Bevacizumab in the first-line treatment of metastatic breast cancer
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Taxane
Progression-free survival
The complex natural product paclitaxel (Taxol), first isolated from Taxus brevifolia, is a member of a large family of taxane diterpenoids. Paclitaxel is extensively used for the treatment of solid tumors, particularly those of the breasts and ovaries. In order to obtain additional information about the mechanism of action of paclitaxel and the environment of the paclitaxel-binding site, several fluorescent analogs of paclitaxel were synthesized, and their biological activities have been evaluated. For the investigation of possible synergistic effects, concurrent modifications on selected positions have been performed and their biological evaluation were studied.
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Paclitaxel (Taxol®) and docetaxel (Taxotere®) are relatively new drugs used in cancer therapy and have shown great promise in the treatment of a variety of cancers. The taxane therapy, however, encounters two major problems. One problem is the low solubility of both paclitaxel and docetaxel; the second problem is multi-drug resistance. In the patent literature from 1995 - 1997 these two problems have been the main focus of research in the taxane field. Numerous taxoids have been disclosed with improved solubility, mainly by acylation of the C-2′ and C-7 hydroxyls. To reduce the multi-drug resistance susceptibility of the drugs, alterations on the taxane core and the phenylisoserine ring have been made. The patent literature also reports the discovery of new classes of compounds (epothilones, discodermolides, eleutherobins and sarcodictyins) that are structurally dissimilar from taxanes but have microtubule stabilisation activity and are potent inhibitors of cancer cells and paclitaxel-resistant cancer cells.
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NBT-287, a third generation taxane analog, and paclitaxel resistance due to MDR-1 and mutant tubulin
3114 Background: The therapeutic utility of taxanes, the most widely used class of anticancer agents, is hampered by resistance due to over-expression of MDR-1 and tubulin mutations. By modifying the paclitaxel (TX) molecule, we have prepared a third-generation taxane designed to circumvent MDR-1. We tested this taxane in human tumor cell lines, including an ovarian cancer cell line characterized by mutant tubulin. Methods: For initial screening, we selected tumors exhibiting various levels of MDR-1 expression. Twenty-four hours following inoculation of tumor cells into 96-well plates, different concentrations of analogs solubilized in DMSO / PBS were added to six replicate wells for 1-hour and 24-hour periods. After five additional days of incubation in drug-free media, we determined cell survival using the MTT or WST-1 assay, and compared the mean O.D.s of sextuplicate wells containing taxane analog treated, untreated, and paclitaxel treated controls. Results: NBT-287 was 4- to 200-fold more potent than paclitaxel in the ovarian mutant tubulin MDR-1 negative tumor, in MDR-1 positive cell lines, and equivalent to paclitaxel in other MDR-1 negative cell lines. Exposure of NCI-AR paclitaxel-resistant breast tumor cells to NBT-287 at a 25% inhibitory concentration did not sensitize the cells to paclitaxel, suggesting that this analog was circumventing rather than reversing MDR-1. The cytotoxic ratios of the ED50 comparing TX and NBT-287 in representative cell lines are tabulated below. Conclusions: The cytotoxic advantage of NBT-287 over paclitaxel in tumor cells is independent of the expression of MDR-1 and of mutant tubulin-associated resistance. The latter mechanism of action may be due to different binding sites on beta-tubulin for paclitaxel and NBT-287. As a result, this taxane may be an appropriate compound for further efficacy and safety studies in mouse xenotransplants and in patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NaPro BioTherapeutics, Inc. Bruce Myers & Associates; NaPro BioTherapeutics, Inc. NaPro BioTherapeutics, Inc.
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It has been reported that bevacizumab in combination with paclitaxel significantly prolongs progression-free survival compared with paclitaxel alone in the initial treatment for metastatic breast cancer. To understand how bevacizumab enhances the efficacy of paclitaxel, we investigated the mechanism in a MX-1 human breast cancer xenograft model. The antitumor activity of bevacizumab at 5 mg/kg in combination with paclitaxel at 20 or 30 mg/kg was significantly higher than that of either agent alone. First, we measured the paclitaxel concentration in tumor to see whether bevacizumab enhances the activity by increasing the tumor concentration of paclitaxel. When given in combination with bevacizumab, the levels of paclitaxel in the tumor increased. Paclitaxel at 30 mg/kg with bevacizumab showed a similar tumor concentration as paclitaxel alone at either 60 or 100 mg/kg, with a similar degree of tumor growth inhibition. In contrast, no remarkable differences in paclitaxel concentration in the plasma or liver were observed between the paclitaxel monotherapy group and the paclitaxel plus bevacizumab group. An increase in paclitaxel concentration by bevacizumab was also found in another model, A549. In the same MX-1 model, vascular permeability in the tumor was significantly decreased by treatment with bevacizumab. There was no difference in microvessel density between the bevacizumab alone group and the combination group. Results suggest that the synergistic antitumor activity of paclitaxel and bevacizumab in combination may be a result of the increase in paclitaxel concentration in tumor resulting from the downregulation of vascular permeability when co-administered with bevacizumab.
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NBT-287, a third generation taxane analog, and paclitaxel resistance due to MDR-1 and mutant tubulin
3114 Background: The therapeutic utility of taxanes, the most widely used class of anticancer agents, is hampered by resistance due to over-expression of MDR-1 and tubulin mutations. By modifying the paclitaxel (TX) molecule, we have prepared a third-generation taxane designed to circumvent MDR-1. We tested this taxane in human tumor cell lines, including an ovarian cancer cell line characterized by mutant tubulin. Methods: For initial screening, we selected tumors exhibiting various levels of MDR-1 expression. Twenty-four hours following inoculation of tumor cells into 96-well plates, different concentrations of analogs solubilized in DMSO / PBS were added to six replicate wells for 1-hour and 24-hour periods. After five additional days of incubation in drug-free media, we determined cell survival using the MTT or WST-1 assay, and compared the mean O.D.s of sextuplicate wells containing taxane analog treated, untreated, and paclitaxel treated controls. Results: NBT-287 was 4- to 200-fold more potent than paclitaxel in the ovarian mutant tubulin MDR-1 negative tumor, in MDR-1 positive cell lines, and equivalent to paclitaxel in other MDR-1 negative cell lines. Exposure of NCI-AR paclitaxel-resistant breast tumor cells to NBT-287 at a 25% inhibitory concentration did not sensitize the cells to paclitaxel, suggesting that this analog was circumventing rather than reversing MDR-1. The cytotoxic ratios of the ED50 comparing TX and NBT-287 in representative cell lines are tabulated below. Conclusions: The cytotoxic advantage of NBT-287 over paclitaxel in tumor cells is independent of the expression of MDR-1 and of mutant tubulin-associated resistance. The latter mechanism of action may be due to different binding sites on beta-tubulin for paclitaxel and NBT-287. As a result, this taxane may be an appropriate compound for further efficacy and safety studies in mouse xenotransplants and in patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NaPro BioTherapeutics, Inc. Bruce Myers & Associates; NaPro BioTherapeutics, Inc. NaPro BioTherapeutics, Inc.
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Successful treatment with nab-paclitaxel after hypersensitivity reaction to paclitaxel and docetaxel
•First case report of successfully treating severe paclitaxel and docetaxel hypersensitivity reaction with nab-paclitaxel•We demonstrated that nab-paclitaxel is a safe taxane chemotherapy treatment option for patients who could not tolerate paclitaxel or docetaxel.
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Purpose: To evaluate the effect of four taxane drugs, namely, paclitaxel, docetaxel, paclitaxel liposomes (Lipusu), and nab-paclitaxel (Keaili) on ovarian cancer cells both in vivo and in vitro.
Methods: BALB/c-nu/nu female mice were used to develop mouse xenograft models. The mice were randomized to 5 groups (4 in each group), namely, control (PBS) group, paclitaxel group, docetaxel group, liposomal paclitaxel group and nab-paclitaxel group. The effect of four taxane drugs were determined via cell proliferation and toxicity tests. Mouse xenograft models were employed to assess the efficacy of four taxane drugs in inhibiting tumor growth.
Results: Nab-paclitaxel has a significant ovarian growth-reducing effect in vitro. In vivo, no significant differences were observed in tumor volume among the four groups (p < 0.05). Nab-paclitaxel produced the lowest animal toxicity when compared with other three drugs as the mice in nab- paclitaxel treatment group showed no significant alterations in body weight (p < 0.05). Hematoxylin and eosin (H & E) staining revealed the lowest degree of liver tissue damage in mice treated with nab-paclitaxel compared to mice administered the other three paclitaxels.
Conclusion: Nab-paclitaxel is more effective in mice with ovarian cancer than traditional paclitaxels. Thus, it promises to offer a viable alternative as first- line chemotherapy for epithelial ovarian cancer in humans, as it has low systemic toxicity and fewer hypersensitivity reactions. However, further investigations, including clinical trials in humans, are required.
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