RESUMEN
The preparation of C-7 paclitaxel ethers is described. Various substituted ethers were prepared via activation of the corresponding methylthiomethyl ether followed by alcohol addition. Variation of the C-7 ether group as well the 3' side chain position led to the discovery of a novel taxane, BMS-184476 (4), with preclinical antitumor activity superior to paclitaxel.
Asunto(s)
Antineoplásicos/síntesis química , Paclitaxel/análogos & derivados , Paclitaxel/síntesis química , Taxoides , Antineoplásicos/química , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Éteres , Humanos , Espectroscopía de Resonancia Magnética , Paclitaxel/química , Paclitaxel/farmacología , Relación Estructura-Actividad , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
[reaction: see text]. A series of 12alpha,13alpha-aziridinyl epothilone derivatives were synthesized in an efficient manner from epothilone A. The final semisynthetic route involves a formal double-inversion of stereochemistry at both the C12 and C13 positions. All aziridine analogues were tested for effects on tubulin binding polymerization and cytotoxicity. The results indicate that the aziridine moiety is a viable isosteric replacement for the epoxide in the case of epothilones.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Aziridinas/síntesis química , Aziridinas/farmacología , Compuestos Epoxi/química , Antineoplásicos/química , Aziridinas/química , Relación Estructura-ActividadRESUMEN
BMS-275183 is a taxane, the mechanism of action of which is like other known taxanes, and is the polymerization of tubulin. BMS-275183 given p.o. was as effective as i.v. paclitaxel in five tumor models [murine M109 lung and C3H mammary 16/C, and human A2780 ovarian (grown in mice and rats) and HCT/pk colon]. It was active in one other tumor model (human HCT-116 colon) but inferior to parenteral paclitaxel. BMS-275183 given p.o. was active in a human, hormone-dependent, prostate tumor model, CWR-22, and just as effective as anti-androgen chemotherapy. In a schedule dependency study, increasing the interval of time between oral administrations resulted in greater cumulative dose tolerance and improved therapeutic outcome. Oral BMS-275183 was evaluated as a combination therapy in conjunction with i.v. paclitaxel. Therapeutic advantages were evident for tumor-bearing mice that received the oral taxane either after induction chemotherapy or between courses of such treatment. BMS-275183 is currently in Phase I clinical trials at multiple sites.
Asunto(s)
Antineoplásicos/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Administración Oral , Animales , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos DBA , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Paclitaxel/farmacología , Ratas , Ratas Desnudas , Factores de Tiempo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BMS-247550, a novel epothilone derivative, is being developed by Bristol-Myers Squibb Company (BMS) as an anticancer agent for the treatment of patients with malignant tumors. BMS-247550 is a semisynthetic analogue of the natural product epothilone B and has a mode of action analogous to that of paclitaxel (i.e., microtubule stabilization). In vitro, it is twice as potent as paclitaxel in inducing tubulin polymerization. Like paclitaxel, BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at low nanomolar concentrations. Importantly, BMS-247550 retains its antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or that have developed resistance to paclitaxel, both in vitro and in vivo. Tumors for which BMS-247550 demonstrated significant antitumor activity encompass both paclitaxel-sensitive and -refractory categories, i.e., (a) paclitaxel-resistant: HCT116/VM46 colorectal (multidrug resistant), Pat-21 breast and Pat-7 ovarian carcinoma (clinical isolates; mechanisms of resistance not fully known), and A2780Tax ovarian carcinoma (tubulin mutation); (b) paclitaxel-insensitive: Pat-26 human pancreatic carcinoma (clinical isolate) and M5076 murine fibrosarcoma; and (c) paclitaxel sensitive: A2780 ovarian, LS174T, and HCT116 human colon carcinoma. In addition, BMS-247550 is p.o. efficacious against preclinical human tumor xenografts grown in immunocompromised mice or rats. Schedule optimization studies indicate that BMS-247550 is efficacious when administered frequently (every 2 days x 5) or intermittently (every 4 days x 3 or every 8 days x 2). These efficacy data demonstrate that BMS-247550 has the potential to surpass Taxol in both clinical efficacy and ease of use (i.e., less frequent treatment schedule and/or oral administration).
Asunto(s)
Antineoplásicos/farmacología , Epotilonas , Compuestos Epoxi/farmacología , Paclitaxel/farmacología , Tiazoles/farmacología , Administración Oral , Animales , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Compuestos Epoxi/química , Compuestos Epoxi/uso terapéutico , Femenino , Humanos , Infusiones Parenterales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Trasplante de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Tiazoles/química , Tiazoles/uso terapéutico , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The stereospecific syntheses of the metabolically blocked 6-alpha-F, Cl, Br paclitaxel, and 6-alpha-F-10-acetyldocetaxel are described and in vitro and in vivo activity is presented.
Asunto(s)
Paclitaxel/síntesis química , Taxoides , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Estabilidad de Medicamentos , Humanos , Concentración 50 Inhibidora , Paclitaxel/análogos & derivados , Paclitaxel/química , Paclitaxel/metabolismo , Paclitaxel/farmacología , Células Tumorales CultivadasRESUMEN
The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.
Asunto(s)
Antineoplásicos/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Clorambucilo/química , Clorambucilo/farmacología , Modelos Animales de Enfermedad , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/química , Paclitaxel/farmacología , Sarcoma/tratamiento farmacológico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The 2,4-diacyl paclitaxel analogues 8a-8r were prepared from paclitaxel by acylation of 4-deacetyl-2-debenzoylpaclitaxel 1,2-carbonate (3) followed either by hydrolysis of the carbonate and acylation or by direct treatment of the carbonate with an aryllithium. Some of the resulting derivatives showed significantly improved tubulin assembly activity and cytotoxicity as compared with paclitaxel; in some cases this improvement was especially significant for paclitaxel-resistant cell lines.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Paclitaxel/análogos & derivados , Supervivencia Celular , Humanos , Proteínas Asociadas a Microtúbulos/biosíntesis , Estructura Molecular , Paclitaxel/síntesis química , Paclitaxel/farmacología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
The syntheses and preliminary biological evaluation of 3'-N-thiocarbamate- and 3'-N-thiourea-bearing paclitaxel analogues, 4a-f and 5a-e, are described. 3'-N-thiocarbamates 4a-e were found to be more potent than paclitaxel in both the tubulin polymerization assay and the in vitro cytotoxicity assay. Several derivatives of this class such as 4c, 4d, and 4e also exhibited some in vivo activity.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Paclitaxel/análogos & derivados , Paclitaxel/farmacología , Antineoplásicos Fitogénicos/síntesis química , Paclitaxel/síntesis química , Paclitaxel/química , Relación Estructura-ActividadRESUMEN
The anticancer drug paclitaxel (Taxol) has been converted to a large number of 2-debenzoyl-2-aroyl derivatives by three different methods. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with enhanced activity as compared with paclitaxel were discovered. Correlation of cytotoxicity in three cell lines with tubulin polymerization activity showed reasonable agreement. Among the cell lines examined, the closest correlation with antitubulin activity was observed with a human ovarian carcinoma cell line.
Asunto(s)
Antineoplásicos Fitogénicos , Paclitaxel , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Biopolímeros , Catálisis , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Paclitaxel/análogos & derivados , Paclitaxel/síntesis química , Paclitaxel/química , Paclitaxel/farmacología , Polietilenglicoles/química , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
A new method for studying cellular uptake has been developed. This method is based on selected reaction monitoring liquid chromatography tandem mass spectrometry analysis of preparations from cell culture. The limit of detection for paclitaxel was approximately 0.1 microM intracellular concentration. This method has been utilized to study the uptake of paclitaxel and an analog (BMS-190616) in normal and multidrug resistant (MDR) cell lines. Paclitaxel and the analog, that had been noted to overcome MDR in animal models, were incubated with normal cells (HCT116) and MDR cells (HCT116(VM)46) at therapeutic concentrations. Intracellular drug concentrations were assayed at intervals from 0 to 1.0 h. Results show that paclitaxel accumulates to a level 12 times greater and BMS-190616 to a level 5 times greater in the normal cells as compared to MDR cells suggesting that paclitaxel is more sensitive to MDR than the analog. Furthermore, the steady state level of BMS-190616 was 4 fold greater than paclitaxel in the MDR cell line suggesting that at least part of this compound's increased therapeutic effect can be attributed to processes of uptake and efflux at the cellular level. These data show that the method is rapid, sensitive and presents a unique advantage over traditional radioisotopic methods in that it can readily be employed on a range of analogs without any additional synthetic effort.
Asunto(s)
Antineoplásicos Fitogénicos/metabolismo , Paclitaxel/metabolismo , Cromatografía Líquida de Alta Presión , Resistencia a Múltiples Medicamentos , Humanos , Espectrometría de Masas , Células Tumorales CultivadasRESUMEN
Eleutherobin is a novel natural product isolated from a marine soft coral that is extremely potent for inducing tubulin polymerization in vitro and is cytotoxic for cancer cells with an IC50 similar to that of paclitaxel. This compound is cross-resistant along with other multidrug-resistant agents against P-glycoprotein-expressing cells and is cross-resistant with paclitaxel against a cell line that has altered tubulin. In mechanistic studies, eleutherobin shares with paclitaxel the ability to induce tubulin polymerization in vitro and is most likely cytotoxic by virtue of this mechanism. Human colon carcinoma cells exposed to eleutherobin contain multiple micronuclei and microtubule bundles, and they arrest in mitosis, depending on concentration, cell line, and length of exposure. These morphological abnormalities appearing in cultured cells are indistinguishable from those induced by paclitaxel. Electron microscopy reveals that eleutherobin induces homogeneous populations of long, rigid microtubules similar to those formed by paclitaxel. Thus, eleutherobin is a new chemotype with a mechanism of action similar to that of paclitaxel and, as such, has promising potential as a new anticancer agent.
Asunto(s)
Alcaloides/farmacología , Diterpenos , Microtúbulos/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Sitios de Unión , Unión Competitiva , Bovinos , Neoplasias del Colon/patología , Femenino , Inhibidores de Crecimiento/farmacología , Humanos , Neoplasias Ováricas/patología , Paclitaxel/farmacología , Polímeros , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
A number of paclitaxel analogues with a 5-membered A-ring (A-nor-paclitaxels, or (15-->1)-abeo-paclitaxels) have been prepared in order to determine whether analogues of this class might have improved bioactivity as compared with paclitaxel. Most of the compounds synthesized were less active than paclitaxel, but one analogue was equivalent to paclitaxel in a tubulin-assembly assay, and another analogue was more cytotoxic than paclitaxel in two different cell lines of the NCI screen.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Paclitaxel/análogos & derivados , Muerte Celular/efectos de los fármacos , Línea Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Paclitaxel/síntesis química , Paclitaxel/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
STUDY DESIGN: Patients presenting with L5-S1 anterior column disease with or without herniation into the spinal canal but without stenosis underwent magnetic resonance imaging screening before surgery to determine surgical suitability for laparoscopic anterior lumbar interbody fusion relative to the aortic bifurcation and approach to the disc space. OBJECTIVES: To analyze and evaluate the laparoscopic approach, technique, and benefit of anterior lumbar discectomy and interbody fusion by distraction and compression-loading of autograft only as compared with cage-spacer-enhanced autograft fusion. SUMMARY OF BACKGROUND DATA: Advancement in minimally invasive spine surgery techniques has provided options with less morbidity for posterior lumbar procedures. General surgical advancements in laparoscopy and advantages of traditional anterior lumbar interbody fusion, including restoration of disc height and exposure for safe nerve decompression, provided a basis for an integrated procedure that would address anterior column abnormality with low surgical morbidity. METHODS: Five patients underwent technically successful laparoscopic anterior lumbar interbody fusion with approach to the disc space by an experienced laparoscopic general surgeon. A sixth patient in the study group was unable to undergo laparoscopic fusion because of an iliac vein tear during the surgical approach. After the approach, a spine surgeon followed with complete manual discectomy and interbody autogenous fusion laparoscopically. Two to three Cloward-type dowels were obtained by separate incision from the anterior iliac crest. RESULTS: All patients by 6-month follow-up examination were clinically fused with no motion on flexion-extension radiographs. One patient had slight anterior retropulsion of one dowel without the necessity of reoperation. CONCLUSIONS: Laparoscopic L5-S1 anterior lumbar interbody arthrodesis may represent a viable option for patients with abnormality, including anterior column and degenerative disc disease.
Asunto(s)
Discectomía/métodos , Laparoscopía/métodos , Vértebras Lumbares/cirugía , Enfermedades de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Adulto , Femenino , Estudios de Seguimiento , Humanos , Vértebras Lumbares/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades de la Columna Vertebral/diagnósticoRESUMEN
Three novel C-4 aziridine-bearing paclitaxel analogs, 3-5, have been synthesized during the course of our continuing effort at C-4 modification. The key step in the synthesis is the aziridine ring formation at the C-4 position via an intramolecular Mitsunobu reaction. The syntheses and the biological evaluation of these C-4 aziridine-containing derivatives are herein discussed.
Asunto(s)
Aziridinas/química , Paclitaxel/análogos & derivados , Paclitaxel/síntesis química , Paclitaxel/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/químicaRESUMEN
The DNA binding of BMS 181176, an antitumor antibiotic derivative of rebeccamycin was characterized by DNA unwinding assays, as well as by fluorescence emission and polarization spectroscopic techniques. Unwinding and rewinding of supercoiled DNA was interpreted in terms of intercalation of BMS 181176 into DNA. BMS 181176 shows an enhanced fluorescence emission upon binding to the AT sequence and no enhancement upon binding to the GC sequence. BMS 181176 appears to be a weaker binder to poly(dAdT).poly(dAdT) compared to doxorubicin and ethidium bromide. When bound to DNA, the rotational motion of BMS 181176 is substantially decreased as evident from the increase in fluorescence polarization. BMS 181176 exhibits a range of binding strengths depending on the DNA. This is demonstrated by the Acridine Orange displacement assay using fluorescence polarization.
Asunto(s)
Antibióticos Antineoplásicos/metabolismo , Carbazoles/metabolismo , ADN/metabolismo , Polarización de Fluorescencia , Glucósidos/metabolismo , Indoles , Sustancias Intercalantes/metabolismo , Naranja de Acridina/metabolismo , Animales , Unión Competitiva , Bovinos , ADN/química , ADN Bacteriano/metabolismo , ADN Superhelicoidal/metabolismo , Doxorrubicina/metabolismo , Etidio/metabolismo , Masculino , Micrococcus/química , Conformación de Ácido Nucleico , Plásmidos/química , Poli dA-dT/metabolismo , Salmón , Espermatozoides/química , Timo/químicaRESUMEN
Very low concentrations of paclitaxel, a clinically active anticancer agent isolated from the bark of the Pacific yew tree, were found to produce micronuclei in human colon carcinoma cells, suggesting inhibition of mitotic spindle assembly or function. The possibility that paclitaxel acts at the level of the mitotic spindle was investigated by evaluating its ability to inhibit the progression of mitotic cells to G1 phase. Paclitaxel inhibited mitotic progression with a median inhibitory concentration of 4 nM, a concentration equivalent to the median cytotoxic concentration, without arresting cells in mitosis. A direct correlation was shown to exist between the cytotoxic potency and ability to inhibit mitotic progression for analogues of paclitaxel and antimicrotubule agents but not for the topoisomerase II-active agents etoposide and teniposide. After release from the nocodazole block, cells synchronized in mitosis remained sensitive to very low concentrations of paclitaxel for < 30 min, the time required for spindle formation, yet remained sensitive to vinblastine for > 90 min. This result indicates that very low concentrations of paclitaxel inhibit formation of mitotic spindles in cells without affecting function of preformed spindles and without arresting cells in mitosis. Continuous exposure to low nanomolar concentrations of paclitaxel for more than one cell cycle resulted in cells with DNA contents > 4C and as much as 8C. These results support a hypothesis, that, by not being capable of segregating sister chromatids, paclitaxel-treated cells eventually reform nuclear membranes around individual or clusters of chromosomes, revert to G1 phase cells containing 4C DNA, and enter S phase, resulting in cells with as much as 8C DNA content. It is proposed that this is the primary cytotoxic mechanism of paclitaxel.
Asunto(s)
Anafase/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Paclitaxel/farmacología , Huso Acromático/efectos de los fármacos , Telofase/efectos de los fármacos , Neoplasias del Colon/patología , Ensayos de Selección de Medicamentos Antitumorales , Fase G1 , Humanos , Nocodazol/farmacología , Células Tumorales CultivadasRESUMEN
A total of 27 selected analogues of VP-16 and VM-26 were compared with VP-16 and VM-26 for their relative abilities to stabilize the enzyme-substrate intermediate normally formed between eukaryote topoisomerase II and DNA. This activity was compared with cytotoxicity results obtained using the human colon HCT116 cell line and antitumor results obtained after intraperitoneal injection of mice with murine leukemia P388. The most potent analogues were those containing OH groups (demethyl) in either the 3' and 4' or the 3', 4', and 5' positions, the latter being twice as potent as VP-16. VM-26 was only 40% more potent than VP-16 in this assay. It was generally found that the 4'-esters had little activity in vitro, yet were cytotoxic and had antitumor activities. All other analogues with little in vitro activity were not very cytotoxic and had little if any antitumor activity. A very good correlation exists between stabilization of topoisomerase II-DNA intermediates, cytotoxicity, and antitumor activity.
Asunto(s)
Etopósido/análogos & derivados , Etopósido/toxicidad , Inhibidores de Topoisomerasa II , Línea Celular , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon , ADN-Topoisomerasas de Tipo II/aislamiento & purificación , ADN Viral/aislamiento & purificación , ADN Viral/metabolismo , Etopósido/química , Humanos , Cinética , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Elsamicin (EM) is a recently discovered antitumour agent that is structurally related to several other compounds displaying anticancer activities, including chartreusin (CT), chrysomycin V (CV) and M (CM), gilvocarcin V (GV) and ravidomycin (RM). The biochemical events resulting in cytotoxicity for most of these compounds have not been clearly elucidated. There is some evidence that GV and CT bind to DNA and that GV is photosensitive, causing DNA damage. Therefore, we investigated the effects of these chemicals on DNA in cells and on pBR322 plasmid DNA. Using alkaline elution techniques, we found that all these compounds induced, to a different extent, DNA breakage in the human lung adenocarcinoma A549 cell line. In addition, all either bound to or intercalated into DNA, as indicated by their ability to alter the electrophoretic migration of DNA in agarose gels. Using the P4 unknotting assay, EM, CT, CV, CM, GV and RM were found to be potent inhibitors of the catalytic activity of topoisomerase II (topo II). Their potencies were compared with the known topo II inhibitors teniposide (VM-26) and doxorubicin (DX). EM was the most potent, with an IC50 of 0.4 mumol/l followed in order by CV, GV, and CT. VM-26 was the least potent with an IC50 of 15 mumol/l. It was concluded from these results that EM, GV, CV, CM and CT are capable of inhibiting topo II and that EM is the most potent inhibitor of topo II yet discovered.
Asunto(s)
Aminoglicósidos , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , Inhibidores de Topoisomerasa II , Adenocarcinoma/tratamiento farmacológico , Benzopiranos/farmacología , División Celular/efectos de los fármacos , Cumarinas/farmacología , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Glicósidos/farmacología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Células Tumorales CultivadasRESUMEN
BMY-25551, 7-(2-hydroxyethoxy)mitosane, was selected from a series of mitomycin A (MMA) analogues for more detailed study. As with other members of this class, it was shown to be 8 to 20 times more potent than mitomycin C (MMC) in cytotoxicity to murine and human tumor cell lines in vitro, in causing DNA cross links in vitro, and in dose levels for tumor inhibition in vivo. BMY-25551 appeared to be more effective in tumor inhibition than MMC against P388 leukemia and B16 melanoma in mice and comparable to MMC against L1210 leukemia and Madison 109 lung carcinoma. BMY-25551 was also comparable to MMC in hematologic depression in mice. Factors affecting its possible utility in humans are discussed.