Effect of Flavone Acetic Acid on Lewis Lung Carcinoma: Evidence for an Indirect Effect1

Abstract

Flavone-8-acetic acid (FAA), a new antitumor agent currently undergoing clinical trial, fails to inhibit the growth of early stage Lewis lung (LL) tumors growing in the lung. However, the growth of advanced subcutaneous tumors, arising from inoculation of either the original in vivo LL line or a tissue culture-adapted cell line (LLTC) derived from the LL line was delayed significantly by FAA treatment. Comparison, by clonogenic survival assays, of the cytotoxic effect of FAA on LLTC cells demonstrated that most cell killing occurred between 2 and 8 hours following in vivo exposure but occurred to a much lesser extent and at later times following in vitro exposure. FAA was inactive against LLTC cells growing in vivo in diffusion chambers, suggesting that a host cellular component was necessary for activity. FAA was found to induce hemorrhagic necrosis in the advanced LL tumors, as well as in a number of human tumor xenografts growing in athymic mice. The human cell lines from which the xenografts were derived, as well as the LL tumor lines and P388 leukemia lines, were inhibited by FAA in vitro. However, the ranking of FAA activity in vivo did not parallel that observed in vitro. Together, these observations strongly suggest that FAA has an indirect mode of antitumor action.

Antitumour responses to flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid in immune deficient mice

“…Although a slightly longer time was required for tumours to become palpable, the tumour volumes were not significantly smaller than those in the control mice (Figure 3). Lewis lung tumours (Finlay et al, 1988) were found to grow equally well in naive control mice or euthymic or T x B mice which had previously been cured of a Colon 38 tumour (data not shown).…”

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels

“…It has been suggested that the site of the tumour is important in determining its responsiveness to FAA (Bibby et al, 1989b). Finlay et al (1988) found that small lung metastases of the Lewis lung tumour failed to respond to FAA treatment, while larger lung nodules and subcutaneous implants of this tumour were sensitive. To determine the role of the vasculature in the anti-tumour action of FAA, we have examined the process of attachment and vascularisation of EMT6 spheroids in the peritoneum, and found tumours which were directly comparable in site and size range to avascular spheroids (AVS).…”

“…This experimental agent is continuing to generate interest despite disappointing results in clinical trials (Kerr et al, 1989) because it appears to act via a novel, indirect mechanism. The low cytotoxicity of FAA against cell lines from FAA-responsive tumours (Finlay et al, 1988), suggests that its antitumour effect involves some interaction with host tissues. FAA affects both tumour structure and physiology, including haemorrhagic necrosis (Smith et al, 1987), a fall in ATP levels (Evelhoch et al, 1988), and a decrease in blood flow (Evelhoch et al, 1988;Bibby et al, 1989a).…”

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

“…Immunosuppression interfered with the anti-tumour action of endotoxin in spite of the fact that haemorrhagic necrosis still occurred. Response of human tumour xenografts to FAA appears to be modest (Giavazzi et al, 1988;Finlay et al, 1988;H. Fiebig personal communication) and there are certainly no published data demonstrating spectacular responses similar to those achieved in subcutaneous murine tumours.…”