The comparative disposition of the pyrolloquinone GR63178A and its 9-hydroxy metabolite GR54374X in sensitive and resistant mouse colon adenocarcinoma.
The novel anticancer compound GR63178A is being evaluated in the clinic, 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 action 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 mg/kg over 21 consecutive days and in contrast shown minimal sensitivity of another similar murine colon adenocarcinoma, MAC 26, in NMRI mice with the same dose regime. We investigated the disposition of both the parent drug and the 9-OH metabolite (GR54374X) in plasma, tissues and tumours, using solid phase extraction followed by reversed-phase high performance liquid chromatography. Although plasma clearance profiles of GR63178A were similar, significant differences were seen in the disposition of the drug to major organs in two mouse strains. Noteably, the liver and kidneys of the sensitive model had higher levels of parent 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 levels of 9-OH metabolite were lower in the plasma and higher in the urine of the sensitive mice, indicating possible rapid renal clearance of this compound. Neither GR63178A nor GR54374X proved cytotoxic in in vitro experiments. The data presented here have revealed considerable variation in drug handling by these two mouse strains, but this did not produce different levels of either parent drug or GR54374X in the tumours, which are the presumed targets, suggesting that differences in disposition are probably not responsible for the different sensitivities of the two tumours. Other possible explanations include the production of a hitherto undetected ultimate cytotoxic metabolite in the sensitive, but not in the resistant, mouse/tumour combination, or differences in inherent tumour sensitivity, or in host-mediated effects. These possibilities are discussed.
French
R C
RC
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
Cummings
J
J
MacLellan
A
A
MacPherson
J S
JS
Ritchie
A A
AA
Smyth
J F
JF
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004351:Drug Resistance; D054833:Isoindoles; D007546:Isoquinolines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011809:Quinones / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D054833:Isoindoles; D007546:Isoquinolines; D009943:Organophosphorus Compounds; D011809:Quinones; C081142:GR 54374X; C072687:fosquidone