The overall goal of this application is to define the mechanisms by which cryptophycin, a new antimicrotubule agent, initiates apoptosis or programmed cell death. The cryptophycins are a new family of tubulin-binding agents that show promise for the eventual use in the treatment of human neoplastic diseases. They have unique activities and, unlike the vinca alkaloids and taxol, are active against drug-resistant tumors in both in vitro and in vivo models. Recently, the study of cancer chemotherapeutic agents was revolutionized by discoveries that agents with diverse primary targets and binding sites initiate apoptosis. These studies will investigate the molecular mechanism of drug action and the signal transduction events initiated by cryptophycin that lead to apoptosis. The hypothesis that cryptophycin prematurely activates cell cycle regulatory proteins that lead to the initiation of apoptosis will be tested. Preliminary data suggest that the phosphorylation of Bcl-2 could be a key event and the investigator's propose to test the hypothesis that Bcl-2 phosphorylation and inactivation are involved in cryptophycin-induced apoptosis. The ability of cancer chemotherapeutic agents to initiate apoptosis may be an important determinant of therapeutic response. Information gained about the mechanisms of action of this new class of agents will be compared to the effects of other microtubule active drugs and insights into their specific mechanisms of action may also be gained. A second goal is to use the different cryptophycin analogs to determine structure-activity relationships of three subunits of the cryptophycin molecule with respect to specific biological effects. The differences in the biological responses of the congeners will determine the relationships between biological events and the ultimate ability to initiate apoptosis.
| Mooberry, Susan L; Leal, Rachel M; Tinley, Tina L et al. (2003) The molecular pharmacology of symplostatin 1: a new antimitotic dolastatin 10 analog. Int J Cancer 104:512-21 |
