Desoxyepothilone B: An efficacious microtubule-targeted antitumor agent with a promising
            <i>in vivo</i>
            profile relative to epothilone B

Chou, Ting‐Chao; Zhang, Xiu Guo; Balog, Aaron; Su, Dai‐Shi; Meng, Dongfang; Savin, Kenneth A.; Bertino, Joseph R.

doi:10.1073/pnas.95.16.9642

Cited by 198 publications

(147 citation statements)

References 16 publications

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“…Another classical example is the identification of the secondary metabolites, epothilones (microtubule depolymerization inhibitors) of the myxobacterium Sorangium cellulosum, which have shown both in vitro and in vivo cytotoxicity in various cancer cells. 38,39 Epothilones are anti-microtubule agents, and their mechanism of action is more or less similar to taxol. However, epothilones have several advantages over taxol.…”

Section: Bacteria-derived Anti-cancer Agentsmentioning

confidence: 99%

Microbial based therapy of cancer: A new twist to an age old practice

Punj

Saint‐Dic²,

Daghfal³

et al. 2004

Cancer Biology & Therapy

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The use of bacteria in the regression of tumors has long been known. Various approaches for using bacteria in cancer therapy include the use of bacteria as sensitizing agents for chemotherapy, as delivery agents for cancer drugs and as agents for gene therapy. The tumor regression stimulated by infecting microorganisms has been attributed to activation of the immune system of the host. However, recent studies indicate that when tumorharboring mice with defective immune systems are infected with certain microorganisms, the regression of the tumor is still observed, suggesting that there are other host factors contributing to the microbial associated regression of tumors. Since the use of live or attenuated bacteria for tumor regression has associated toxic effects, studies are in progress to identify a pure microbial metabolite or any component of the microbial cell that might have anti-cancer activity. It has now been demonstrated that a redox protein from Pseudomonas aeruginosa, a cupredoxin, can enter into human cancer cells and trigger the apoptotic cell death. In vivo, this cupredoxin can lead to the regression of tumor growth in immunodeficient mice harboring xenografted melanomas and breast cancer tumors without inducing significant toxic effects, suggesting that it has potential anti-cancer activity. This bacterial protein interacts with p53 and modulates mammalian cellular activity. Hence, it could potentially be used as an anti-cancer agent for solid tumors and has translational value in tumor-targeted or in combinational-biochemotherapy strategies for cancer treatments. Here, we focus on diverse approaches to cancer biotherapy, including bacteriolytic and bacterially-derived anti-cancer agents with an emphasis on their mechanism of action and therapeutic potential.

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Section: Bacteria-derived Anti-cancer Agentsmentioning

confidence: 99%

Microbial based therapy of cancer: A new twist to an age old practice

Punj

Saint‐Dic²,

Daghfal³

et al. 2004

Cancer Biology & Therapy

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“…Lin et al (15) have tested patupilone (epothilone B) in an s.c. RPMI 8226 MM xenograft mouse model and showed a modest prolongation of survival. Because of its high toxicity, the clinical application of epothilone B is limited (33,34). Our in vivo data in both subcutaneous and disseminated MM xenograft models showed Flu to be much more effective than dEpoB.…”

Section: Discussionmentioning

confidence: 79%

Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo

Cho

Katz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B [Fludelone (Flu)] has shown broad antitumor activity in solid tumor models. In the present study, we showed, in vitro, that Flu significantly inhibited multiple myeloma (MM) cell proliferation (with 1-15 nM IC 50), whereas normal human bone marrow stromal cells (HS-27A and HS-5 lines) were relatively resistant (10-to 15-fold higher IC 50). Cell-cycle analysis demonstrated that Flu caused G2͞M phase arrest and induced cell apoptosis. After Flu treatment, caspase-3, -8, and -9 were activated, cytochrome c and second mitochondrial-derived activator of caspase were released to the cytosol, and c-Jun N-terminal kinase was activated, indicating that mitochondria were involved in the apoptosis. Flu toxicity to human hematopoietic stem cells was evaluated by CD34 ؉ cell-apoptosis measurements and hematopoietic-progenitor assays. There was no significant toxicity to noncycling human CD34 ؉ cells. We Epothilones have emerged as a highly promising family of microtubule-stabilizing agents. The epothilones have higher solubility in water than paclitaxel and are poorer substrates for the P-glycoprotein, proving more effective than paclitaxel against tumors showing multidrug resistance (5, 6). Epothilones also have a simpler molecular architecture, which has allowed for the total synthesis of the natural epothilones and many synthetic analogs.Our group achieved the total synthesis, and the structure-activity relationship evaluation, of several epothilones (9-11). This work soon led to the synthesis of 12,13-desoxyepothilone B (dEpoB), which proved highly effective in various in vivo xenograft tumor models (10, 11). More recently, we reported the total synthesis of (E)-9,10-dehydro-12, 13-desoxyepothilone B (9) and 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B, named Fludelone (Flu) (12). In mice, Flu appears to have a particularly broad therapeutic index in vivo. It seems to be curative over a range of tumor types, without tumor relapse upon suspension of treatment. Moreover, Flu is orally available and is completely curative against human tumor xenografts by parenteral and oral therapy. In addition, treatment with Flu gave complete tumor remission against Taxol-resistant tumors (10, 12). These very promising antitumor data were obtained in s.c. solid tumor models; however, drug efficacy in orthotopic models has not been investigated. In the present study, we focused on the evaluation of the anti-multiplemyeloma (MM) effects of the second generation analog Flu, in comparison with dEpoB, in a disseminated MM model. Our data demonstrated that Flu had a profound antitumor activity in human MM both in vitro and in vivo, indicating that this compound might be a promising agent against MM, particularly in late-stage refractory disease. Materials and MethodsCell Lines and Primary Specimens. For information about cell lines and primary specimens, see Supporting Materials and Methods, which is published as supporting information on the PNAS web site.Reagents. Flu and dEpoB...

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“…By contrast, adriamycin, paclitaxel, and vinblastine exhibited only partial suppressive effects. These results provide a differential perspective on our initial findings (19,27,28), in which dEpoB showed comparable efficacy to paclitaxel in several sensitive tumors but proved superior over paclitaxel in a broad range of drug-resistant tumors (e.g., tumors resistant to VBL, Adr, or paclitaxel). The striking difference presented by these experiments suggests that even sensitive tumors can be more responsive to dEpoB than conventional anticancer agents.…”

Section: Therapeutic Efficacy Of Various Anticancer Agents Against Humanmentioning

confidence: 86%

“…Pharmacological evaluations in xenograft mouse models revealed that EpoB, although the most potent drug in the epothilone series, possessed poor therapeutic efficacy at its maximal-tolerated dose (19). In contrast, we discovered that 12,13-desoxyepothilone B (dEpoB) displays a much more promising therapeutic index despite its slightly decreased in vitro cytotoxicity relative to EpoB (19,20).…”

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confidence: 81%

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The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

Chou

O’Connor

Tong

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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108

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We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC50) for a variety of anticancer agents were measured in CCRF-CEM͞VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, 8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins.

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Desoxyepothilone B: An efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B

Cited by 198 publications

References 16 publications

Microbial based therapy of cancer: A new twist to an age old practice

Microbial based therapy of cancer: A new twist to an age old practice

Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo

The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

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