Effect of NQ01 induction on the antitumor activity of RH1 in human tumors in vitro and in vivo
Effect of NQ01 induction on the antitumor activity of RH1 in human tumors in vitro and in vivo
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DOI：
10.1007/s00280-004-0961-4
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发表时间：
2005-09-01
影响因子：
3
通讯作者：
Begleiter, A
中科院分区：
文献类型：
--
作者：
Digby, T;Leith, MK;Begleiter, A
NQO 1是一种还原酶，对许多生物还原剂的活化很重要，并且是癌症治疗的酶导向方法的靶标。它可以在许多肿瘤类型中被包括富马酸二甲酯和萝卜硫素在内的许多化合物选择性诱导。丝裂霉素C是临床上用于治疗实体瘤的生物还原剂。RH 1（2，5-diaziridinyl-3-（hydroxymethyl）- 6-methyl-1，4-benzoquinone）是一种新型生物还原剂，目前正在临床试验中。我们以前已经表明，诱导NQO 1可以增强丝裂霉素C在肿瘤细胞中的抗肿瘤活性在体外和体内。由于RH 1被NQO 1选择性激活，而丝裂霉素C被许多还原酶激活，我们研究了NQO 1的诱导是否会产生比丝裂霉素C更大的RH 1抗肿瘤活性增强。将HCT 116人结肠癌细胞和T47 D人乳腺癌细胞与富马酸二甲酯或萝卜硫素一起孵育或不孵育，随后进行丝裂霉素C或RH I处理，并通过克隆形成（HCT 116）或MTT测定（T47 D）测量细胞毒性活性。富马酸二甲酯和莱菔硫烷治疗增加NQO 1活性的1.4- 2.8倍，并导致显着增强丝裂霉素C的抗肿瘤活性，但不是RH 1。这似乎是由于肿瘤细胞中存在足够组成水平的NQO 1活性以完全激活RH 1。小鼠被植入HL 60人早幼粒细胞白血病细胞，其具有低水平的NQO 1活性。小鼠喂食对照或含富马酸二甲酯的饲料，并接受RHL NQO 1治疗，肿瘤中的NQO 1活性增加，但RH 1在喂食对照或富马酸二甲酯饲料的小鼠中未产生抗肿瘤活性。这与无RH 1活化和最大RH 1活化之间的NQO 1活性的窄窗口一致。这项研究表明，在肿瘤细胞中选择性诱导NQO 1不太可能是增强RH 1抗肿瘤活性的有效策略。此外，我们发现RH 1治疗在小鼠中产生了显著的白细胞减少，这可能是临床上关注的问题。这些结果表明，NQO 1减少RH 1的情况使其成为酶导向癌症治疗方法的不良候选者。
NQO1 is a reductive enzyme that is important for the activation of many bioreductive agents and is a target for an enzyme-directed approach to cancer therapy. It can be selectively induced in many tumor types by a number of compounds including dimethyl fumarate and sulforaphane. Mitomycin C is a bioreductive agent that is used clinically for treatment of solid tumors. RH1 (2,5-diaziridinyl-3-(hydroxymethyl)- 6-methyl-1,4-benzoquinone) is a new bioreductive agent currently in clinical trials. We have shown previously that induction of NQO1 can enhance the antitumor activity of mitomycin C in tumor cells in vitro and in vivo. As RH I is activated selectively by NQO1 while mitomycin C is activated by many reductive enzymes, we investigated whether induction of NQO1 would produce a greater enhancement of the antitumor activity of RH1 compared with mitomycin C. HCT116 human colon cancer cells and T47D human breast cancer cells were incubated with or without dimethyl fumarate or sulforaphane followed by mitomycin C or RH I treatment, and cytotoxic activity was measured by a clonogenic (HCT116) or MTT assay (T47D). Dimethyl fumarate and sulforaphane treatment increased NQO1 activity by 1.4- to 2.8-fold and resulted in a significant enhancement of the antitumor activity of mitomycin C, but not of RH1. This appeared to be due to the presence of a sufficient constitutive level of NQO1 activity in the tumor cells to fully activate the RH1. Mice were implanted with HL60 human promyelocytic leukemia cells, which have low levels of NQO1 activity. The mice were fed control or dimethyl fumarate-containing diet and were treated with RHL NQO1 activity in the tumors increased but RH1 produced no antitumor activity in mice fed control or dimethyl fumarate diet. This is consistent with a narrow window of NQO1 activity between no RH1 activation and maximum RH1 activation. This study suggests that selective induction of NQO1 in tumor cells is not likely to be an effective strategy for enhancing the antitumor activity of RH1. In addition, we found that RH1 treatment produced significant leukopenia in mice that may be of concern in the clinic. These results suggest that the case of reduction of RH1 by NQO1 makes it a poor candidate for an enzyme-directed approach to cancer therapy.