The invention provides novel inhibitors of
protein translation
initiation and inhibitors of eIF4F activity that can increase chemosensitivity or diminish or reverse chemoresistance in growth transformed cells and thereby reduce hyperproliferative conditions, such as
cancer progression, in select patient populations having particular tumor genotypes. The invention also provides methods which target translation
initiation controls in growth-transformed cells, such as tumor subtypes with altered expression of a
gene activity, including the human akt, bcl-2, eIF4E, eIF4A or
PTEN activities, to restore
drug sensitivity
in vivo in a
genotype selective manner. In one aspect, the inhibitors of translation
initiation of the invention are rocaglates, i.e., cyclopenta[b]benzofurons, which increases chemosensitivity or diminishes or reverses chemoresistance either alone or in combination, additively or synergistically, with other agents that alter growth or death. Preferably, the rocaglate is silvestrol, which is used alone or in combination with
doxorubicin to reverses chemoresistance in
PTEN-deficient lymphomas or eIF4E-over-expressing lymphomas and to promote
cancer remission.