Flavone acetic acid--an interesting novel therapeutic agent or just another disappointment?

نویسنده

  • M. C. Bibby
چکیده

There is a real need to develop drugs which are active in common solid cancers but which are not limited in their usage by life threatening host toxicity. A tall order perhaps but nevertheless a worthwhile goal for the experimentalist. The search therefore goes on to identify new targets which will provide that elusive tumour cell specificity. One way of achieving selectivity might be to progress compounds on the basis of differential anti-cancer activity in pre-clinical screens. One agent which has greater activity against solid tumours in mice than against murine leukaemias, i.e. solid tumour specificity, is flavone acetic acid, NSC 347512 (FAA). This compound also has the advantage of being a novel chemical structure compared with existing anti-cancer drugs and belonging to a class of chemical with a wide range of biological properties (Cody et al., 1988). Early in the developmental programme of the National Cancer Institute (NCI) more than 200 flavonoids were screened against murine tumour systems including adenocarcinoma 755, sarcoma 180 and leukaemia L1210. None of these was shown to be active but quercetin was retested in 1971 and modest activity was seen against P388 leukaemia implanted in the peritoneal cavity (Plowman et al., 1986). As a result of these early observations the NCI screened a series of flavones from Lyonnaise Industrielle Pharmaceutique (Lipha) with a view to utilising the new screen which emerged in 1975. They used P388 as a pre-screen followed by a new panel of solid tumours for secondary evaluation (Venditti et al., 1984). Flavone acetic acid ester, NSC 293015 (LM985) (Figure 1) emerged as a lead compound from this screen as it showed good activity against P388 and also against the generally refractory subcutaneously implanted colon adenocarcinoma 38 (Plowman et al., 1986). As a result of the pre-clinical solid tumour activity, flavone acetic acid ester was selected for clinical trial. LM985 did not cause myelosuppression or major organ toxicity so there was the suggestion of a novel mechanism of action. LM985 went into phase I clinical trial in the UK in 1985 (Kerr et al., 1985, 1987) and the authors suggested that the hydrolysis product FAA (LM975) may be the active principal and that substantially higher doses of FAA might be given without dose limiting hypotension. Pharmacokinetic studies of LM985 in mice demonstrated rapid hydrolysis to FAA so it was clear that the acid was responsible for the dramatic anti-tumour effects seen in subcutaneous mouse tumours (Double et al., 1986; Bibby et al., 1987). The identification of FAA led for the first time to an agent with very broad, perhaps nearly universal solid tumour activity (Corbett et al., 1986) and a considerable amount of effort went into further characterising the activity in an attempt to identify a mechanism of action. Zaharko et al. (1986) introduced the concept of a therapeutic window below which no activity was seen and above which lethality occurred. This observation was based on therapeutic experiments in mice and toxicity studies in dogs related to projected pharmacokinetic behaviour in these species. Subsequent clinical studies with FAA showed that clearance and metabolism are elevated in humans compared with mice (Cummings et al., 1989) but nevertheless the therapeutic

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عنوان ژورنال:
  • British Journal of Cancer

دوره 63  شماره 

صفحات  -

تاریخ انتشار 1991