Bioreductive antitumor
quinones require reductive metabolism to produce their cytotoxic effects. A series of these compounds was screened for relative rates of reduction by the two-electron
reductase,
NAD(P)H:
quinone oxidoreductase (DTD). The antitumor
quinones streptonigrin (SN), 2,5-diaziridinyl-3-phenyl-1,4-benzoquinone (PDZQ), 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinine (
MeDZQ), and [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-
indole-4,7-dione)-propen ol] (
EO9) were all excellent substrates for recombinant rat and human DTD. All four compounds were reduced by DTD at least 100 times faster than the clinically important bioreductive
alkylating agent,
mitomycin C (MC). Reduction of the antitumor
quinones was generally 4-5 times more efficient by rat DTD than by human DTD. The exception was
EO9, which, surprisingly, was reduced 23 times faster by rat DTD than by human DTD. The rate of reduction of each individual
quinone was similar under either aerobic or anaerobic conditions, suggesting that DTD may be an important activating
enzyme in the hypoxic fraction of solid
tumors. The cytotoxicity of
MeDZQ and MC was examined in a panel of human breast and
lung cancer cell lines. The data showed good correlations between DTD activity and toxicity for both
MeDZQ (r = 0.57, p = 0.054) and MC (r = 0.69, p = 0.020), confirming biochemical data that both compounds are bioactivated by DTD. In addition, IC50 values were in general lower for
MeDZQ than for MC in cell lines containing elevated DTD, a finding that was consistent with metabolic data that indicated that
MeDZQ was a better substrate for DTD than MC. SR, defined as the ratio of the IC50 value for the H596 NSCLC cell line (undetectable DTD activity) to the IC50 value for the H460 NSCLC cell line (high DTD activity), were determined for all five antitumor
quinones. SN was the most selective (SR = 86) followed by
EO9 (SR = 62),
MeDZQ (
SR = 17), and MC (SR = 11). Surprisingly, PDZQ, an excellent substrate for DTD, was toxic to both cell lines (SR = 1.8). These data suggest that antitumor quionones that are substrates for DTD may be selectively toxic to
tumors with high DTD activity and may be useful in the treatment of those
tumors.