FLAVONE ACETIC-ACID FROM LABORATORY TO CLINIC AND BACK

Flavone acetic acid ester (NSC 293015, LM 985) emerged from a series of flavonoids from Lyonnaise Industrielle Pharmaceutique (Lipha) screened by the National Cancer Institute. LM 985 showed modest but sufficient activity in the P388 pre-screen to progress to secondary evaluation on the solid colon 38, where significant activity was seen. On the basis of this particular profile LM 985 was selected by the Cancer Research Campaign (CRC) UK for phase I clinical trial. It was not recommended for phase II trial because of drug associated hypotension and the fact that it appeared to act as a pro-drug for flavone acetic acid (NSC 347512, LM 975, FAA) which was shown to be responsible for the dramatic solid tumor activity in mice. This was manifested as dramatic hemorrhagic necrosis and involves a complex mechanism of action. FAA proceeded to clinical trial but unfortunately no anti-tumor activity was seen. A large amount of effort has been channelled into identifying the mechanisms of action of FAA in mice and it is clear that activity relies on a number of factors. Subcutaneous tumors respond dramatically whereas ascites tumors and tumor deposits in other sites are usually less responsive. Establishment of a tumor blood vasculature system appears necessary for response and adequate drug concentrations within a therapeutic window are necessary. From the large body of information available at present the most likely explanation for discrepancies in activity between mouse and man seems to relate to differences in the ability of the immune system to respond to FAA, although variation in the composition of the vasculature cannot yet be ruled out. Analogs of this type of compound are worth pursuing but it is necessary to examine them in appropriate model systems in order to predict for possible clinical activity.