Double-stranded interfering RNA, and vectors containing it, useful for treatment of cancer, modulate expression of the ERK2 protein and thus cell proliferation

摘要

Double-stranded interfering RNA (I) that inhibits selectively expression of mRNA for the ERK2 protein (II) of the MAP (mitogen-activated protein) kinase pathway in humans (Ia); both rats and mice (Ib) or mice only (Ic). An independent claim is also included for molecules (A) containing (I) and a vector that allows their introduction into a cell. ACTIVITY : Cytostatic. MECHANISM OF ACTION : Gene therapy. (I) form RNA-induced silencing complexes with (II)-encoding RNA, so inhibit expression of (II), which is involved in regulating the cell cycle, and thus cell proliferation. Rat hepatocytes were transformed with duplex interfering RNA (100 nM) containing the sequence GUGCUGUGUCUUCAAGAGC (Ib) as coding strand. In the interval 24-48 hours after transformation, the degree of cell replication (assessed by incorporation of tritiated thymidine) was about 50 units (counts per minute per mu g of protein) compared with about 150 units in a control, and in the 48-72 hour interval corresponding figures were about 40 and 90 units. Analysis of proteins by Western blotting showed that expression of ERK1 was normal but that of ERK2 was undetectable.