Structure-activity relationships for benzotriazine DI-N-oxides

Zeman, Elaine M.; Baker, Margaret; Lemmon, Marilyn J.; Pearson, Cecelia I.; Adams, Jeffrey A.; Brown, J. Martin; Lee, W.W.; Tracy, Michaël

doi:10.1016/0360-3016(89)90899-7

Cited by 66 publications

(31 citation statements)

References 18 publications

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“…A novel class that exhibits selective toxicity toward hypoxic cells is the 1,2,4-benzotriazine 1,4-dioxides [45][46][47], an iminium type. Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide, 4), the lead member, exhibits superior selectivity to that of many other hypoxic cytotoxins, such as, mitomycin C and misonidazole, and is currently undergoing phase II and III clinical trials for treatment of various cancers [48].…”

Section: B Tirapazaminementioning

confidence: 99%

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Kovacic

Osuna²

2000

CPD

150

105

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A large body of evidence has accumulated indicating involvement of oxidative stress (OS) in the mode of action of various bioactive substances, including those of the immune system. The data for anticancer drugs (main and miscellaneous) are summarized herein. Although diverse origins pertain, reactive oxygen species (ROS) are frequently generated by redox cycling via electron transfer (ET) groups, such as quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products) and conjugated imines (or iminium species). We believe it is not coincidental that these functionalities are frequently found in anticancer agents or their metabolites. Generally, the ET moieties display reduction potentials in the physiologically active range. Often ROS are also implicated in more traditional rationales, namely, enzyme inhibition, membrane or DNA insult, and interference with DNA or protein synthesis. A multi-faceted approach to mechanism appears to be the most logical. Significantly, the unifying theme of ET-OS also applies to other drug categories, as well as to toxins, carcinogens, hormones, and enzymes. Since this theoretical framework aids in our understanding of drug action, it can serve as a useful tool in the design of more active and safer pharmaceuticals.

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Section: B Tirapazaminementioning

confidence: 99%

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Kovacic

Osuna²

2000

CPD

150

105

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“…Hypoxic cell fractions, believed to be present in mammalian solid tumours, are thought to be the reason for the unsuccessful ability to cure some human malignancies by radiotherapy (Moulder & Rockwell, 1987). The benzotriazine di-N-oxide, amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of a new series of hypoxic cell cytotoxins currently being investigated as anticancer drugs (Zeman et al, 1989). It is up to 150 times more effective at preventing colony formation if the tumour cells were treated with SR 4233 under hypoxic conditions than under aerobic conditions in vitro (Zeman et al, 1986) suggesting that it may be useful in radiation therapy.…”

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confidence: 99%

Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

O'Brien²

1993

Br J Cancer

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Summary SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared.(

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“…The drugs investigated were the bioreductive quinone antibiotic mitomycin C (Kennedy et al, 1980); a monofunctional alkylating 2-nitroimidazole RSU-1069 (Adams et al, 1984;Stratford et al, 1986); and the benzotriazine-di-N-oxide SR4233 (Zeman et al, 1986(Zeman et al, , 1989.…”

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confidence: 99%

The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation

Keohane

Godden²,

Stratford³

et al. 1990

Br J Cancer

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Summary We have investigated the cross-sensitivity of a number of cell lines to three different classes of bioreductive drugs under both aerobic and hypoxic conditions. The cell lines used were selected for their sensitivity to DNA-damaging agents and fall into two groups. One group, MMC cells derived from CHO-KI cells (Robson et al., 1985), show a range of sensitivities to mitomycin C in air. The second group, irs cells were cloned from V79 Chinese hamster fibroblasts (Jones et al., 1987) and exhibit sensitivity to ionising radiation. The sensitivity of both groups of cells to mitomycin C (MMC), RSU-1069 Hypoxic cells within tumours are known to limit the efficacy of radiotherapy. Bioreductive and radiosensitising drugs are under development in order to improve tumour therapy by sensitising the hypoxic tumour cells to either radiation or cytotoxic chemotherapy. One process by which hypoxic cells can be selectively killed is to utilise the reductive metabolic pathways which can be exploited readily under poorly oxygenated conditions.The mechanism of action of three different classes of bioreductive compounds have been investigated in vitro, using cell lines selected for their sensitivity to DNA damaging agents. The drugs investigated were the bioreductive quinone antibiotic mitomycin C (Kennedy et al., 1980); a monofunctional alkylating 2-nitroimidazole RSU-1069 (Adams et al., 1984;Stratford et al., 1986); and the benzotriazine-di-N-oxide SR4233 (Zeman et al., 1986(Zeman et al., , 1989.The cell lines used fall into two groups, both of which were cloned from Chinese hamster cell lines. The first, MMC cells, were isolated from Chinese hamster ovary cells, CHO-K1 (Robson et al., 1985), and were either hypersensitive (MMC-2 and MMC-3), or resistant (MMCl) to mitomycin C. The concentrations of MMC required to reduce cell survival to 0.37 of the control following 24 hour aerobic exposure (D37 value) have been determined by Robson et al. (1985) and Hoban et al. (1990) for each cell line. These are: CHO-KI, 0.32; MMC-2, 0.05; MMC-3, 0.07; MMCr, 6.07,UM respectively. The second group of cells, irs cells were originally cloned from V79 Chinese hamster fibroblasts (Jones et al., 1987) and exhibit a range of sensitivities to ionising radiation in air. For these cell lines D37 values (Gy) have been determined as; V79, 4.2; irs 1, 1.34; irs 2, 1.41; irs 3, 2.06 (Jones et al., 1987).The cross-sensitivity of these cell lines to MMC, RSU-1069 and SR4233 has been assessed under both hypoxic and aerobic conditions. This type of study may help to determine the mechanism of action of these agents and the factors influencing cellular sensitivity to bioreductive cytotoxic drugs, in particular the enzymes involved in drug activation and cellular repair pathways. gassed with N2 + 5% CO2 at 37°C for 3 h. The drug-containing medium was then removed from the dishes, replaced with fresh medium and cells assayed 7-10 days later for colony formation.

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Structure-activity relationships for benzotriazine DI-N-oxides

Cited by 66 publications

References 18 publications

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Mechanisms of Anti-Cancer Agents Emphasis on Oxidative Stress and Electron Transfer

Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation

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