Abstract:
: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 RH1 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 RH1 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 RH1. 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 ease of reduction of RH1 by NQO1 makes it a poor candidate for an enzyme-directed approach to cancer therapy.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Digby T,Leith MK,Thliveris JA,Begleiter Adoi
10.1007/s00280-004-0961-4keywords:
subject
Has Abstractpub_date
2005-09-01 00:00:00pages
307-16issue
3eissn
0344-5704issn
1432-0843journal_volume
56pub_type
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
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更新日期:2005-03-01 00:00:00
abstract:PURPOSE:The purpose of these extensive non-clinical studies was to assess pharmacokinetics and dispositional properties of sunitinib and its primary active metabolite (SU12662). METHODS:Sunitinib was administered in single and repeat oral doses in mice, rats, and monkeys. Assessments were made using liquid-chromatogra...
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abstract:PURPOSE:In order to determine the sensitivity and specificity of the test and to optimize experimental conditions utilizing the SBT in a rat model of chemotherapy-induced small intestinal damage. METHODS:Initially, a 13C-sucrose dose-response study was performed in rats to determine an optimal sucrose concentration fo...
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doi:10.1007/s00280-009-1098-2
更新日期:2010-04-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:1995-01-01 00:00:00
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更新日期:2011-07-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:1999-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,评审
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更新日期:2005-11-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1991-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2002-11-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1986-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2010-10-01 00:00:00
abstract:PURPOSE:Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. METHODS:The effect of axitinib on corr...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00280-015-2677-z
更新日期:2015-03-01 00:00:00
abstract:PURPOSE:Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. METHODS:Bevacizumab w...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-014-2384-1
更新日期:2014-03-01 00:00:00
abstract:PURPOSE:Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabi...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00280-018-3588-6
更新日期:2018-07-01 00:00:00
abstract::MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4- oxothiazolidin-2-ylidenemethyl] pyridinium chloride), a novel rhodacyanine dye in phase I/II clinical trials, may provide a new approach to cancer therapy based on the accumulation in the mitochondria of the cells of certain carcinomas, for example, ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050898
更新日期:1999-01-01 00:00:00
abstract:PURPOSE:The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patien...
journal_title:Cancer chemotherapy and pharmacology
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doi:10.1007/s00280-015-2730-y
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abstract::The plasma pharmacokinetics of the anti-tumor antibiotic geldanamycin (GM: NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 microgram/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00689048
更新日期:1995-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-010-1436-4
更新日期:2011-07-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00570487
更新日期:1987-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2007-09-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,评审
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更新日期:2018-08-01 00:00:00
abstract::Tumor-tissue and plasma concentrations of platinum were studied prospectively in two groups of eight patients who were suffering from advanced non-small-cell lung cancer. Treatments including two different schedules of cisplatin administration (25 vs 100 mg/m2 on day 1) were compared. At 30 min after the beginning of ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00689280
更新日期:1990-01-01 00:00:00
abstract::Patients with carcinoid syndrome usually die from carcinomatosis, rather than the pharmacological effects of the tumour. Functioning carcinoid tumours are resistant to radiotherapy. Twenty-four different cytotoxic drugs or combinations have been used to treat the carcinoid syndrome, but only actinomycin D, cyclophosph...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00258469
更新日期:1981-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-007-0519-3
更新日期:2008-04-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
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更新日期:2010-05-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-017-3328-3
更新日期:2017-06-01 00:00:00
abstract:PURPOSE:Evasion to new treatments of advanced melanoma is still associated with a poor prognosis. Choosing the best combination of agents that can bypass resistance mechanisms remains a challenge. Sphaeropsidin A (Sph A) is a fungal bioactive secondary metabolite previously shown to force melanoma cells to undergo apop...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2017-05-01 00:00:00
abstract:PURPOSE:Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localiz...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2001-09-01 00:00:00