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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 -
Bioinformation 2020Lipocalin 2 (Lcn2, also called as neutrophil gelatinase-associated lipocalin) is a member of the lipocalin family and a known target for breast cancer. Therefore, it is...
Lipocalin 2 (Lcn2, also called as neutrophil gelatinase-associated lipocalin) is a member of the lipocalin family and a known target for breast cancer. Therefore, it is of interest to use Docetaxel as a scaffold to design molecules with improved efficiency from naturally derived phytochemicals. We document 10 analogues (4Deacetyltaxol, 7Acetyltaxol, Cabazitaxel, Cephalomannine, Docetaxal, Deacetyltaxol, Docetaxeltrihydrate, Ortataxel, Paclitaxel, Taxoline) having optimal binding with Lipocalin 2 in comparison with Docetaxel. This data is highly useful for consideration in the design and development of drugs for breast cancer.
PubMed: 32884206
DOI: 10.6026/97320630016438 -
Clinical Investigation 2013The oral taxanes are analogues of existing taxanes with a possible broad range of antitumor activity. They also have the potential advantages of ease of administration,...
The oral taxanes are analogues of existing taxanes with a possible broad range of antitumor activity. They also have the potential advantages of ease of administration, better efficacy and lesser toxicity than currently available taxanes. These drugs have been used in several Phase I clinical trials, the methodology and results of which will be reviewed here.
PubMed: 26146540
DOI: 10.4155/cli.13.18 -
International Journal of Cancer Jun 2001Loss of p53 function has been linked to increased responsiveness to taxane treatment of ovarian carcinoma in clinical studies. We recently reported that the acquisition...
Loss of p53 function has been linked to increased responsiveness to taxane treatment of ovarian carcinoma in clinical studies. We recently reported that the acquisition of cisplatin resistance in an ovarian carcinoma cell line (IGROV-1) was associated with mutation of p53 and collateral sensitivity to paclitaxel. The increased sensitivity to paclitaxel of the cisplatin-resistant subline appeared to be pharmacologically relevant since it was reflected in an in vivo sensitization to taxanes. To investigate the cellular and molecular basis of this phenomenon, we performed a comparative study of cellular response to taxanes (paclitaxel and the novel analog IDN 5109) in the parental cell line, containing wild-type p53 and its cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). IDN 5109 was included in this study because of its higher potency and efficacy compared with paclitaxel on both tumor systems. The pattern of cellular response of the two ovarian cell lines was different. In IGROV-1 cells, apoptosis was an early event consequent to a transient mitotic arrest. The cell death of IGROV-1/Pt1 cells was a somewhat slow and delayed event, following mitotic arrest and appearance of hyperploid cells. The increased cytotoxic effect of IDN 5109, compared with paclitaxel, was associated with more marked p34(cdc2) dephosphorylation in IGROV-1 cells and higher Bcl-2 phosphorylation in IGROV-1/Pt1 cells after 24 hr of treatment. In each cell line, these biochemical events were not correlated with parallel levels of mitotic cells. Attempts to reintroduce wild-type p53 in IGROV-1/Pt1 were unsuccessful. However, in other p53-deficient cells (osteosarcoma SAOS), taxane treatment was associated with hyperploid progression and the introduction of wild-type p53 resulted in a reduced sensivity. Although our approach does not allow definitive conclusions, these results suggest that loss of p53-dependent post-mitotic checkpoint results in a different time-course of taxane-induced cell death following DNA reduplication. These events, more evident after exposure to the potent analog IDN 5109, support the notion that the enhanced sensitivity of p53 mutant cells is closely related to the different mode of cell death.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Bridged-Ring Compounds; Cell Cycle; DNA, Neoplasm; Female; Humans; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Taxoids; Tubulin; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 11340581
DOI: 10.1002/1097-0215(20010601)92:5<738::aid-ijc1249>3.0.co;2-2 -
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 -
Zeitschrift Fur Naturforschung. C,... 2009In order to find the minimal structural requirements to maintain microtubule binding, 12 taxol analogues have been docked to the taxol binding site of tubulin. By...
In order to find the minimal structural requirements to maintain microtubule binding, 12 taxol analogues have been docked to the taxol binding site of tubulin. By comparing the interactions of each analogue with beta-tubulin, the structure-activity relationships are summarized as follow: C-2 benzoyl and taxane ring systems are the essential groups for microtubule binding, the improvements of bioactivity and bioavailability are dependent on the substituents at positions C-1, C-4, C-7, C-9, C-10, and C-14, whereas the C-13 side chain mainly provides a specific binding.
Topics: Binding Sites; Bridged-Ring Compounds; Docetaxel; Kinetics; Microtubules; Models, Molecular; Paclitaxel; Structure-Activity Relationship; Taxoids; Thermodynamics; Tubulin
PubMed: 19791508
DOI: 10.1515/znc-2009-7-814 -
International Journal of Cancer Sep 1997Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core...
Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core synthon of the 2 above prototypes, were tested in vitro for their growth-inhibitory activity on different human cancer cell lines, including some expressing the classic multidrug-resistant (MDR) phenotype (MCF-7 ADRr and CEM VBLr). The 14-OH-DAB derivatives showed enhanced anti-proliferative activity as compared to the parent compounds on the MDR-positive cancer cell lines. Particularly, IDN 5109 showed a 25- to 30-fold higher activity than paclitaxel. The fold change in activity between paclitaxel and analogs (IC50 paclitaxel/IC50 analogs) on the MDR-positive cell lines was calculated and a significant correlation observed. As far as the MDR-negative MDA-MB 231 cells are concerned, docetaxel and IDN 5109 exhibited a more potent activity than paclitaxel. On the basis of the data obtained on cell growth inhibition, we selected the most active compounds to study their effect on the cell cycle. Cell cycle analysis showed that all of the compounds tested were able to induce cell cycle block at G2/M in a concentration-dependent manner. The amount of cell block, measured as a G1/G2 ratio, was correlated significantly (p < 0.001) with apoptosis, as evaluated in the sub-G1 region (% of DNA fragmentation), thereby suggesting that the G2/M-blocked cells underwent apoptosis. To confirm the occurrence of apoptosis in this system, DNA gel agarose electrophoresis was performed and showed the typical ladder pattern.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Division; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Female; Humans; Leukemia; Mitosis; Paclitaxel; Structure-Activity Relationship; Taxoids; Triterpenes; Tumor Cells, Cultured
PubMed: 9311603
DOI: 10.1002/(sici)1097-0215(19970904)72:5<844::aid-ijc22>3.0.co;2-7 -
Molecular BioSystems Oct 2012The effects on tubulin dynamics of paclitaxel, ortataxel and two recently developed taxol derivatives bearing a five-membered heterocyclic ring fused at the 1,14...
The effects on tubulin dynamics of paclitaxel, ortataxel and two recently developed taxol derivatives bearing a five-membered heterocyclic ring fused at the 1,14 position were analysed by means of molecular dynamic simulations and the MM-PBSA approach. Tubulin polymerization kinetics and microtubule morphology assays were also conducted, providing support to computational results. In particular, it has been shown that the two recently developed 1,14-heterofused taxanes IDN5839 and IDN5798 are able to speed up the in vitro tubulin assembly by promoting the nucleation phase and to affect the microtubule network in cells earlier than paclitaxel.
Topics: Bridged-Ring Compounds; Cell Line, Tumor; Computational Biology; Humans; Kinetics; MCF-7 Cells; Microtubules; Models, Molecular; Molecular Dynamics Simulation; Paclitaxel; Protein Binding; Protein Conformation; Protein Multimerization; Taxoids; Tubulin
PubMed: 23073462
DOI: 10.1039/c2mb25326g