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Angewandte Chemie (International Ed. in... Oct 2003
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bridged-Ring Compounds; Doxorubicin; Drug Carriers; Drug Delivery Systems; Humans; Ligands; Mandelic Acids; Neoplasms; Oligopeptides; Paclitaxel; Taxoids
PubMed: 14562338
DOI: 10.1002/anie.200301666 -
Clinical Cancer Research : An Official... Aug 2002Taxane-based therapies appear to have a significant efficacy in clinical trials on hormone-refractory prostate carcinoma. In the present study, we investigated the...
Taxane-based therapies appear to have a significant efficacy in clinical trials on hormone-refractory prostate carcinoma. In the present study, we investigated the cellular response of androgen-independent prostate carcinoma cell lines to the novel taxane IDN 5109 (BAY 59-8862) and evaluated its antitumor activity. In previous preclinical studies, this new paclitaxel (PTX) analogue was characterized by high tolerability and antitumor efficacy, ability to overcome multidrug resistance, and activity by oral administration. Upon treatment, DU145 and PC3 prostate carcinoma cell lines underwent a transient mitotic arrest. This was followed by G1 arrest and rapid occurrence of apoptosis in DU145 cells, whereas in PC3 cells, which are defective for the postmitotic checkpoint, a slow cell death was preceded by DNA endoreduplication. At the biochemical level, such events were associated with tubulin polymerization, activation of the mitosis-promoting factor, and phosphorylation of Bcl-X(L)/Bcl-2/Raf-1. In addition, IDN 5109 shared with PTX the ability to down-regulate the expression of the two potent angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. These findings indicated that IDN 5109 affected the same pathways involved in the cellular response to PTX and suggested that an antiangiogenic effect mediated by inhibition of paracrine stimulation of endothelial cells might contribute to the antitumor effect of both drugs. In in vivo experiments, the new taxane displayed a superior and more persistent effect compared with PTX against DU145 tumor xenografts. Such an effect was associated with pronounced reduction of the tumor microvessel density, superior to that achieved by PTX. These results support a potential therapeutic advantage of IDN 5109 over PTX against hormone-refractory prostate carcinoma.
Topics: Antineoplastic Agents; Blotting, Western; Bridged-Ring Compounds; CDC2 Protein Kinase; Cell Cycle; Cell Death; Cell Division; Cell Nucleus; Cell Separation; Dose-Response Relationship, Drug; Down-Regulation; Endothelial Growth Factors; Fibroblast Growth Factor 2; Flow Cytometry; Humans; In Situ Nick-End Labeling; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Maturation-Promoting Factor; Mitosis; Neoplasm Transplantation; Neovascularization, Pathologic; Paclitaxel; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-raf; Subcellular Fractions; Taxoids; Time Factors; Tubulin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; bcl-X Protein
PubMed: 12171897
DOI: No ID Found -
IUBMB Life 2002P-glycoprotein (P-GP)-based multidrug resistance (MDR) and undesirable side effects are significant drawbacks to the clinical use of paclitaxel and docetaxel. Extensive... (Review)
Review
P-glycoprotein (P-GP)-based multidrug resistance (MDR) and undesirable side effects are significant drawbacks to the clinical use of paclitaxel and docetaxel. Extensive SAR studies of taxanes in these laboratories led to the discovery of new generation taxanes that are highly active against not only drug-sensitive but also drug-resistant human cancer cell lines as well as tumor xenografts in mice. One of these second generation taxanes, SB-T-110131 (IDN5109), exhibited excellent pharmacological profile in the preclinical studies and has been selected for clinical development (recoded as Bay 59-8862), which is currently in the phase II clinical trials. Bay 59-8862 is orally active with high bioavailability, showing excellent activity against a variety of drug-resistant tumors. "Advanced second generation taxanes" show essentially no difference in cytotoxicity against drug-resistant and drug-sensitive cell lines, virtually overcoming MDR. Photoaffinity labeling of P-GP using photoreactive radiolabeled paclitaxel analogs has disclosed the paclitaxel-binding domain of P-GP. Highly efficient taxane-based MDR reversal agents (TRAs) have also been developed, which can recover the cytotoxicity of paclitaxel to practically the original level against paclitaxel-resistant MDR expressing cancer cells. Highly promising results have emerged from the study of taxane-monoclonal antibody (MAb) immunoconjugates, which have been proved to specifically deliver extremely cytotoxic agents to tumor in an animal model.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Binding Sites; Bridged-Ring Compounds; Clinical Trials as Topic; Drug Resistance, Multiple; Humans; Mice; Models, Chemical; Models, Molecular; Neoplasm Transplantation; Paclitaxel; Protein Structure, Tertiary; Taxoids
PubMed: 12121008
DOI: 10.1080/15216540212658 -
Bulletin Du Cancer Apr 2002This review describes the experimental and clinical properties of new taxanes and epothilones. Six new taxanes are currently in clinical trials: BMS 184476, BMS 188797,... (Review)
Review
This review describes the experimental and clinical properties of new taxanes and epothilones. Six new taxanes are currently in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A et RPR 116258 All these derivatives share the same feature which is a decreased recognition by Pgp-170, the product of the MDR1 gene. This confers innovative properties such as in vitro and in vivo activities on tumors expressing the Pgp-170, activity by the oral route. Identification of other families of molecules bearing the same mechanism of action as taxol has been a goal pursued by many groups. The discovery of epothilones led to the pharmaceutical development of two molecules: EPO 906 (which corresponds to the natural compound epothilone B) and BMS 247550. Phase I clinical trials have established that all these investigational drugs (taxanes and epothilones) can be safely administered in patients, the limiting toxicity being most of the time febrile neutropenia. Many tumor responses have been noted.
Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Clinical Trials, Phase I as Topic; Drug Screening Assays, Antitumor; Humans; Mice; Neutropenia; Paclitaxel; Taxoids
PubMed: 12016034
DOI: No ID Found -
International Journal of Cancer Mar 2002Constitutive bcl-2 overexpression increases the tumorigenic and metastatic potential of doxorubicin-resistant, estrogen-independent, MCF-7 ADR human breast cancer cells....
Constitutive bcl-2 overexpression increases the tumorigenic and metastatic potential of doxorubicin-resistant, estrogen-independent, MCF-7 ADR human breast cancer cells. We evaluated the sensitivity to taxanes (paclitaxel, docetaxel and IDN 5109) of 2 bcl-2-overexpressing MCF-7 ADR clones and control neomycin-transfected MCF-7 ADR neo cells. The 2 bcl-2-overexpressing MCF-7 ADR clones were relatively resistant to all 3 taxanes, whereas the MCF-7 ADR neo cells were relatively resistant to paclitaxel and docetaxel, but sensitive to IDN 5109. We found that both MCF-7 ADR neo and bcl-2-overexpressing MCF-7 ADR clones express high levels of the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor-alpha (TGF-alpha). Therefore, we tested the growth inhibitory effect of ZD1839 (Iressa, AstraZeneca, Macclesfield, UK), an orally active, selective EGFR tyrosine kinase inhibitor (EGFR-TKI) that is in clinical development. ZD1839 inhibited the growth in soft agar of all 3 clones in a dose-dependent manner (IC(50) of approximately 0.1 microm). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-alpha, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). To determine whether the blockade of EGFR signaling might affect the sensitivity of bcl-2-overexpressing MCF-7 ADR cells to taxanes, cells were treated with ZD1839 in combination with paclitaxel, docetaxel or IDN 5109, and dose-dependent cooperative growth inhibition as well as apoptosis potentiation were observed. Combined treatment with IDN 5109 and ZD1839 also resulted in a significant inhibition of bcl-2 expression in bcl-2-overexpressing MCF-7 ADR cells. These results demonstrate the ability of ZD1839 to overcome taxane resistance in a model of hormone-independent, multidrug-resistant, human breast cancer.
Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Bridged-Ring Compounds; Cell Division; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors; ErbB Receptors; Female; Fibroblast Growth Factor 2; Gefitinib; Humans; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Quinazolines; Taxoids; Transfection; Transforming Growth Factor alpha; Tumor Cells, Cultured
PubMed: 11920601
DOI: 10.1002/ijc.10230 -
Chemistry & Biology Jan 2002SB-T-1213 and IDN5109 are semisynthetic, orally available taxanes that are up to 400-fold more active than paclitaxel against drug-resistant cells. IDN5109 is in...
SB-T-1213 and IDN5109 are semisynthetic, orally available taxanes that are up to 400-fold more active than paclitaxel against drug-resistant cells. IDN5109 is in clinical trials. We investigated the primary target for SB-T-1213 and IDN5109 and whether the compounds interact with microtubules differently than paclitaxel. Unlike paclitaxel, at 1-10 microM both novel taxanes initiate microtubule polymerization in vitro with no lag. They enhance polymerization equally or more potently than paclitaxel. SB-T-1213 induces unusual microtubules with attached extra protofilaments or open sheets, and IDN5109 induces large protofilamentous sheets. Both inhibit HeLa cell proliferation, block mitosis at the metaphase/anaphase transition, bundle microtubules at high drug concentrations, and induce abnormal metaphase spindles and apoptosis. They target microtubules but alter their polymerization and structure differently than paclitaxel. These differences may play a role in their enhanced cytotoxicity and efficacy.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Bridged-Ring Compounds; Dose-Response Relationship, Drug; HeLa Cells; Humans; Microscopy, Electron; Microtubules; Mitosis; Paclitaxel; Taxoids; Tubulin
PubMed: 11841942
DOI: 10.1016/s1074-5521(01)00097-7 -
Cancer Dec 2001The development of effective chemotherapy for central nervous system tumors is hampered by the blood-brain barrier and by limited drug diffusion in the brain tissue. BAY...
BACKGROUND
The development of effective chemotherapy for central nervous system tumors is hampered by the blood-brain barrier and by limited drug diffusion in the brain tissue. BAY 59-8862 is a new taxane analog that was selected and developed for its activity against tumors with a P-glycoprotein-mediated, multidrug-resistant phenotype. Because P-glycoprotein is implicated in limiting the access of drugs to central nervous system tumor targets, the objective of this study was to evaluate the ability of intravenously administered BAY 59-8862 to affect the growth of central nervous system tumors.
METHODS
The U-87 MG human glioma cell line was xenografted orthotopically (intracranially) in nude mice. Paclitaxel or BAY 59-8862 was delivered intravenously four times every fourth day, and antitumor efficacy was assessed by examining the effects on mouse survival time and by histologic examination of mouse brain. Drug levels in plasma and brain were determined according to a high-performance liquid chromatography method.
RESULTS
The analog was as potent as paclitaxel in inhibiting the proliferation of three human glioma cell lines (U-87 MG, SW1783, and GBM) and was as effective as paclitaxel in inhibiting the heterotopic (subcutaneous) tumor growth in nude mice of U-87 MG cells (tumor weight inhibition, approximately 60%). In contrast, BAY 59-8862 was more active than paclitaxel (P < 0.05 in two of three experiments) in increasing the survival time of mice that were injected orthotopically with U-87 MG cells. The results were supported by the pharmacokinetic data, which indicated a much higher (about 15-fold) brain:plasma level ratio in BAY 59-8862-treated animals compared with paclitaxel-treated animals.
CONCLUSIONS
The study provides evidence of an additional pharmacologic advantage of BAY 59-8862, i.e., the ability to affect the growth of intracranial tumors, probably due to the lack of recognition by the P-glycoprotein-mediated transport systems. The favorable behavior of BAY 59-8862 supports the potential interest in the analog for clinical studies in patients with brain tumors or metastases.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents, Phytogenic; Blood-Brain Barrier; Brain Neoplasms; Bridged-Ring Compounds; Glioma; Humans; Indoles; Infusions, Intravenous; Mice; Mice, Nude; Paclitaxel; Taxoids; Transplantation, Heterologous
PubMed: 11753988
DOI: 10.1002/1097-0142(20011215)92:12<3085::aid-cncr10150>3.0.co;2-s -
Rapid Communications in Mass... 2001A sensitive, specific, accurate and reproducible high-performance liquid chromatography (HPLC) analytical method was developed and validated for the quantification of...
High-performance liquid chromatography/tandem mass spectrometry for the quantitative analysis of a novel taxane derivative (BAY59-8862) in biological samples and characterisation of its metabolic profile in rat bile samples.
A sensitive, specific, accurate and reproducible high-performance liquid chromatography (HPLC) analytical method was developed and validated for the quantification of the novel oral taxane analogue BAY59-8862 in mouse plasma and tissue samples. A fully automated solid-phase extraction procedure was applied to the plasma after internal standard (IS) addition, with only 0.2 mL volume of the sample loaded on a CN-Sep-pak cartridge. In the case of the tissues a very simple acetonitrile extraction was used to recover BAY59-8862 and its internal standard from liver. The procedure for the quantification of BAY59-8862 and its IS (IDN5127) is based on high-performance liquid chromatography/ion spray-tandem mass spectrometry, operating in selected ion monitoring mode. The retention times of BAY and IS were 7.21 and 10.36 min, respectively. In both plasma and tissue specimens the assay was linear in the range 50-5000 ng/mL (ng/g). The overall precision and accuracy were assessed on three different days. The results for plasma were within 6.1% (precision) and between 99 and 112% (accuracy), and for the liver samples within 7.3% and between 104 and 118%, respectively. The LOD was 5 ng/mL and 20 ng/g in the plasma and liver, respectively. In addition, the biliary excretion of the compound in rats was studied. The study showed that an oxidative chemical reaction was the preferred metabolic pathway for biliary excretion, and two sets of mono- and dihydroxylated metabolites were detected by LC/ISP-MS/MS experiments. With this method, BAY59-8862 pharmacokinetic was determined in mice. The combined results demonstrate that the methodology can be considered a valid approach to conduct pharmacokinetic and metabolic studies during preclinical and clinical investigations.
Topics: Animals; Antineoplastic Agents, Phytogenic; Bile; Bridged-Ring Compounds; Chromatography, High Pressure Liquid; Liver; Mass Spectrometry; Mice; Mice, Nude; Molecular Conformation; Molecular Structure; Paclitaxel; Rats; Regression Analysis; Reproducibility of Results; Sensitivity and Specificity; Taxoids
PubMed: 11565098
DOI: 10.1002/rcm.438 -
Journal of the National Cancer Institute Aug 2001The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein...
BACKGROUND
The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein (Pgp), which removes the drug from the cells. The orally active paclitaxel analog IDN-5109 has been reported to overcome Pgp-mediated drug resistance. We tested whether IDN-5109 acts by modulating Pgp activity.
METHODS
Human MDA435/LCC6mdr1 and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [3H]IDN-5109 and paclitaxel to determine intracellular drug accumulation. Flow cytometry was used to analyze intracellular retention of two Pgp substrates, rhodamine 123 (Rh-123) and doxorubicin, in both breast carcinoma cell lines and in human colon carcinoma cells (SW-620, DLD1, and HCT-15, whose Pgp levels vary) treated with different taxanes. The effects of IDN-5109 and paclitaxel on tumor growth in vivo were studied with the use of tumors established through xenografts of Pgp-expressing SW-620 and DLD1 cells in severe combined immunodeficiency mice. All statistical tests were two-sided.
RESULTS
Pgp-expressing cells treated with IDN-5109 or with the taxane-based drug resistance reversal agent tRA96023, which blocks Pgp activity, retained 8.1- and 9.4-fold more Rh-123 (P =.0001), respectively, and 1.7- and 1.9-fold more doxorubicin (P =.001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/LCC6mdr1 cells retained 5.3-fold more [3H]IDN-5109 than [3H]paclitaxel after 2 hours (P =.01). IDN-5109 showed statistically significantly higher tumor growth inhibition than paclitaxel against the SW-620 xenograft (P =.003).
CONCLUSIONS
IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Colonic Neoplasms; Doxorubicin; Drug Screening Assays, Antitumor; Female; Flow Cytometry; Fluorescence; Humans; Male; Paclitaxel; Taxoids; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured
PubMed: 11504769
DOI: 10.1093/jnci/93.16.1234 -
Current Pharmaceutical Design Sep 2001Paclitaxel and docetaxel are two key molecules in the treatment of a variety of cancers with major impact in the treatment of breast, lung and ovarian cancers. A number... (Review)
Review
Paclitaxel and docetaxel are two key molecules in the treatment of a variety of cancers with major impact in the treatment of breast, lung and ovarian cancers. A number of taxoids have then been synthesized in an effort to improve some of the features of the existing drugs. Although the literature is still scant of preclinical data due to the highly competitive field, several compounds are already in clinical trials. Most of these will be reviewed and have, either improved water solubility or reduced cross-resistance with marketed taxoids or reduced interaction with P-glycoprotein. In addition, the reduced recognition of several compounds by multi-drug-resistance related transport systems has yielded some orally bioavailable compounds with marked in vivo antitumor activity. It is likely that these additional properties should lead to an expanded spectrum of clinical activity compared to that of clinically available taxoids.
Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Docetaxel; Neoplasms, Experimental; Paclitaxel; Taxoids
PubMed: 11472265
DOI: 10.2174/1381612013397465