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Michelle Prudhomme - One of the best experts on this subject based on the ideXlab platform.
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A three-step synthesis from Rebeccamycin of an efficient checkpoint kinase 1 inhibitor.
European Journal of Medicinal Chemistry, 2009Co-Authors: Fabrice Anizon, Roy Golsteyn, Stéphane Leonce, Bruno Pfeiffer, Michelle PrudhommeAbstract:Rebeccamycin derivative 1 bearing a sugar moiety linked to both indole nitrogens and an amino substituent on the carbohydrate unit was synthesized in three steps from the bacterial metabolite. This compound was found to be a highly potent checkpoint kinase 1 inhibitor with an IC50 value of 2.8 nM.
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Pyrrolocarbazoles as Checkpoint 1 kinase inhibitors
Anti-Cancer Agents in Medicinal Chemistry, 2008Co-Authors: Hélène Henon, Roy Golsteyn, Samir Messaoudi, Elisabeth Conchon, Bernadette Hugon, Michelle PrudhommeAbstract:The carbazole framework is found in many natural compounds of biological interest. Indolocarbazoles such as Rebeccamycin and staurosporine which are either a topoisomerase I inhibitor (Rebeccamycin) or a non selective kinase inhibitor (staurosporine) are bacterial metabolites. In the search for new antitumor agents, DNA damage checkpoint kinases, in particular Checkpoint kinase 1, have recently emerged as attractive targets for cancer therapy. This review reports the synthesis and Chk1 inhibitory activities of pyrrolocarbazole compounds bearing four or five fused rings.
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Synthesis and biological activities of 7-aza Rebeccamycin analogues bearing the sugar moiety on the nitrogen of the pyridine ring.
Bioorganic and Medicinal Chemistry, 2006Co-Authors: Samir Messaoudi, Fabrice Anizon, Roy Golsteyn, Stéphane Leonce, Bruno Pfeiffer, P. Peixoto, M.h. David-cordonnier, Michelle PrudhommeAbstract:The synthesis of a new family of 7-aza-Rebeccamycin analogues in which the sugar moiety is attached to the nitrogen of the pyridine ring is described. The capacity of the newly synthesized compounds to bind to DNA and to inhibit topoisomerase I has been evaluated. Their cytotoxicities toward four tumor cell lines, one murine leukemia L1210 and three human tumor cell lines, one prostate carcinoma DU145, one colon carcinoma HT29, and one non-small cell lung carcinoma A549, have been determined. Their abilities to inhibit the checkpoint kinase Chk1 have been evaluated
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Cytotoxicities of three Rebeccamycin derivatives in the National Cancer Institute screening of 60 human tumor cell lines
Anti-cancer drugs, 2005Co-Authors: Pascale Moreau, Michelle Prudhomme, S. Holbeck, E. SausvilleAbstract:Among the biologically active indolocarbazoles, Rebeccamycin, a microbial metabolite produced by Saccharothrix aerocolonigenes, is a well-known topoisomerase (Topo) I poison. In the course of structure-activity relationship studies on Rebeccamycin analogs, we have prepared a large number of indolocarbazole derivatives and have shown that, depending on the structural modifications, the cytotoxic effects may be, or not, directly correlated to DNA binding and Topo I inhibition. This suggests that if DNA binding and Topo I play a part in the biological activity of these compounds, other cellular targets might be involved. This paper reports the results of the antiproliferative activities (evaluated in the National Cancer Institute's in vitro panel of 60 tumor cell lines) and the results of a COMPARE analysis run with Rebeccamycin derivatives to identify other potential biological targets for these compounds.
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Rebeccamycin analogues bearing amine substituents or other groups on the sugar moiety
Bioorganic & medicinal chemistry, 2003Co-Authors: Fabrice Anizon, Christian Bailly, Martine Sancelme, Pascale Moreau, William Laine, Michelle PrudhommeAbstract:Abstract In the course of structure–activity relationship studies on Rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized with the aim of improving the solubility and interaction with the macromolecular target(s). The syntheses of amino derivatives and the corresponding chloro, iodo and azido intermediates are described. Their interaction with DNA and effects on human DNA topoisomerases I and II were investigated. Their antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis , a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also determined. 6′-Amino compound 7 and 6′- N -methylamino 14 very efficiently inhibit the growth of E. coli . The introduction of an amino group at the 6′-position strongly enhances the capacity of the drugs to interact with DNA but almost abolishes their poisoning effect on topoisomerase I. Unlike the vast majority of Rebeccamycin analogues previously studied, the newly designed compounds do not stimulate DNA cleavage by topoisomerase I. The enhanced capacity of the 6′-amino glycosyl Rebeccamycin derivatives to bind to DNA likely account for the improved biological profiles. DNA and topoisomerase I represent two independent targets which can both be used for the development of antitumor Rebeccamycin derivatives.
Christian Bailly - One of the best experts on this subject based on the ideXlab platform.
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Semi-synthesis, topoisomerase I and kinases inhibitory properties, and antiproliferative activities of new Rebeccamycin derivatives.
Bioorganic & medicinal chemistry, 2003Co-Authors: Pascale Moreau, Christian Bailly, Fabrice Anizon, Christelle Marminon, Alain Pierre, Nathalie Gaillard, Nathalie Dias, Brigitte Baldeyrou, John A. Hickman, Bruno PfeifferAbstract:Abstract In the course of structure–activity relationship studies, new Rebeccamycin derivatives substituted in 3,9-positions on the indolocarbazole framework, and a 2′,3′-anhydro derivative were prepared by semi-synthesis from Rebeccamycin. The antiproliferative activities against nine tumor cell lines were determined and the effect on the cell cycle of murine leukemia L1210 cells was examined. Their DNA binding properties and inhibitory properties toward topoisomerase I and three kinases PKCζ, CDK1/cyclin B, CDK5/p25 and a phosphatase cdc25A were evaluated. The 3,9-dihydroxy derivative is the most efficient compound of this series toward CDK1/cyclin B and CDK5/p25. It is also characterized as a DNA binding topoisomerase I poison. Its broad spectrum of molecular activities likely accounts for its cytotoxic potential. This compound which displays a tumor cell line-selectivity may represent a new lead for subsequent drug design in this series of glycosylated indolocarbazoles.
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Rebeccamycin analogues bearing amine substituents or other groups on the sugar moiety
Bioorganic & medicinal chemistry, 2003Co-Authors: Fabrice Anizon, Christian Bailly, Martine Sancelme, Pascale Moreau, William Laine, Michelle PrudhommeAbstract:Abstract In the course of structure–activity relationship studies on Rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized with the aim of improving the solubility and interaction with the macromolecular target(s). The syntheses of amino derivatives and the corresponding chloro, iodo and azido intermediates are described. Their interaction with DNA and effects on human DNA topoisomerases I and II were investigated. Their antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis , a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also determined. 6′-Amino compound 7 and 6′- N -methylamino 14 very efficiently inhibit the growth of E. coli . The introduction of an amino group at the 6′-position strongly enhances the capacity of the drugs to interact with DNA but almost abolishes their poisoning effect on topoisomerase I. Unlike the vast majority of Rebeccamycin analogues previously studied, the newly designed compounds do not stimulate DNA cleavage by topoisomerase I. The enhanced capacity of the 6′-amino glycosyl Rebeccamycin derivatives to bind to DNA likely account for the improved biological profiles. DNA and topoisomerase I represent two independent targets which can both be used for the development of antitumor Rebeccamycin derivatives.
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Syntheses and antiproliferative activities of 7-azaRebeccamycin analogues bearing one 7-azaindole moiety.
Journal of medicinal chemistry, 2003Co-Authors: Christelle Marminon, Christian Bailly, Stéphane Leonce, Bruno Pfeiffer, Alain Pierre, Pierre Renard, Valérie Pérez, John A. Hickman, Alexandra Joubert, Michelle PrudhommeAbstract:Rebeccamycin analogues containing one azaindole unit, with and without a methyl group on the imide nitrogen and with the sugar moiety coupled either to the indole nitrogen or to the azaindole nitrogen were synthesized. To increase the solubility and induce stronger interactions with the target macromolecules, a bromo or nitro substitutent was introduced on the indole unit. The DNA binding and topoisomerase I inhibition properties were investigated together with the antiproliferative activities toward nine tumor cell lines. In addition, the effect of the compounds on the cell cycle of L1210 leukemia cells was examined. The nonaza analogues were found to be cytotoxic against all cell lines of the panel whereas the aza-analogues showed a selective action toward certain cell lines. They strongly inhibited the proliferation of SK-N-MC neuroblastoma, A431 epidermoid carcinoma and NCI-H69 small cell lung carcinoma cells, but showed little or no cytotoxic effect against IGROV ovary carcinoma, HT29 colon carcinoma, and A549 non small cell lung carcinoma cells. Whatever their cytotoxicity profile, all compounds induce similar cell cycle effects, with a marked G2+M block observed with L1210 leukemia cells. The data suggest that the molecular mechanism of action of the aza-analogue derivatives is different from that of Rebeccamycin.
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Dimers from dechlorinated Rebeccamycin: synthesis, interaction with DNA, and antiproliferative activities.
European journal of medicinal chemistry, 2002Co-Authors: Christelle Marminon, Christian Bailly, Bruno Pfeiffer, Michael Facompré, Hickman John, Alain Pierre, Pierre Renard, Michelle PrudhommeAbstract: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. Four tumour cell lines, murine L1210 leukaemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukaemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells were also investigated.
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DNA targeting of two new antitumour Rebeccamycin derivatives.
European journal of medicinal chemistry, 2002Co-Authors: Michael Facompré, Christian Bailly, Pierre Colson, Michelle Prudhomme, Fabrice Anizon, Christelle Marminon, Brigitte Baldeyrou, Claude HoussierAbstract:In the course of a medicinal chemistry program aimed at discovering novel tumour-active Rebeccamycin derivatives targeting DNA and/or topoisomerase I, a series of analogues with the sugar residue linked to the two indole nitrogens was recently developed. Two promising drug candidates in this staurosporine-Rebeccamycin hybrid series were selected for a DNA-binding study reported here. The DNA interaction of the cationic indolocarbazole glycosides MP059 bearing a N,N-diethylaminoethyl side chain and MP072 containing a sugar bearing an amino group was compared with that of the uncharged analogue MP024. The results show that the addition of a cationic substituent, either directly on the indolocarbazole chromophore or on the carbohydrate residue, significantly reinforces the interaction of the drugs with nucleic acids. The two cationic molecules MP059 and MP072 recognise preferentially sequences containing GpT.ApC and TpG.CpA steps but they do not inhibit topoisomerase I, in contrast to the parent uncharged derivative MP024 which stimulates DNA single strand breaks by topoisomerase I. The cytotoxic activity of the indolocarbazole derivatives bearing positively charged groups is one order of magnitude higher than that of the neutral compound MP024. The high cytotoxic potential can be attributed to the enhanced DNA binding and sequence recognition capacity of the cationic compounds. The study provides useful information for further structure-activity relationship studies in the indolocarbazole series.
Fabrice Anizon - One of the best experts on this subject based on the ideXlab platform.
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A three-step synthesis from Rebeccamycin of an efficient checkpoint kinase 1 inhibitor.
European Journal of Medicinal Chemistry, 2009Co-Authors: Fabrice Anizon, Roy Golsteyn, Stéphane Leonce, Bruno Pfeiffer, Michelle PrudhommeAbstract:Rebeccamycin derivative 1 bearing a sugar moiety linked to both indole nitrogens and an amino substituent on the carbohydrate unit was synthesized in three steps from the bacterial metabolite. This compound was found to be a highly potent checkpoint kinase 1 inhibitor with an IC50 value of 2.8 nM.
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Rebeccamycin derivatives as dual DNA damaging agents and potent checkpoint kinase 1 inhibitors.
Molecular Pharmacology, 2008Co-Authors: Christelle Marminon, Fabrice Anizon, Roy Golsteyn, Bruno Pfeiffer, Pascale Moreau, M.h. David-cordonnier, Alain Pierre, Paul Peixoto, Marie-paule Hildebrand, Olivier LozachAbstract:Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on Rebeccamycin derivatives, we have synthesized analogues with the sugar moiety attached to either one or both indole nitrogens. Some analogues, especially those with substitutions at the 6' position of the carbohydrate moiety exhibit potent inhibitory activity toward Checkpoint kinase 1 (Chk1), a kinase that has a major role in the G2/M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These Rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.
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Synthesis and biological activities of 7-aza Rebeccamycin analogues bearing the sugar moiety on the nitrogen of the pyridine ring.
Bioorganic and Medicinal Chemistry, 2006Co-Authors: Samir Messaoudi, Fabrice Anizon, Roy Golsteyn, Stéphane Leonce, Bruno Pfeiffer, P. Peixoto, M.h. David-cordonnier, Michelle PrudhommeAbstract:The synthesis of a new family of 7-aza-Rebeccamycin analogues in which the sugar moiety is attached to the nitrogen of the pyridine ring is described. The capacity of the newly synthesized compounds to bind to DNA and to inhibit topoisomerase I has been evaluated. Their cytotoxicities toward four tumor cell lines, one murine leukemia L1210 and three human tumor cell lines, one prostate carcinoma DU145, one colon carcinoma HT29, and one non-small cell lung carcinoma A549, have been determined. Their abilities to inhibit the checkpoint kinase Chk1 have been evaluated
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Synthesis and cytotoxicities of 7-aza Rebeccamycin analogues bearing various substituents on the sugar moiety, on the imide nitrogen and on the carbazole framework
Eur. J. Med. Chem., 2005Co-Authors: Samir Messaoudi, Fabrice Anizon, Stéphane Leonce, A. Pierre, B. Pfeiffer, M PrudhommeAbstract:The synthesis of a family of Rebeccamycin analogues in which one indole unit has been replaced by a 7-azaindole moiety is described. Substitutions have been carried out on the imide nitrogen, on the carbazole framework and on the sugar part. Compounds with a lactam upper heterocycle have also been prepared. The cytotoxicities of the newly synthesized compounds toward four tumor cell lines, one murine leukemia (L1210) and three human tumor cell lines (prostate carcinoma DU145, colon carcinoma HT29, and non-small cell lung carcinoma A549) have been evaluated and compared to those of Rebeccamycin and parent non-aza and aza compounds
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Synthesis of bridged aza-Rebeccamycin analogues
Tetrahedron, 2005Co-Authors: S. Messaoudi, Fabrice Anizon, B. Pfeiffer, M PrudhommeAbstract:The syntheses of Rebeccamycin analogues possessing a 7-azaindole moiety instead of an indole unit, and with both indole and azaindole moieties linked to the carbohydrate are described. In these bridged aza compounds, the oxygen of the pyranose heterocycle is oriented towards either the indole, or the azaindole unit. In these series, compounds bearing a free imide nitrogen were synthesized by coupling the corresponding aglycones with a sugar pre-tosylated in 2-position via a Mitsunobu reaction. To obtain a precursor for bridged aza-Rebeccamycin analogues substituted in 6-position on the sugar moiety, a 2,6-ditosylated sugar was used
Christopher T. Walsh - One of the best experts on this subject based on the ideXlab platform.
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The FAD cofactor of RebC shifts to an IN conformation upon flavin reduction
2016Co-Authors: Katherine S. Ryan, Annaleise R. Howard-jones, Christopher T. Walsh, David P. Ballou, Sumita Chakraborty, Catherine L. DrennanAbstract:ABSTRACT: RebC is a putative flavin hydroxylase functioning together with RebP to carry out a key step in the biosynthesis of Rebeccamycin. To probe the mechanism of flavin-based chemistry in RebC, we solved the structure of RebC with reduced flavin. Upon flavin reduction, the RebC crystal undergoes a change in its unit cell dimension concurrent with a 5 Å movement of the isoalloxazine ring, positioning the flavin ring adjacent to the substrate-binding pocket. Additionally, a disordered helix becomes ordered upon flavin reduction, closing off one side of the substrate-binding pocket. This structure, along with previously reported structures, increases our understanding of the RebC enzyme mechanism, indicating that either the reduction of the flavin itself or binding of substrate is sufficient to drive major conformational changes in RebC to generate a closed active site. Our finding that flavin reduction seals the active site such that substrate cannot enter suggests that our reduced flavin RebC structure is off-pathway and that substrate binding is likely to precede flavin reduction during catalysis. Along with kinetic data presented here, these structures suggest that the first cycle of catalysis in RebC may resemble that of p-hydroxybenzoate hydroxylase, with substrate binding promoting flavin reduction. Rebeccamycin, a human DNA-topoisomerase I inhibitor, is a natural product generated in the bacterium LecheValieri
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Crystallographic trapping in the Rebeccamycin biosynthetic enzyme RebC
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Katherine S. Ryan, Annaleise R. Howard-jones, Christopher T. Walsh, Michael J. Hamill, Sean J. Elliott, Catherine L. DrennanAbstract:The biosynthesis of Rebeccamycin, an antitumor compound, involves the remarkable eight-electron oxidation of chlorinated chromopyrrolic acid. Although one Rebeccamycin biosynthetic enzyme is capable of generating low levels of the eight-electron oxidation product on its own, a second protein, RebC, is required to accelerate product formation and eliminate side reactions. However, the mode of action of RebC was largely unknown. Using crystallography, we have determined a likely function for RebC as a flavin hydroxylase, captured two snapshots of its dynamic catalytic cycle, and trapped a reactive molecule, a putative substrate, in its binding pocket. These studies strongly suggest that the role of RebC is to sequester a reactive intermediate produced by its partner protein and to react with it enzymatically, preventing its conversion to a suite of degradation products that includes, at low levels, the desired product.
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Nonenzymatic oxidative steps accompanying action of the cytochrome P450 enzymes StaP and RebP in the biosynthesis of staurosporine and Rebeccamycin.
Journal of the American Chemical Society, 2007Co-Authors: Annaleise R. Howard-jones, Christopher T. WalshAbstract:In the biosynthesis of the indolocarbazole natural products staurosporine and Rebeccamycin, a complex set of oxidative transformations results in dimerization and oxidative cross-linking of a pair ...
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Enzymatic generation of the chromopyrrolic acid scaffold of Rebeccamycin by the tandem action of RebO and RebD.
Biochemistry, 2005Co-Authors: Annaleise R. Howard-jones, Christopher T. WalshAbstract:During the biosynthesis of the fused six-ring indolocarbazole scaffolds of Rebeccamycin and staurosporine, two molecules of L-tryptophan are processed to a pyrrole-containing five-ring intermediate known as chromopyrrolic acid. We report here the heterologous expression of RebO and RebD from the Rebeccamycin biosynthetic pathway in Escherichia coli, and tandem action of these two enzymes to construct the dicarboxypyrrole ring of chromopyrrolic acid. Chromopyrrolic acid is oxidized by six electrons compared to the starting pair of L-tryptophan molecules. RebO is an L-tryptophan oxidase flavoprotein and RebD a heme protein dimer with both catalase and chromopyrrolic acid synthase activity. Both enzymes require dioxygen as a cosubstrate. RebD on its own is incompetent with L-tryptophan but will convert the imine of indole-3-pyruvate to chromopyrrolic acid. It displays a substrate preference for two molecules of indole-3-pyruvic acid imine, necessitating a net two-electron oxidation to give chromopyrrolic acid.
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Enzymatic Generation of the Chromopyrrolic Acid Scaffold of Rebeccamycin by the Tandem Action of RebO and RebD†
2005Co-Authors: Annaleise R. Howard-jones, Christopher T. WalshAbstract:ABSTRACT: During the biosynthesis of the fused six-ring indolocarbazole scaffolds of Rebeccamycin and staurosporine, two molecules of L-tryptophan are processed to a pyrrole-containing five-ring intermediate known as chromopyrrolic acid. We report here the heterologous expression of RebO and RebD from the Rebeccamycin biosynthetic pathway in Escherichia coli, and tandem action of these two enzymes to construct the dicarboxypyrrole ring of chromopyrrolic acid. Chromopyrrolic acid is oxidized by six electrons compared to the starting pair of L-tryptophan molecules. RebO is an L-tryptophan oxidase flavoprotein and RebD a heme protein dimer with both catalase and chromopyrrolic acid synthase activity. Both enzymes require dioxygen as a cosubstrate. RebD on its own is incompetent with L-tryptophan but will convert the imine of indole-3-pyruvate to chromopyrrolic acid. It displays a substrate preference for two molecules of indole-3-pyruvic acid imine, necessitating a net two-electron oxidation to give chromopyrrolic acid. Rebeccamycin 1 and staurosporine 2 (Figure 1) are indolocarbazole antibiotics originally isolated from the actinomycetes LecheValieria aerocolonigenes and Strepto-myces longisporoflaVus, respectively. Rebeccamycin is an inhibitor of DNA topoisomerase I, with a minimum inhibi
Eric P. Winer - One of the best experts on this subject based on the ideXlab platform.
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Rebeccamycin analog for refractory breast cancer: A randomized phase II trial of dosing schedules
Investigational New Drugs, 2007Co-Authors: Harold J. Burstein, Percy Ivy, Beth Overmoyer, Rebecca Gelman, Paula Silverman, Jennifer Savoie, Kathryn Clarke, L. Dumadag, Jerry Younger, Eric P. WinerAbstract:Rebeccamycin analog (NSC 655649) is a synthetic antibiotic cytotoxic agent thought to inhibit topoisomerase function. We sought to determine the response rate to Rebeccamycin analog among patients with refractory advanced breast cancer using two different treatment schedules. Eligible patients had measurable disease, central venous access, and one or two prior chemotherapy regimens for advanced cancer, or recurrence within 12 months of adjuvant chemotherapy. Patients were randomized to Rebeccamycin analog on one of two treatment schedules: arm 1, 500 mg/m2 IV bolus every 21 days; arm 2, 140 mg/m2 IV bolus daily ×5 days, every 21 days. The primary study endpoint was response rate; a two stage accrual design evaluated each schedule separately. Forty-two women entered the trial, 21 on each arm. Prior chemotherapy regimens for metastatic breast cancer were: 0, n =4; 1, n =21; 2, n =17. Prior treatments (including adjuvant therapy) anthracyclines: 88%, taxanes 67%, 5FU-based therapy, 50%. There were 5 partial responses (overall response rate 12%), two in arm 1 and 3 in arm 2, all in patients with prior anthracycline-based adjuvant chemotherapy. Median time to progression was 2.1 months (range 1–14+ months). An additional 9 patients had stable disease as best response. Grade 3 or 4 toxicity rates were: anemia 5%, neutropenia 33%, thrombocytopenia 12%, RBC transfusion 14%, nausea/vomiting 10%. Toxicity profiles were similar between the treatment arms. Rebeccamycin analog is reasonably well tolerated on two different treatment schedules for advanced breast cancer, with modest clinical activity in this heavily pretreated population.
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Rebeccamycin analog for refractory breast cancer: a randomized phase II trial
Journal of Clinical Oncology, 2004Co-Authors: Harold J. Burstein, Beth Overmoyer, Rebecca Gelman, Paula Silverman, Jennifer Savoie, Kathryn Clarke, L. Dumadag, Jerry Younger, Eric P. WinerAbstract:547 Background: Rebeccamycin analog (NSC 655649) is a synthetic antibiotic cytotoxic agent thought to inhibit topoisomerase function. We sought to determine the response rate to Rebeccamycin analog among patients with refractory advanced breast cancer using two different treatment schedules. Methods: Eligible patients had advanced breast cancer and measurable tumor (RECIST), and 1 or 2 prior chemotherapy regimens for advanced breast cancer, or recurrence within 12 months of adjuvant chemotherapy. Central venous access was required, as were adequate bone marrow, hepatic, and renal reserve. Patients were randomized to receive Rebeccamycin analog on one of two treatment schedules: arm 1, 500 mg/m2 IV bolus every 21 days; arm 2, 140 mg/m2 IV bolus daily x 5 days, every 21 days. The primary study endpoint was response rate. A two stage accrual design was used to evaluate each schedule separately. At least 3 responses among 21 patients in either arm were required to reject the null hypothesis of a 5% response r...
