Abstract
5,6-Dimethylxanthenone-4-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 (MAC15A) 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 MAC15A 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.
Highlights
Flavone acetic acid (FAA) is a synthetic flavonoid which was selected for clinical trials on the basis of its anti-tumour activity against a wide range of murine subcutaneously (s.c.) transplantable solid tumours which are generally refractive to conventional cytotoxic agents (Corbett et al, 1986; Plowman et al, 1986; Bibby et al, 1987)
In vitro data suggest that FAA possesses very little direct cytotoxic activity, requiring long exposure times and high concentrations to kill any of the cell lines tested (Bibby et al, 1987; Capolongo et al, 1987; Schroyens et al, 1987), and an indirect mechanism of action was proposed
Studies by Bibby et al (1989a) suggested that tumour site was important as, good responses were seen against s.c. solid tumours, no activity was observed against the same tumour cells when implanted intraperitoneally (i.p.) or intravenously (i.v.) to produce systemic lung deposits
Summary
5,6-MeXAA was a gift from the Cancer Research Campaign. For in vivo use 5,6-MeXAA was made up immediately before use in physiological saline, at an appropriate concentration for the desired dose to be administered in 0.lml per lOg body weight. All treatments were administered i.p. For in vitro use 5,6-MeXAA and FAA (a gift from Lipha, Lyon, France) were dissolved to the appropriate concentration in complete RPMI-1640 (RPMI) tissue culture medium immediately before use and serially diluted
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