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E7107 is a new potent antitumor agent chemically derived from a series of novel natural products designated as pladienolides. The agent has been shown to cause strong tumor regression in many human tumor cells xenografts, and complete tumor regression in several xenografts. For a novel agent like E7107, one of the most important aspects of its development is to find predictive markers that would make possible the identification of patients who would benefit from E7107-treatment. In order to find predictive factors to E7107-sensitivity, we attempt to find common molecular characteristics among E7107-sensitive tumor cells. At first, we investigated the molecular expression profile of BSY-1, in which xenografts showed complete tumor regression after treatment with E7107. We examined its molecular characteristics focusing on cell cycle regulatory proteins related to G1/S transition as it has been reported that most breast tumors have aberrations at this site. We found that BSY-1 is a cyclin E overexpressing tumor with functional loss of pRB (retinoblastoma protein). We then studied whether the molecular profile of ‘’pRB loss and high cyclin E” was a common characteristic among E7107-sensitive tumor cells or not. When the molecular status of pRB and cyclin E on 25 tumor cells implanted on nude mice was assessed, we found that the seven most sensitive tumor cell lines have all functional loss of pRB and that among them the five most sensitive cell lines have extraordinary high expression of cyclin E. From this result, it appears that the molecular profile of “pRB loss and high cyclin E” may be predictive of the sensitivity of tumor cells to E7107. At present, we are studying the effects of pRB or cyclin E introduction on the sensitivity to their transfectants. Considering that ‘pRB loss’ is a typical characteristic of several tumors, such as retinoblastoma, small cell lung cancer, and a subtype of breast cancer, these tumors may be probable clinical targets of E7107.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]