AbstractThe effect of temperature, pH, light, drug concentration and aeration on the stability of aqueous solutions of GR63178A, a novel anticancer compound, has been investigated. The effect of light upon the stability of GR63178A in a clinical infusion system and in biological fluids, has also been investigated. A high performance liquid chromatographic assay was used to separate the parent compound from a number of degradation products. Data presented here demonstrate that GR63178A is stable in aqueous solutions at normal ambient temperatures in neutral or alkaline pH ranges. The compound is unstable when exposed to light (t½ 3·2–233 min) and shows an inverse relationship between concentration and rate of degradation. The drug is also unstable under acidic conditions, but shows a more limited spectrum of degradation products than those arising from photolysis.

01 Jan 1993·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

The comparative disposition of the pyrolloquinone GR63178A and its 9-hydroxy metabolite GR54374X in sensitive and resistant mouse colon adenocarcinoma

Q4 · MEDICINE

Article

Author: Raymond C. French ; Alex MacLellan ; Alison A. Ritchie ; Janet S. MacPherson ; Jeffrey Cummings ; John F. Smyth

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.

01 Aug 1992·Biochemical PharmacologyQ2 · MEDICINE

Studies on the molecular pharmacology of GR63178A

Q2 · MEDICINE

Article

Author: Jeffrey Cummings ; Brigid M. Hoey ; Ian D. Hickson ; Raymond French ; Gordon Leonard ; Martin A. Graham ; John Butler ; John F. Smyth ; Andrew M. Fry

GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.

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