apaziquone and 2-5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1-4-benzoquinone

Solid tumours contain regions of very low oxygen concentrations that are said to be hypoxic. Hypoxia is a natural phenotype of solid tumours resulting from an imperfect vascular network. There are a number of consequences associated with tumour hypoxia including: resistance to ionising radiation, resistance to chemotherapy and the magnification of mutated p53. In addition tissue hypoxia has been regarded as a key factor for tumour aggressiveness and metastasis by activation of signal transduction pathways and gene regulatory mechanisms. It is clear that hypoxia in solid tumours promotes a strong oncogenic phenotype and is a phenomenon that occurs in all solid tumours. As such this provides a significant target for drug discovery particularly for tumour-targeting agents. A range of chemical classes (N-oxides, quinones, nitro-aromatics) have been explored as bioreductive agents that target tumour hypoxia. The most advanced agent, tirapazamine, is in phase III clinical trials in combination with cis-platin. The aim of this review is to give a brief overview of the current molecules and strategies being explored for targeting tumour hypoxia.

Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Clinical Trials, Phase III as Topic; Drug Screening Assays, Antitumor; Humans; Imidazoles; Indolequinones; Neoplasms; Prodrugs; Quinolines; Radiation-Sensitizing Agents; Tirapazamine; Triazines

RH1 (2,5-diaziridinyl-3-(hydroxylmethyl)-6-methyl-1,4-benzoquinone) has shown preferential activity against human tumour cell lines which express high levels of DTD (EC 1.6.99.2; NAD(P)H:quinone oxidoreductase, NQO1, DT-diaphorase) 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 substrate for DTD but clinical trials were disappointing, as a result of rapid plasma clearance and reversible dose-limiting kidney toxicity. It is an obvious concern that RH1 does not exhibit the same limitations. We therefore describe the antitumour activity and pharmacology of RH1 in mice and compare its pharmacological characteristics to those of EO9. Significant antitumour activity (P = 0.01) was seen for RH1 (0.5 mg/kg, i.p.) against the high DTD-expressing H460 human lung carcinoma. Pharmacokinetic analysis of RH1 in mice showed a t1/2 of 23 min with an area under the curve of 43.0 ng hr mL(-1) resulting in a calculated clearance of 5.1 mL min(-1), 10-fold slower than EO9. RH1 was also more stable than EO9 in murine blood, where the breakdown was thought to be DTD-related. NADH-dependent microsomal metabolism of RH1 and EO9 in both liver and kidney was slow (<100 pmol/min/g tissue), reflecting the low microsomal DTD expression (<35 nmol/mg/min). Liver cytosol metabolism was rapid for both compounds (>4500 pmol/min/g tissue), although DTD levels were low (21.4+/-0.6 nmol/mg/min). DTD activity in the kidney cytosol was high (125+/-8.2 nmol/mg/min) and EO9 was rapidly metabolised (4396+/-1678 pmol/min/g), but the metabolic rate for RH1 was 7-fold slower (608+/-86 pmol/min/g), even though RH1 was shown to be an excellent substrate for DTD (Vmax = 800 micromol/min/mg and a Km of 11.8 microM). The two DTD substrates RH1 and EO9 are clearly metabolised differently, suggesting that RH1 may have different pharmacological properties to those of EO9 in the clinic.

Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Drug Screening Assays, Antitumor; Drug Stability; Humans; Indolequinones; Indoles; Kinetics; Lung Neoplasms; Mice; NAD(P)H Dehydrogenase (Quinone); Neoplasm Transplantation