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.

SummanrE09 [3-hydroxy-5-azinrdinyl-l-methyl-2( 1 H-indole4.7-dione)-prop-fren-a-ol] was selected for clinical tnral in Europe because of its preclinical profile but also because of its distinct mechanism of bioactivation. Several studies have shown that cells rich in DT-diaphorase may be particularly sensitive to E09-The present study examined the relationship between DT-diaphorase activity and sensitivity to E09 in a panel of cell lines largely derived from human and rodent leukaemias lymphoma and solid tumours (Collard et al., 1993). The present study examined initially the relationship between levels of DT-diaphorase and sensitivity to E09 in a panel of cell lines derived from rodent and human leukaemias and solid tumours and hamster fibroblasts. A number of the human lines were subsequently established as xenografts in nude mice and tumour levels of DT-diaphorase and sensitivity to E09 determined in vivo. The aims of these studies were to investigate whether cell lines reflected the solid tumour levels of DT-diaphorase and also to determine whether it was possible to predict in vivo sensitivity to E09 on the basis of enzyme level. Materials and metbodsChemicals E09 was synthesised originally by Oostveen and Speckamp (1987) and was supplied for this study by the EORTC New Drug Development Office. For cell culture work E09 was dissolved in RPMI-1640 medium and stored at -20°C until required. For in vivo studies E09 was dissolved in stenrle physiological saline immediately before use. The chemical stability of the compound was checked by high-performance liquid chromatography (HPLC) using a previously descnrbed method (Phillips et al., 1992). DCPIP (2,6-dichlorophenolindophenol), dicoumarol(bis-hydroxycoumarin) and NADH were purchased from Sigma, Poole, Dorset, UK. Cell lines and culture conditionsA panel of cell lines (Table I)

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The in vitro activity of the novel chloroethylating agent, Clomesone, was investigated in a panel of established murine and human tumour cell lines. In vivo anti-tumour activity was examined against three transplantable adenocarcinomas of the mouse colon and in vivo bone marrow toxicity was assessed using a spleen colony forming unit assay. The pharmacokinetic behaviour of the drug in vivo and drug stability in vitro was analysed by gas chromatography with electron capture detection. Clomesone exhibited no activity in vitro against the majority of cell lines derived from solid human colorectal carcinomas. Anti-tumour activity against the murine tumours in vivo was not impressive and was accompanied by myelosuppression. Pharmacokinetic data suggested that the lack of in vivo activity was due to the failure to achieve effective anti-neoplastic drug concentrations at the tumour site. It was concluded that this study found no evidence to suggest that Clomesone was toxicologically more selective than the chloroethylnitrosoureas.

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