Studies on the mechanism of resistance to mitomycin C and porfiromycin in a human cell strain derived from a cancer-prone individual

Marshall, R. S.; Paterson, Malcolm C.; Rauth, Andrew M.

doi:10.1016/0006-2952(91)90108-h

Cited by 38 publications

(9 citation statements)

References 23 publications

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“…Together, these observations strongly implicate a common enzyme, presumably DT-diaphorase (Tsuda et al, 1984), in the bioreduction of the two procarcinogens. In accord with this notion, the aerobic reduction of both 4NQO (Tsuda et al, 1984) and MMC (Keyes et al, 1989;Marshall et al, 1991b) has been demonstrated to be inhibited by dicumarol, a potent (although not specific) inhibitor of DT-diaphorase (Ernster, 1967). In our earlier work the level of DT-diaphorase activity was also determined for the five fibroblast strains in the polyposis/sarcoma family.…”

Section: Discussionsupporting

confidence: 49%

Hyperresistance to 4-nitroquinoline 1-oxide cytotoxicity and reduced DNA damage formation in dermal fibroblast strains derived from five members of a cancer-prone family

Mirzayans¹,

Sabour²,

Rauth³

et al. 1993

Br J Cancer

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Summary Dermal fibroblasts cultured from members of a family presenting multiple polyps and sarcomas were compared with fibroblast strains from unrelated healthy donors for sensitivity to killing by four genotoxic agents. Cells from the sister of the male proband (strain 3437T), mother (strain 3703T), two of his paternal aunts (3701T and 3704T) and one paternal uncle (3702T) displayed marked resistance (1.8 to 4.3 times greater than the normal mean) to 4-nitroquinoline 1-oxide (4NQO), a procarcinogen whose DNAdamaging properties encompass those of both far (254 nm) ultraviolet (UV) light and ionising radiation. These same 4NQO-resistant cells, however, responded normally to reproductive inactivation by UV light, 'Co radiation or the alkylating agent methylnitrosourea, signifying that the abnormal resistance of these cells to 4NQO is not associated with aberrant DNA metabolism. In keeping with this conclusion, exposure to a given dose of 4NQO produced decreased amounts of DNA damage and stimulated lower levels of repair DNA synthesis in all five 4NQO-resistant strains than in normal controls. Moreover, exogenous radiolabelled 4NQO accumulated to a lesser extent in the 4NQO-resistant than in the normal fibroblasts. Cell sonicates of strains 3437T, 3701T and 3702T exhibited reduced capacities (40-60% of normal) to catalise the conversion of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide. However, the 4NQO-resistant strains 3703T and 3704T carried out 4NQO bioreduction at normal rates. Our data therefore indicate that enhanced resistance to 4NQO cytotoxicity in 3437T, 3701T and 3702T is a consequence of anomalies in both intracellular accumulation and enzymatic reduction of 4NQO, whereas 4NQO resistance in 3703T and 3704T appears to result solely from reduced intracellular drug accumulation.

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Section: Discussionsupporting

confidence: 49%

Hyperresistance to 4-nitroquinoline 1-oxide cytotoxicity and reduced DNA damage formation in dermal fibroblast strains derived from five members of a cancer-prone family

Mirzayans¹,

Sabour²,

Rauth³

et al. 1993

Br J Cancer

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“…Its unique structural properties and biological activity have motivated numerous studies to determine its cellular target sites and mechanism of action. Complete characterization of MMC (29,30) has been followed by studies examining the basis of its selectivity against mammalian tumor cells and the mechanisms that render mammalian tumor cells MMC resistant (5,14,18,22,26,27). However, the molecular basis for MMC resistance in the producing organism, S. lavendulae, has not been established.…”

mentioning

confidence: 99%

Cloning and analysis of a locus (mcr) involved in mitomycin C resistance in Streptomyces lavendulae

1994

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“…Mitomycin C is the prototype bioreductive agent which shows clinical activity against some solid tumours but exhibits little selectivity towards hypoxic tumour cells (Stratford and Stephens, 1989; Workman, 1992). It (Oostveen and Speckamp, 1987) is structurally related to mitomycin C (Fig. l), is less myelosuppressive (Hendriks et al, 1993) and is in clinical trial in Europe under the auspices of the EORTC.…”

mentioning

confidence: 97%

Unusually marked hypoxic sensitization to indoloquinone E09 and mitomycin C in a human colon‐tumour cell line that lacks DT‐diaphorase activity

Plumb

Workman

1994

Intl Journal of Cancer

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Studies with purified DT-diaphorase have shown that the enzyme is capable of catalyzing a two-electron reduction of the novel indoloquinone E 0 9 to a DNA-damaging alkylating species. The aim of this study was to determine to what extent DT-diaphorase may be involved in the metabolic activation of E09 and mitomycin C in both aerobic and hypoxic conditions. Two human colon-carcinoma cell lines were used; H l 2 9 has high levels of DT-diaphorase whilst BE lacks this activity because of a point mutation in the NQOl gene. In aerobic conditions the 2 cell lines show similar sensitivities to a number of qtotoxic drugs including cisplatin, doxorubicin and etoposide. They are equally sensitive to the benzotriazine di-N-oxide SR 4233 but H R 9 is more sensitive than BE to mitomycin C and E09. Sensitivity to SR 4233 is increased by about 100-fold for both cell lines in hypoxic conditions. DT-diaphorase-deficient BE cells show markedly increased sensitivity to mitomycin C and particularly E 0 9 in hypoxic conditions, whereas DTdiaphorase-rich H R 9 cells show little hypoxic sensitization to these agents unless exposed in the presence of dicoumarol.These results suggest that DT-diaphorase can reduce E09 and mitomycin C to potent cytotoxic species in aerobic conditions, and this activii predominates over the one-electron-reducing enzymes even in hypoxic conditions. In the absence of DTdiaphorase activity, E 0 9 and mitomycin C are reduced in hypoxic conditions, presumably by one-electron-reducing enzymes, to a similar or greater extent than is achieved with DT-diaphorase.8 1994 Wfq-Liss, Znc.The presence of hypoxic areas in solid tumours suggests a target for the development of selective anti-cancer agents. The main classes of bioreductive agents which show specificity for hypoxic cells are quinone, nitro and N-oxide compounds (Workman, 1992). Hypoxic cell specificity is dependent on preferential metabolic activation by reductase enzymes in hypoxic conditions (Workman, 1992). Mitomycin C is the prototype bioreductive agent which shows clinical activity against some solid tumours but exhibits little selectivity towards hypoxic tumour cells (Stratford and Stephens, 1989; Workman, 1992). It (Oostveen and Speckamp, 1987) is structurally related to mitomycin C (Fig. l), is less myelosuppressive (Hendriks et al., 1993) and is in clinical trial in Europe under the auspices of the EORTC. E09 also requires metabolic activation and has been shown to be a much better substrate for both human and rat DT-diaphorase than mitomycin C (Walton et al., 1991).In hypoxic conditions one-electron reduction of quinone bioreductive agents by enzymes such as cytochrome P450 reductase and xanthine oxidase results in the production of semiquinone free radicals. However, in aerobic conditions toxic oxygen radicals are produced due to back oxidation of these unstable metabolites. In contrast, obligate two-electron reduction by DT-diaphorase (Iyanagi and Yamazaki, 1970) results in production of more stable hydroquinone metabolites under both aerobic an...

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Studies on the mechanism of resistance to mitomycin C and porfiromycin in a human cell strain derived from a cancer-prone individual

Cited by 38 publications

References 23 publications

Hyperresistance to 4-nitroquinoline 1-oxide cytotoxicity and reduced DNA damage formation in dermal fibroblast strains derived from five members of a cancer-prone family

Hyperresistance to 4-nitroquinoline 1-oxide cytotoxicity and reduced DNA damage formation in dermal fibroblast strains derived from five members of a cancer-prone family

Cloning and analysis of a locus (mcr) involved in mitomycin C resistance in Streptomyces lavendulae

Unusually marked hypoxic sensitization to indoloquinone E09 and mitomycin C in a human colon‐tumour cell line that lacks DT‐diaphorase activity

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