THE COMPARATIVE DISPOSITION OF THE PYROLLOQUINONE GR63178A AND ITS 9-HYDROXY METABOLITE GR54374X IN SENSITIVE AND RESISTANT MOUSE COLON ADENOCARCINOMA

The novel anticancer compound GR63 178A is being evaluated in the clin ic, having demonstrated activity against a wide range of experimental tumour systems in animals without significant toxic side-effects being apparent. In this work, we have demonstrated significant antitumour a ction of this compound against one murine colon cancer model (colon 38 tumour in BDF-1 mice, specific growth delay = 1.2) when given at 10 m g/kg over 21 consecutive days and in contrast shown minimal sensitivit y of another similar murine colon adenocarcinoma, MAC 26, in NMRI mice with the same dose regime. We investigated the disposition of both th e parent drug and the 9-OH metabolite (GR54 374X) in plasma, tissues a nd tumours, using solid phase extraction followed by reversed-phase hi gh performance liquid chromatography. Although plasma clearance profil es of GR63 178A were similar, significant differences were seen in the disposition of the drug to major organs in two mouse strains. Noteabl y, the liver and kidneys of the sensitive model had higher levels of p arent drug and 9-OH metabolite at both 30 min and 4 h post-injection. However, this was not apparent in the tumours themselves, and the leve ls of 9-OH metabolite were lower in the plasma and higher in the urine of the sensitive mice, indicating possible rapid renal clearance of t his compound. Neither GR63 178A nor GR54 374X proved cytotoxic in in v itro experiments. The data presented here have revealed considerable v ariation in drug handling by these two mouse strains, but this did not produce different levels of either parent drug or GR54 374X in the tu mours, which are the presumed targets, suggesting that differences in disposition are probably not responsible for the different sensitiviti es of the two tumours. Other possible explanations include the product ion of a hitherto undetected ultimate cytotoxic metabolite in the sens itive, but not in the resistant, mouse/tumour combination, or differen ces in inherent tumour sensitivity, or in host-mediated effects. These possibilities are discussed.