Preclinical in vitro and in vivo activity of 5,6-dimethylxanthenone-4-acetic acid

Abstract

Summary 5.6-Dimethylxanthenone4-acetic acid (5.6-MeXAA) is a fused tricyclic analogue of flavone acetic acid (FAA) which was developed in an attempt to improve on the activity of FAA. Previous studies have shown 5.6-MeXAA to be curative in 80% of mice bearing colon 38 tumours and 12 times more dose potent than FAA. This investigation has demonstrated that a murine colon tumour cell line (MAC1SA) is approximately 60 times more sensitive to 5.6-MeXAA than to FAA. although these differences were not seen in three human cell lines tested. 5,6-MeXAA caused significant blood flow shutdown and haemorrhagic necrosis in subcutaneous MAC15A tumours in syngeneic and nude hosts. but measurable changes in tumour volume were seen only in syngeneic hosts. 5,6-MeXAA was inactive against intraperitoneal MACISA but produced significant anti-tumour effects against the same cell line inoculated via an intravenous route. FAA has been shown previously to be inactive in this model. Interestingly, the effects against lung colonies were not accompanied by obvious necrotic changes, suggesting that they may be the result of increased direct cytotoxicity rather than an indirect host mechanism. Further studies to investigate the effects against systemic tumour deposits are under way.

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study

“…The mechanism of antitumour action of DMXAA, like that of FAA, differs from that of directly cytotoxic drugs. 5,6-Dimethylxanthenone acetic acid has selective activity in targeting tumour vasculature in vivo, producing vascular shutdown, reducing tumour blood flow, and consequently causing haemorrhagic necrosis (Zwi et al, 1994b;Laws et al, 1995).…”

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

“…In animal models, this culminates in extensive tumour necrosis predominantly within the tumour core (Zwi et al, 1994;Laws et al, 1995;Ching et al, 1999Ching et al, , 2004Joseph et al, 1999). The therapeutic potential of ASA404 appears to lie in its combination with other treatments (Wilson et al, 1998;Murata et al, 2001).…”

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

“…A series of analogues with the structurally related xanthenone chromophore were developed Rewcastle et al, 1989Rewcastle et al, , 1991a, and DMXAA (VII) was identified as an agent that produced a similar degree of haemorrhagic necrosis to FAA against the colon tumours but at 10 -15-fold lower doses (Rewcastle et al, 1991c;Laws et al, 1995). As with FAA, DMXAA produced numerous immune effects in vivo although these occurred at much lower concentrations.…”