Molecular targeting of mitomycin C chemotherapy

Nishiyama, Masahiko; Suzuki, Katsuyuki; Kumazaki, Tatsuo; Yamamoto, Wataru; Toge, Tetsuya; Okamura, Takehiko; Kurisu, Kaoru

doi:10.1002/(sici)1097-0215(19970807)72:4<649::aid-ijc17>3.0.co;2-6

Cited by 27 publications

(16 citation statements)

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“…In this regard, an association between the expression of the dihydropyrimidine dehydrogenase enzyme and 5-fluorouracil resistance in human cancer cells has been demonstrated (Kirihara et al, 1999). Similar findings have been reported for glutathione transferase enzyme activity and resistance to mitomycin C (Singh et al, 1992;Nishiyama et al, 1997). To date only indirect data indicated the presence of CYP3A in healthy colorectal tissue.…”

Section: Discussionsupporting

confidence: 53%

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

et al. 2002

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Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity+s.d. for colorectal cancer microsomes was 67.8+36.6 pmol min 71 mg 71 . The K m of the tumoral enzyme (42+8 mM) is similar to that in healthy colorectal epithelium (36+8 mM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1+1.2 pmol min 71 mg 71 . The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a K I value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs.

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Section: Discussionsupporting

confidence: 53%

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

et al. 2002

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“…10,[12][13][14][15] The probes used for hybridization were a 3. Electrophoresis and western blot analysis Protein fractions were separated by sodium dodecyl sulfate-polyacrylamide electrophoresis on 7% to 13.5% polyacrylamide gels, followed by transfer to polyvinylidene difluoride membranes for 30 min using a semidry blotting apparatus.…”

Section: )mentioning

confidence: 99%

O⁶‐Methylguanine‐DNA Methyltransferase (MGMT) as a Determinant of Resistance to Camptothecin Derivatives

Okamoto

Takano

Okamura

et al. 2002

Japanese Journal of Cancer Research

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The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O 6 -methylguanine-DNA methyltransferase (MGMT), participated in resistance to irinotecan hydrochloride (CPT-11), its active metabolite SN-38, and a novel CPT derivative, DX-8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 µ µ µ µM O 6 -benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR/MGMTsense into U-251MG and pCR/MGMT-antisense into T98G and HEC-46 cells revealed that increased MGMT expression decreased the sensitivity to CPT-11, SN-38, and DX-8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT-expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose-dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo Imediated DNA damage and/or the repair process.

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“…DT-diaphorase plays an important role in activating bioreductive anti-tumour agents like MMC (Begleiter et al, 1989;Ross et al, 1993;Mikami et al, 1996;Nishiyama et al, 1997), EO9 (Plumb   et al, 1994), streptonigrin (Beall et al, 1996) and RH1 (Winski et al, 1998). Cell lines with high levels of DT-diaphorase are more sensitive to MMC (Begleiter et al, 1989;Ross et al, 1993;Mikami et al, 1996), and studies have shown a good correlation between the level of DT-diaphorase activity and the sensitivity to MMC in human tumour cell lines (Fitzsimmons et al, 1996).…”

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confidence: 99%

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

et al. 1999

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Summary DT-diaphorase is a two-electron reducing enzyme that activates the bioreductive anti-tumour agent, mitomycin C (MMC). Cell lines having elevated levels of DT-diaphorase are generally more sensitive to MMC. We have shown that DT-diaphorase can be induced in human tumour cells by a number of compounds, including 1,2-dithiole-3-thione. In this study, we investigated whether induction of DT-diaphorase could enhance the cytotoxic activity of MMC in six human tumour cell lines representing four tumour types. DT-diaphorase was induced by many dietary inducers, including propyl gallate, dimethyl maleate, dimethyl fumarate and sulforaphane. The cytotoxicity of MMC was significantly increased in four tumour lines with the increase ranging from 1.4-to threefold. In contrast, MMC activity was not increased in SK-MEL-28 human melanoma cells and AGS human gastric cancer cells, cell lines that have high base levels of DT-diaphorase activity. Toxicity to normal human marrow cells was increased by 50% when MMC was combined with 1,2-dithiole-3-thione, but this increase was small in comparison with the threefold increase in cytotoxicity to tumour cells. This study demonstrates that induction of DT-diaphorase can increase the cytotoxic activity of MMC in human tumour cell lines, and suggests that it may be possible to use non-toxic inducers of DT-diaphorase to enhance the efficacy of bioreductive anti-tumour agents.

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Molecular targeting of mitomycin C chemotherapy

Cited by 27 publications

References 11 publications

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

O⁶‐Methylguanine‐DNA Methyltransferase (MGMT) as a Determinant of Resistance to Camptothecin Derivatives

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

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Molecular targeting of mitomycin C chemotherapy

Cited by 27 publications

References 11 publications

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

O6‐Methylguanine‐DNA Methyltransferase (MGMT) as a Determinant of Resistance to Camptothecin Derivatives

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

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O⁶‐Methylguanine‐DNA Methyltransferase (MGMT) as a Determinant of Resistance to Camptothecin Derivatives