Anti-tumour activity of flavone acetic acid (NSC 347512) in mice – influence of immune status

Mc Bibby,Ja Double,G Pratesi,Rm Phillips

doi:10.1038/bjc.1991.12

Abstract

Flavone acetic acid (FAA) is a synthetic flavonoid with dramatic pre-clinical anti-tumour activity involving a vascular component in its mechanism but no clinical effects have been seen to date. As FAA also has immunomodulatory activity, immunological factors might explain differences in activity between mouse and man. This study examines the influence of host immune status on the anti-tumour activity of FAA. Two human colon tumour xenografts (COBA, HT-29) fail to respond to FAA in nude mice. The lack of activity of FAA against HT-29 xenografts cannot be explained on the basis of limited drug bioavailability as achievable plasma, and tumour levels of FAA are similar to those seen in sensitive murine colon tumours. The immune status of the host also influences the activity of FAA against two transplantable tumours of the mouse colon. Both these tumours are highly responsive to FAA in their normal NMRI hosts, but neither tumours exhibited significant growth delay in thymectomised NMRI or nude hosts. Histological examination of treated tumours revealed significant areas of haemorrhagic necrosis in all three hosts. These data suggest a clear immunological component in the mechanism of action of FAA which is separate from the previously described haemorrhagic necrosis.

Highlights

Flavone acetic acid (FAA) is a synthetic flavonoid with interesting pre-clinical activity against a broad spectrum of murine transplantable solid tumours that are refractory to conventional cytotoxic agents (Corbett et al, 1986; Plowman et al, 1986; Bibby et al, 1987b; Bibby et al, 1988a)
Fiebig personal communication) and there are certainly no published data demonstrating spectacular responses similar to those achieved in subcutaneous murine tumours. The aims of this present study are to examine the influence of FAA on the growth of human colon tumour xenografts (HT29, COBA) in immune suppressed mice and to compare the pharmacokinetics of FAA in nude mice with previously published mouse data (Bibby et al, 1987b; Bibby et al, 1988a; Bibby et al, 1989a)
FAA treatment at maximum tolerated dose (MTD) on day 0 and day 7 has no influence on the growth of COBA-P, COBA-M and HT-29 tumours growing in nude mice (Figures 1 and 2) and histological examination revealed no additional necrosis in the treated tumours

Summary

Introduction

Flavone acetic acid (FAA) is a synthetic flavonoid with interesting pre-clinical activity against a broad spectrum of murine transplantable solid tumours that are refractory to conventional cytotoxic agents (Corbett et al, 1986; Plowman et al, 1986; Bibby et al, 1987b; Bibby et al, 1988a). Previous in vitro studies with a variety of tumour cell lines have indicated that high drug concentrations, or long exposure times, are necessary to achieve direct drug cytotoxicity with FAA (Bibby et al, 1987; CapolongQ et al, 1987; Schroyens et al, 1987). These drug profiles are not achieved in mice in vivo suggesting that the anti-tumour effects against subcutaneous mouse tumours are not the result of a direct cytotoxic mechanism

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