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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 -
Current Opinion in Drug Discovery &... Sep 2000Nature provides a large spectrum of agents that either inhibit the polymerization of tubulin or prevent the disassembly of microtubules. Some of them are already used as...
Nature provides a large spectrum of agents that either inhibit the polymerization of tubulin or prevent the disassembly of microtubules. Some of them are already used as anticancer drugs, but acquired resistance limits their application. Recently, a variety of new substances that inhibit tubulin aggregation have been synthesized or isolated from natural sources. Examples are vinflunine, the combretastatin analog AC-7700, indanocine, the sulfonamide T-138067, oncocidin A1, natural and modified dolastatins, and cryptophycins. Among the substances which stabilize microtubules, the taxanes play the dominant role. A second generation of synthetically modified derivatives is in development as exemplified by IDN-5109. A number of other natural products, such as the epothilones, eleutherobin, sarcodictyin and discodermolide, share the mode of action with the taxanes, but exceed them in potency and activity in multidrug-resistant cells. However, toxicity and availability might prevent their medical application.
PubMed: 19649885
DOI: No ID Found -
Oncology Research 1999The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained...
The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained in liquid culture and on three human cancer cell lines (MDA-MB231, MCF-7 ADRr, CEM VBLr). Concomitantly, DNA analysis was also performed. For unfractionated peripheral blood progenitor cells (PBPC) toxicity was also assessed by clonogenic assay. The cytotoxic effects induced by taxanes toward PBPC as measured by clonogenic assay were correlated with those found for multidrug resistance (MDR)-positive cell lines (IDN5109 > IDN5111 > IDN5127 > docetaxel > paclitaxel). We established a therapeutic index (TI) between the antitumor activity in MDR-positive cells and the toxicity toward PBPC. Paclitaxel and IDN5109, as determined by TI, showed the best value in MDR-negative and MDR-positive cells, respectively. The ranking of the cytotoxic effects observed in PB CD34+ was not correlated with that obtained in clonogenic assay and in cancer cells (IDN5127 > IDN5109 > docetaxel > IDN5111). Remarkably, in DNA analysis docetaxel induced the maximal cell cycle blocking activity. Newly developed taxanes IDN5109 and IDN5111 are endowed of a profile of anticancer activity in MDR-bearing cells and toxicity toward hematopoietic progenitors better than that of docetaxel. However, mechanism(s) underlying toxicity toward hematopoietic progenitors could be, at least in part, different from that of docetaxel and likely dependent on the interaction with P-glycoprotein function in PB CD34+ cells.
Topics: Antigens, CD34; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Cell Cycle; Cell Division; Docetaxel; Drug Resistance, Multiple; Flow Cytometry; Hematopoietic Stem Cells; Humans; Inhibitory Concentration 50; Leukocytes, Mononuclear; Paclitaxel; Taxoids; Time Factors; Tumor Cells, Cultured
PubMed: 10850888
DOI: No ID Found -
Clinical Cancer Research : An Official... May 2000A novel taxane (IDN 5109), originally selected for its ability to overcome P-glycoprotein-mediated drug resistance, is characterized by an improved preclinical profile... (Comparative Study)
Comparative Study
A novel taxane (IDN 5109), originally selected for its ability to overcome P-glycoprotein-mediated drug resistance, is characterized by an improved preclinical profile in terms of efficacy and tolerability. Because P-glycoprotein may critically influence intestinal absorption and oral bioavailability of taxanes, the purpose of the study was to evaluate the bioavailability, the pharmacokinetic behavior, and the antitumor activity of the new taxane after oral administration. A comparative study of antitumor activity of Taxol and IDN 5109 given orally was performed in a human breast carcinoma model, MX-1, which is highly responsive to i.v. treatment with both of the taxanes. In contrast to Taxol, which was completely ineffective after administration to MX-1-bearing mice, oral IDN 5109 exhibited an activity comparable with that of i.v. treatment (ie., 100% cures). Again, the maximal tolerated doses were comparable (90 mg/kg, every 4 days for four doses) after i.v. and oral treatment. Three other tumor models (LoVo, IGROV/DDP, and U87) with a variable sensitivity to the drug were used to compare the antitumor effects of i.v. and oral treatment with IDN 5109. The efficacy after oral administration was only slightly lower than that found after i.v. treatment at equivalent doses; but optimal effects were comparable likely as a consequence of the long (>6 h) terminal half-life of oral IDN 5109. The bioavailability of IDN 5109 assessed by comparing area-under-the-curve values after oral and i.v. administrations was approximately 50%. The oral efficacy of the novel taxane, likely related to the inability of the P-glycoprotein to recognize the drug, which allowed an adequate intestinal absorption, is a unique feature among the taxanes and may represent a pharmacological breakthrough in their clinical use.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Area Under Curve; Biological Availability; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Paclitaxel; Taxoids; Transplantation, Heterologous; Treatment Outcome; Tumor Cells, Cultured
PubMed: 10815934
DOI: No ID Found -
Cancer Research Feb 2000IDN5109 is a new taxane, derived from 14beta-hydroxy-10-deacetylbaccatin III, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug...
IDN5109 is a new taxane, derived from 14beta-hydroxy-10-deacetylbaccatin III, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug resistant phenotype. Because, unlike paclitaxel, IDN5109 is a poor substrate for P-glycoprotein, we hypothesized that IDN5109 given p.o. could improve bioavailability compared with paclitaxel. Here, we studied the p.o. and i.v. pharmacokinetics of IDN5109 together with its antitumor activity. Using a high-performance liquid chromatography method, the bioavailability of IDN5109 was determined to be 48% after oral delivery. IDN5109 given p.o. was highly active against the two human ovarian carcinoma xenografts 1A9 and HOC18 (90-100% tumor regressions) and showed significant activity on the paclitaxel-resistant MNB-PTX1 xenograft (10% tumor regressions). The p.o. administration was as active as the i.v. route at doses reflecting the pharmacokinetic data. IDN5109 is the first taxane with good oral bioavailability and potent antitumor activity and represents a potential candidate for clinical investigation.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Taxoids
PubMed: 10706091
DOI: No ID Found -
Journal of Chromatography. B,... Dec 1999An HPLC assay was developed to determine the paclitaxel analogue 13-(N-tert.-butoxycarbonyl-beta-isobutylisoserinyl)-14-hydroxyb accatin-1,14-carbonate (IDN5109) and its...
An HPLC assay was developed to determine the paclitaxel analogue 13-(N-tert.-butoxycarbonyl-beta-isobutylisoserinyl)-14-hydroxyb accatin-1,14-carbonate (IDN5109) and its epimer in mouse plasma. The method involves solid-phase extraction on cyano cartridges (recovery >75%), HPLC separation on symmetry shield column, a mobile phase of NaH2PO4 (10 mM) pH 5.2, acetonitrile (47:53) and detection at 227 nm. Retention times of IDN5109, its epiform and internal standard were 15, 24 and 25.5 min, respectively. The assay was linear from 0.10 to 10 microg/ml (r2 = 0.999), with a C.V. <5% and accuracy in the range of 95-107%. LOQ was 50 ng/ml for both compounds. Using this method IDN5109 pharmacokinetic was determined in mice.
Topics: Animals; Bridged-Ring Compounds; Chromatography, High Pressure Liquid; Drug Stability; Female; Freezing; Kinetics; Mice; Paclitaxel; Quality Control; Reproducibility of Results; Sensitivity and Specificity; Taxoids
PubMed: 10676993
DOI: 10.1016/s0378-4347(99)00450-8 -
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