of the enzymatic antioxidant defence system. Drying-tolerant dried seeds displayed high CAT and GR activities and low SOD and APX activities, while the opposite condition was observed in immature dried seeds. The shift in antioxidant enzymes corresponded to the beginning of the maturation-drying phase. These results suggest that oligosaccharide metabolism and enzymatic antioxidant defences may be involved in acquisition of drying tolerance during bean seed development, but are not related to seed vigour.

Adaptation, Physiological↗
PubMed2001

The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison.

BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entered clinical trials. BN 80915 is a difluoro-hCPT where the six-membered alpha-hydroxylactone ring of camptothecin (CPT) is replaced by a seven-membered beta-hydroxylactone ring. Preclinical data reported here show that in spite of the modification to the crucial E-ring of CPTs, BN 80915 retains topoisomerase I poisoning activity as shown in living HT29 cells as well as in cell-free assays, where BN 80915 always performs better than SN-38 or TPT. In antiproliferative assays BN 80915 is also very potent as evidenced by IC50s values consistently lower than those of SN38 in sensitive cell lines as well as in their related multidrug-resistant lines overexpressing P-glycoprotein or multidrug resistance-associated protein. Furthermore, in human plasma, in contrast to CPT analogs, the hydrolysis of BN 80915 is slow, leading to improved plasma stability, and irreversible, thus avoiding toxicity related to the accumulation of active principle during excretion in the urinary tract. These findings may account for the good in vivo efficacy observed in PC3 xenograft experiments where BN 80915 administered orally at very low doses doubled the tumor growth delay in comparison to CPT-11 administered i.p. Altogether, these results strongly support further development of BN 80915.

Adenocarcinoma↗
PubMed2001

[Standards, Options and Recommendations for the surgical management of carcinoma of the endometrium].

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. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the surgical management of carcinoma of the endometrium. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the surgical management of carcinoma of the endometrium are: 1) where-ever possible, surgery is the primary treatment of both localised and advanced disease; 2) surgery is performed according to the stage of the cancer and the status of the patient; 3) surgery for stages I and II disease entails total abdominal hysterectomy and bilateral salpingo-oophorectomy. A modified radical hysterectomy is undertaken in cases of macroscopic cervical involvement. An omenectomy is recommended for serous papillary types. Pelvic lymphadenectomy for the purposes of precise staging is undertaken if the patient is of good performance status and without bad pronostic factors. Para-aortic lymphadenectomy can be undertaken to determine involvement of para-aortic nodes; 4) surgery for stages III and IV: radical surgery must be undertaken if at all possible with additional treatment as indicated. In the case of advanced disease, debulking surgery is indicated.

Algorithms↗
PubMed2001

[Standards, options, and recommendations for the radiotherapy of patients with endometrial cancer. FNCLCC (National Federation of Cancer Campaign Centers) and CRLCC (Regional Cancer Campaign Centers)].

OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the radiotherapy of carcinoma of the endometrium. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the radiotherapy of carcinoma of the endometrium are: 1) For grade 1 and 2 stage IA tumours, follow-up alone is standard as additional treatment. For grade 1 and 2 stage IB tumours, vaginal brachytherapy or follow-up alone are options. For grade 3, stage IB tumours and stage IC disease, there are two treatment options: external pelvic radiotherapy with a brachytherapy boost or vaginal brachytherapy. 2) Treatment for stage II disease can be preoperative when stage II disease has been suggested by a positive endometrial curettage. Postoperative vaginal brachytherapy is given for stage IIA tumours if the penetration of the myometrium is less than 50% or if the tumour is grade 1 or 2. In the case of deep penetration, or higher grade disease, or for stage IIB external radiotherapy with brachytherapy boosting must be undertaken routinely. 3) After surgery, for stage IIIA disease, either external pelvic radiotherapy or abdomino-pelvic radiotherapy is indicated, along with medical treatment in certain patients. For stage IIIB tumours, postoperative external radiotherapy with brachytherapy (if possible) should be undertaken. For stage IIIC tumours, standard treatment is external (pelvic or pelvic and para-aortic) radiotherapy followed or not by a brachytherapy boost. In case of extrauterine sites involved abdomino-pelvic irradiation is recommended. 4) Standard treatment for inoperable stage I and II disease is external radiotherapy and brachytherapy. For patients with inoperable stage III or IV disease, treatment is often symptomatic, combining external radiotherapy and medical treatment.

Brachytherapy↗
PubMed2001

Radar based rainfall forecast for sewage systems control.

There has been an increasing demand for accurate rainfall forecast in urban areas from the water industry. Current forecasting systems provided mainly by meteorological offices are based on large-scale prediction and are not well suited for this application. In order to devise a system especially designed for the dynamic management of a sewerage system the "RADAR" project was launched. The idea of this project was to provide a short-term small-scale prediction of rain based on radar images. The prediction methodology combines two methods. An extrapolation method based on a sophisticated cross correlation of images is optimised by a neural network technique. Three different application sites in Europe have been used to validate the system.

Cities↗
PubMed2001

[Melanoma in xeroderma pigmentosum: 12 cases].

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.

Adolescent↗