Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice

RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-dibenzoquinone) has sh own preferential activity against human tumour cell lines which express hig h levels of DTD (EC 1.6.99.2; NAD(P)H:quinone oxidoreductase, NQO1, DT-diap horase) and is a candidate for clinical trials. EO9 (3-hydroxy-5-aziridinyl -1-methyl-2-[1H indole-4,7-dione]prop-beta-en-alpha-ol) is a known substrat e for DTD but clinical trials were disappointing, as a result of rapid plas ma clearance and reversible dose-limiting kidney toxicity. It is an obvious concern that RH1 does not exhibit the same limitations. We therefore descr ibe the antitumour activity and pharmacology of RH1 in mice and compare its pharmacological characteristics to those of EO9. Significant antitumour ac tivity (P = 0.01) was seen for RH1 (0.5 mg/kg, i.p.) against the high DTD-e xpressing H460 human lung carcinoma. Pharmacokinetic analysis of RH1 in mic e showed a t(1/2) of 23 min with an area under the curve of 43.0 ng hr mL(- 1) resulting in a calculated clearance of 5.1 mt min(-1), 10-fold slower th an EO9. RH1 was also more stable than EO9 in murine blood, where the breakd own was thought to be DTD-related. NADH-dependent microsomal metabolism of RH1 and EO9 in bo ch liver and kidney was slow (<100 pmol/min/g tissue), re flecting the low microsomal DTD expression (<35 nmol/mg/min). Liver cytosol metabolism was rapid for both compounds (>4500 pmol/min/g tissue), althoug h DTD levels were low (21.4 +/- 0.6 nmol/mg/min). DTD activity in the kidne y cytosol was high (125 +/- 8.2 nmol/mg/min) and EO9 was rapidly metabolise d (4396 +/- 1678 pmol/min/g), but the metabolic rate for RH1 was 7-fold slo wer (608 +/- 86 pmol/min/g), even though RH1 was shown to be an excellent s ubstrate for DTD (V-max = 800 mu mol/min/mg and a K-m of 11.8 mu M). The tw o DTD substrates RH1 and EO9 are clearly metabolised differently, suggestin g that RH1 may have different pharmacological properties to those of EO9 in the clinic. BIOCHEM PHARMACOL 59;7: 831-837, 2000. (C) 2000 Elsevier Scien ce Inc.