Linkage between O6-methylguanine-DNA methyltransferase (O6-MT) activity and cellular resistance to antitumour nitrosoureas in cultured rat brain tumour cell strains

Mineura, Katsuyoshi; Fushimi, Susumu; Kowada, Masayoshi; Isowa, Gohei; Ishizaki, Kanji; Ikenaga, Mituo

doi:10.1007/bf01420193

Cited by 17 publications

(6 citation statements)

References 10 publications

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“…Xenografted C6-1 tumors which poorly responded to ACNU or MCNU exhibited higher 06-AT values (11). During some 10 years, drug sensitivity of the C6-1 cells in our stock to ACNU has been rather consistent with SDlO concentrations ranging between 50-80 pM (8,10,12). In contrast to the C6-1 cells, the C6-2 cells obtained from the JCRB were exceedingly sensitive to CENUs.…”

Section: Discussionsupporting

confidence: 55%

“…Rosenblum & Berger (9) suggested that more than one mechanism might be responsible for drug sensitivity, even in cell lines derived in a similar manner. Using rat glioma cell lines we showed a close correlation between O6-a1kylguanine-DNA alkyltransferase ( 06-AT) activity and resistance to antitumor CENUs (10). 9L cells with a low 06-AT activity were sensitive to ACNU, while C6-1 cells with a high activity were markedly resistant.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we evaluated colony-forming ability after 2-h exposures as a degree of sensitivity or resistance (8,10,12). Two-hour exposures produced a great capacity to repair from sublethal damage, showing a large shoulder in the dose-response curves at lower concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Development of Resistance to Antitumor Chloroethylnitrosoureas in Vitro in Brain Tumor Cells

1992

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Rat brain tumor cell lines (9L, C6-1, C6-2), human brain tumor cells (T98G), and HeLa S3 cells were studied to assess their acquired resistance to the chloroethylnitrosoureas (CENUs), 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-ni~osourea hydrochloride (ACNU) and methyl-6-[ 3 4 2-chloroethyl) -3-nitrosoureido] -6deoxy-a-D-glucopyranoside (MCNU), after 10 repeated exposures of a panel of different drug concentrations. Assay end-point was colony-forming ability after 24-h drug exposure. Intrinsic resistance was tested at the 10% survival dose (SD10) and CGl, T98G, and HeLa S3 cell lines were 3 to 16 times more resistant to ACNU than 9L and C6-2 cell lines. After repeated exposures to ACNU, 9L and C6-2 cells acquired 2-and 5-fold resistance to ACNU respectively, whereas C6-1 and T98G cells retained a resistance almost equivalent to the respective parent cells. HeLa S3 cells also acquired resistance to ACNU, as evidenced by a 3.5-fold increase. The SDlO of the cells to MCNU ranged from 4.3 p M (C6-2 cells) to 151.7 pM (T98G cells). After long-term exposure to MCNU, all five cell lines became significantly resistant compared to their respective parent cells. The easily obtained acquired resistance to CENUs suggests a clinical disadvantage of continual and repeated adjuvant monochemotherapy with these agents.Chloroethylnitrosoureas (CENUs) permeate the bloodbrain barrier and are not cell cycle specific and therefore often used for chemotherapy of human brain tumors. Their therapeutic effectiveness, however, remains quite uncertain, and clinical surveys have shown unsatisfactory results (1). Besides intrinsic drug resistance also acquired resistance can explain the poor effectiveness. The latter phenomenon suggests a clinical disadvantage of longstanding adjuvant CENU therapy.With this background, we have studied acquired resistance to 1 -( 4-amino-2-methyl-5-pyrimidinyl)methyl-3-( 2- glucopyranoside ( MCNU), after long-term exposure using an in vitro colony formation assay. Material and MethodsCell strains and culture. The cell strains included rat cell lines (9L, C6-1, C6-2), a human glioma cell line (T98G).and HeLa S3 cells. The 9L cell line derived from a Fisher 344 rat brain tumor (2). The C6 glioma was originally induced by N-methylnitrosourea in a Wistar rat (3): the culture of the C6-1 cell line has been maintained in our laboratory for some 10 years, and the C6-2 cell line was supplied by the Japanese Cancer Research Resources Bank (JCRB, Tokyo. Japan). The T98G cells were also given by the JCRB, and the HeLa S3 cells were kindly provided by Dr. K. Ishizaki, Radiation Biology Center, Kyoto University, Japan.All strains were maintained in Eagle's minimal essential medium (MEM, Flow Lab.. McLean. VA., U.S.A.) supple-mented with 10% (vol./vol.) fetal bovine serum, penicillin G (50 units/ml), streptomycin (50 pglml), and fungizone (2.5 pg/ml). The cells were grown in a humidified atmosphere of 95% air and 5% carbon dioxide at 37°C.Long-term culture in CENU-containimg medium. After digestion of cel...

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Development of Resistance to Antitumor Chloroethylnitrosoureas in Vitro in Brain Tumor Cells

1992

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“…The methods for measurement of the 06-AT activity were described elsewhere in detail (Mineura et al 1990). Briefly, frozen samples were cut into pieces on a block of dry ice.…”

Section: Methodsmentioning

confidence: 99%

“…Mer-tumors possess low activity of 06-AT enzyme and are substantially sensitive to chemotherapeutic alkylating agents. The 06-AT activity has been reported to correlate well with cellular resistance to antitumor CENUs, subject to chemotherapeutic alkylating agents in brain tumor cells and xenografted brain tumors (Schold et al 1989 ;Mineura et al 1990Mineura et al , 1991.…”

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confidence: 99%

O6-Alkylguanine-DNA Alkyltransferase Activity in Human Brain Tumors.

Mineura

Izumi

Watanabe

et al. 1991

Tohoku J. Exp. Med.

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and KOWADA, M. 06-Alkylguanine-DNA Alkyltransferase Activity in Human Brain Tumors. Tohoku J. Exp. Med., 1991, 165 (3), [223][224][225][226][227][228] It is well known that resistance in tumor cells to alkylating agents and, in particular, chloroethylnitrosoureas (CENUs), which are widely used in the chemotherapy of brain tumors, correlate well with activity of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (06-AT). We measured O6-AT activity in human brain tumors in order to obtain basic knowledge of whether or not CENU chemotherapy can be applied selectively on brain tumors. The subjects included 17 gliomas (seven malignant astrocytomas, two glioblastomas, two medulloblastomas, two oligodendrogliomas, two ependymomas, one fibrillary astrocytoma, one primitive neuroectodermal tumor) and five non-glial tumors (three meningiomas, two neurinomas). The value of O6-AT activity for the gliomas varied widely and indicated 111±65 fmol of 3H-methyl adducts transferred /mg protein extract/hr (mean±s.D., range 0-258,18 tumors), while the non-glial tumors showed a relatively high value of 270±43 fmol/mg/hr (range 225-330, 5 tumors). A significant difference in the O6-AT activity was noted between the gliomas and the nonglial tumors at the p-value of 0.001. Six (38%) out of 17 glioma cases showed a value below 100 fmol/mg/hr and four cases (24%) a value below 60 fmol/mg/hr. These results provide a biological basis for applying CENU chemotherapy on glioma patients with a lower value of 06-AT enzyme. brain tumors ; gliomas ; O6-alkylguanine-DNA alkyltransferase ; chloroethylnitrosoureas

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Inhibition of methionine uptake byCIS-diamminedichloroplatinum (II) in experimental brain tumors

Mineura

Sasajima

et al. 1996

Int. J. Cancer

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cis-diamminedichloroplatinum (II) (CDDP) has been used both alone and in combination with other chemotherapeutics for cancer chemotherapy. Although CDDP acts primarily on DNA, it can also act at the tumor-cell membrane to inhibit methionine transport. The latter mechanism of CDDP is reported to have an important role as a chemical modulator in enhancing chemotherapeutic effects of 5-fluorouracil in tumor cells. We report here the effects of CDDP on methionine uptake in an in vivo brain-tumor model. C6 brain-tumor cells were stereotactically inoculated in the right basal ganglia of 6-week-old male Sprague-Dawley rats. Ten days after the inoculation, autoradiographic images were obtained using (14C-methyl)-L-methionine. The tracer uptake, represented as differential absorption ratio (DAR) and an acid-insoluble fraction (AIF), was measured in both brain tumors and normal brain with or without an intravenous injection of CDDP. The tumor/non-tumor DAR and AIF decreased significantly (P < 0.01, as determined by the Mann-Whitney U-test) after CDDP treatment, whereas the non-tumor DAR and AIF remained almost unchanged. These findings indicate that CDDP inhibits methionine uptake selectively in brain-tumor tissue and may therefore be a potent chemical modulator in the chemotherapy of brain tumors.

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Linkage between O6-methylguanine-DNA methyltransferase (O6-MT) activity and cellular resistance to antitumour nitrosoureas in cultured rat brain tumour cell strains

Cited by 17 publications

References 10 publications

Development of Resistance to Antitumor Chloroethylnitrosoureas in Vitro in Brain Tumor Cells

Development of Resistance to Antitumor Chloroethylnitrosoureas in Vitro in Brain Tumor Cells

O6-Alkylguanine-DNA Alkyltransferase Activity in Human Brain Tumors.

Inhibition of methionine uptake byCIS-diamminedichloroplatinum (II) in experimental brain tumors

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