2,4-Dinitro-5-ethyleneiminobenzamide (CB 1954): A potent and selective inhibitor of the growth of the Walker carcinoma 256

Cobb, L. M.; Connors, T. A.; Elson, L. A.; Khan, Abdul Hameed; Mitchley, B. C. V.; Ross, W. C. J.; Whisson, M E

doi:10.1016/0006-2952(69)90267-6

Cited by 131 publications

(57 citation statements)

References 4 publications

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“…In these they reported on the nitroreduction of CB1954 5-(aziridin-l-yl)-2, 4-dinitrobenzamide by DT-diaphorase in the rat. CB1954 is a cytotoxic drug, with radiosensitising properties, and a nitro group (Cobb et al, 1969). Our interest in the papers by Knox et al stems from the earlier toxicology of this drug in which histopathological changes were observed in the lung airway epithelium, the centrilobular areas of the liver, and the lens epithelium -a tissue lying within eight or so cells of the meibomian gland secretions (Cobb, 1970).…”

Section: Discussionmentioning

confidence: 99%

NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole

Cobb¹,

Hacker²,

Nolan³

1990

Br J Cancer

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Hack and Helmy's method for the histochemical identification of NAD(P)H nitroblue tetrazolium reductase activity was employed to pinpoint reductase activity in certain cells in the mouse. High activity was observed in the following: lower airway epithelium, liver (centrilobular zone), eyelid (meibomian and sebaceous glands), vulval gland and parotid gland (striated cells of intralobular ducts). All of these cells had previously been identified as sites of binding of the reactive metabolites formed from the enzymic reduction of misonidazole (MISO) (Cobb et al., 1989). It had previously been thought that MISO binding would only take place in significant amounts in hypoxic tissues (tumour and possibly liver) since in normoxic tissues oxygen should reverse the initial one electron enzymic reduction, thus preventing progressive reduction to reactive species. We suggest that the very high levels of reductase in the above listed, probably normoxic, tissues contribute significantly to the accumulation of bound reactive MISO metabolite(s). Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7

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Section: Discussionmentioning

confidence: 99%

NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole

Cobb¹,

Hacker²,

Nolan³

1990

Br J Cancer

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“…4 It entered limited clinical trial in 1970 but no antitumour activity was seen in humans. It was subsequently shown that CB1954 was reduced by the rat nitroreductase (NTR) enzyme DT diaphorase to form a potent bifunctional alkylating agent that crosslinked DNA and killed noncycling cells.…”

Section: Introductionmentioning

confidence: 99%

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

et al. 2007

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Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC 50 ¼ 0.35 mM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiationinduced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4 0 ,6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

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“…However, there are some exceptions; in particular a number of compounds which show sensitizing efficiency much greater than would be predicted from their electron affinities. One such compound is the aziridinyl dinitrobenzene, CB 1954, synthesized originally as a cytotoxic agent (Cobb et al, 1969) and shown to have both alkylating and anti-metabolite properties (Connors & Malzack, 1971;Connors et al, 1972). CB 1954 has an electron affinity similar to that of MISO but its ability to sensitize hypoxic cells to radiation is greater than that of MISO both in vitro and in vivo (Chapman et al, 1979;Stratford et al, 1981;Stratford, 1982).…”

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confidence: 99%

Radiation sensitization and chemopotentiation: Rsu 1069, a compound more efficient than misonidazole in vitro and in vivo

Adams¹,

Ahmed²,

Sheldon³

et al. 1984

Br J Cancer

142

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Summary Electron affinity as measured by the one-electron reduction potential, E7,, is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E1 -398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater thdn that of misonidazole, e.g. 0.2mM RSU 1069 gives an enhancement ratio of 2.2 compared to 1.5 for the same concentration of misonidazole. Radiosensitization studies with the MT tumour in vivo also showed RSU 1069 to be a more efficient sensitizer than misonidazole. An administered dose of only 0.08 mg g1 RSU 1069 yielded an enhancement of 1.8 to 1.9 using tumour cell survival and tumour cure as end-points.The ability of RSU 1069 to potentiate the cytotoxic action of melphalan towards the MT tumour was also examined. RSU 1069 (0.08 mgg -1) given to mice 1 h before melphalan resulted in an enhancement of 3.0. In contrast, previous studies had shown with a series of nitroimidazoles including misonidazole that Ro 03-8799 was the most effective potentiating agent, but this only gave an enhancement of 2.3 at a 10-fold higher dose than RSU 1069.RSU 1069 is a compound of substantial promise both as a radiosensitizer and chemopotentiating agent and warrants further investigation.

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2,4-Dinitro-5-ethyleneiminobenzamide (CB 1954): A potent and selective inhibitor of the growth of the Walker carcinoma 256

Cited by 131 publications

References 4 publications

NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole

NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

Radiation sensitization and chemopotentiation: Rsu 1069, a compound more efficient than misonidazole in vitro and in vivo

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