its mechanism by Horwitz and the support of the NCI. Although interest in novel microtubule-active drugs was at a low point 20 years ago, Horwitz and her collaborators discovered that Taxol had the unusual characteristic of bundling microtubules at high drug concentrations rather than destroying them as the vinca alkaloids were known to do. The novelty of this observation provided the needed push to encourage development of a drug that has become one of the success stories of modern pharmacology. Subsequently, there has been a rush to develop improved taxane-like molecules, which has led to a strong industrial interest in a number of marine natural products, including eleutherobins, sarcodictyins, and discodermolide (Faulkner, 2000; Jordan, 2001).

The story does not end there. In more recent developments, we have been studying the effects of Taxol and vinca alkaloids on the very important dynamics of cellular microtubules. We have found that although there are important differences between the actions of Taxol and the vinca alkaloids involving their effects on microtubule mass at high drug concentrations, at another mechanistic level, surprisingly, they act similarly to suppress microtubule dynamics (Wilson and Jordan, 1995; Jordan and Wilson, 1998; Jordan, 2001). Both classes of drugs, the microtubule stabilizers and the microtubule depolymerizers, act at very low but physiologically relevant concentrations to stabilize the dynamics of microtubules in dividing cells. We have found that the stabilization of microtubule dynamics blocks cancer cells in mitosis at a well-defined stage of the cell cycle and sends the cells into a death program known as apoptosis, thereby killing the cancer cells. These recent discoveries have led to the industrial pursuit of a number of similar compounds from the sea, including the dolastatins and halichondrins. These drugs are currently in clinical trials for cancer or are scheduled for clinical trials. Other microtubule-active agents, such as curacin A, have high potential but have encountered stumbling blocks that can be overcome with further research.

Despite their success and efficacy, the current microtubule-active drugs have significant shortcomings. They are useful in treating only specific kinds of cancer, and patients often become resistant to these drugs, the result being that the cancer eventually returns with a vengeance. We desperately need novel cancer drugs that will be effective against a number of very resistant tumors, such as kidney, pancreatic, and brain tumors. The large number of undeveloped marine compounds holds promise for filling this need.

Each of the antimicrotubule drugs discovered so far acts differently on