Antitumor activity of Epo

To conclude the discussion on the in vivo antitumor activity of Epo B, it should be noted that the disparate results of in vivo experiments by the Sloan-Kettering and the Novartis groups are not necessarily incompatible, but they may simply reflect differences in the experimental setups, such as tumor models, formulation, and/or dosing regimens. The results of the prechnical evaluation of Epo B at Novartis have led to the initiation of chnical trials with the compormd in 1999 (vide infra). 

As indicated above, the antitumor activity of Epo B is based on its ability to bind to microtubules and to alter their intrinsic stability and dynamic properties. (For excellent reviews on microtubule structure and function see ref. 6 and 47-49.) Epothilones prevent the Ca or cold-induced depolymerization of pre-existing microtubule polymers in cell-free systems at the same time, they promote the polymerization of soluble tubulin into microtubule-like polymers under conditions that would normally destabilize microtubules.As demonstrated by kinetic experiments, epothilones inhibit the binding of taxol to microtubules in a competitive manner and they bind to the taxol binding site on p-tubulin with affinities that exceed (Epo B) or are comparable (Epo A) to taxol affinity likewise Epo B is a more potent tubulin-polymerizing agent than taxol or Epo Structural studies on... 

Treatment of human cancer cells with low nanomolar concentrations of Epo B produces aberrant mitotic spindles, results in cell cycle arrest in mitosis, and eventually leads to apoptotic cell death. ICjoS for cancer cell growth inhibition are in the nanomolar or even sub-nanomolar range, depending on the specific cell type, In addition, apoptosis induction by Epo B has been suggested to involve the formation of reactive ojygen species in mitochondria it has also been linked to the activation of the nuclear translocation of the transcription factor NFkB in a process that would be independent of the microtubule effects of the compound. The true significance of these findings for the antitumor activity of Epo B still needs to be established. 

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