|
"The main advantage of the epothilones is they seem to be rather insensitive to multi-drug resistance, which in the end deprives many cancer therapies of their long-term effectiveness," says Samuel J. Danishefsky, Ph.D., Memorial Sloan-Kettering Cancer Center researcher and NCI grant recipient. "There is a good possibility that the epothilones could take over for Taxol when that treatment fails."
At Danishefsky's request, NCI's Rapid Access to Intervention Development (RAID) program helped initially in the preparation of an epothilone compound for mouse studies. In Danishefsky's NCI-funded studies, the mice tolerated the epothilone agent well and the drug was "virtually curative" against a variety of tumors, says Edward Sausville, M.D., Ph.D., former associate director of NCI's Developmental Therapeutics Program, which operates RAID. Follow up studies by NCI grantee Danishefsky in mice, rats, and dogs were encouraging in their results and set the stage for human trials.
Kosan Biosciences, Inc., in collaboration with Hoffmann-LaRoche, is developing epothilones commercially and has advanced the Danishefsky-studied epothilone D into three phase II clinical trials. Other companies with epothilone drugs in their development pipelines are Bristol-Myers Squibb and Novartis Oncology.
Drug companies are meanwhile exploring structural variations on epothilones that could prove less toxic or more potent than those currently in human studies, and are also seeking alternatives to current, costly production methods.
Promising second generation epothilones synthesized in Danishefsky's laboratory are undergoing pre-clinical evaluation.
|
