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

Abstract

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.

Preclinical efficacy spectrum and pharmacokinetics of ixabepilone

“…It was also important to establish the in vivo stability of ixabepilone to better understand the dynamics of its metabolism following administration. Importantly, the half-life of ixabepilone (13 h at 6 mg/kg and 16 h at 10 mg/kg) was considerably longer than that of desoxyepothilone B, which has a lactone at position 16 and a half-life in mice of approximately 20 min [36]. This suggests that replacing the lactone oxygen with a lactam improves the metabolic stability of the molecule through overcoming lactone hydrolysis by esterases in the mouse.…”

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

“…Many analogues of epothilones have been synthesized such as Desoxyepothilone B, which are more promising because of their efficacy against a range of tumors and relative lack of toxicity. 40,41 Some studies have also demonstrated the role of the anthrax toxin as an anti-tumor agent. The anthrax toxin has a role in MEK signaling (MAP/ ERK kinase) and offers a novel strategy to use in cancer treatment.…”

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

“…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.…”