(14C-Methyl)-L-methionine uptake in rat brain tumors before and after treatment with the protein synthesis inhibitor cycloheximide

Mineura, Katsuyoshi; Sasajima, Toshio; Kuwahara, Naoyuki; Kowada, Masayoshi; Murakami, M; Uemura, Kazunori

doi:10.1007/bf01050068

Cited by 5 publications

(2 citation statements)

References 13 publications

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“…Tumours have high MET requirements because of accelerated protein synthesis and transmethylation reactions to yield S-adenosylmethionine, serine, sarcosine, glycine and various phospholipids (Mineura et al, 1993;Kubota et al, 1995). Twenty-five per cent of human tumours are estimated to be absolutely dependent of MET and cannot use HCY to either proliferate or survive (Guo, 1993).…”

Section: Discussionmentioning

confidence: 99%

Regulation of O6-methylguanine-DNA methyltransferase by methionine in human tumour cells

Kokkinakis

Wronski²,

Vuong³

et al. 1997

Br J Cancer

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Summary Methionine (MET)-dependent cell lines require MET to proliferate, and homocysteine (HCY) does not act as a substitute for this requirement. From six O6-methylguanine-DNA methyltransferase (MGMT)-efficient (mer) cell lines tested, two medulloblastomas (Daoy and D-341) and a lung non-small-cell adenocarcinoma with metastatic potential (H-1623) were most sensitive to MET deprivation, while two glioblastomas (U-138, D-263) and a small-cell lung carcinoma H-1944 were moderately to weakly dependent. Regardless of the degree of MET dependence, all of these lines down-regulated their MGMT activity within 48-72 h of transfer from MET+HCY-to MET-HCY+ media, long before the eradication of the culture. Reduction of MGMT activity was due to a decline of both MGMT mRNA and protein levels. However, the reduction was not related to the methylation status of the MGMT promoter at the Smal site or the Hpall sites in the body of the gene; such sites have been shown to be associated in MGMT regulation and in defining the mer phenotype. MET-dependent, met tumour cells cultured in MET-HCY+ were more sensitive to BCNU (IC50 = 5-1 0 gIM) than those cultured in MET+HCY-(IC50 = 45-90 gM), while MET-independent or mer cell lines were unaffected. This indicates that reduction of MGMT, imposed by the absence of MET, renders mer tumour cells more susceptible to alkylating agents. The relatively selective suppression of MGMT activity in mer MET-dependent tumour cells, in combination with the inability of such cells to proliferate in the absence of MET, may lead to the development of more effective treatment strategies for mer MET-dependent tumours.

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Section: Discussionmentioning

confidence: 99%

Regulation of O6-methylguanine-DNA methyltransferase by methionine in human tumour cells

Kokkinakis

Wronski²,

Vuong³

et al. 1997

Br J Cancer

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“…C6 cells (5 x 106/10 ml) were stereotactically inoculated in the right basal ganglia of 6-week-old male Sprague-Dawley rats weighing 130 to 160 g (Mineura et al, 1993). Ten days after inoculation, the rats received an i.v.…”

Section: Rat Brain-tumor Model and Cddp Treatmentmentioning

confidence: 99%

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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Sasajima

Mineura

Kowada

et al. 1997

Journal of Neuro-Oncology

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The aim of the present study is to understand the therapeutic effects of recombinant human tumor necrosis factor-alpha (rH-TNF) on hemocirculation and metabolism of brain tumors. Using double-label autoradiographic technique, we have monitored changes in regional cerebral blood flow (rCBF) and protein-bound fraction of (3H-methyl)-L-methionine, expressed as acid-insoluble fraction (AIF), in rat brain tumors following treatment with intracarotid rH-TNF. The central portion of tumors showed a significant decrease in rCBF and AIF at 4 hours after the injection (p < 0.01, p < 0.05, respectively, as compared with non-treated control rats), turned microscopically necrotic at 24 hours, and became more extensively necrotic at 72 hours. Tumor cells remained viable only in the peripheral portion of the tumors after the treatment. The peripheral portion also showed a moderate decrease in rCBF, but less change in AIF to 4 to 72 hours after the treatment. Neither ipsilateral nor contralateral non-involved cortex demonstrated appreciable changes in rCBF and AIF during the observed period. Intracarotid rH-TNF selectively reduces tumor rCBF and AIF, resulting in histological modification.

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(14C-Methyl)-L-methionine uptake in rat brain tumors before and after treatment with the protein synthesis inhibitor cycloheximide

Cited by 5 publications

References 13 publications

Regulation of O6-methylguanine-DNA methyltransferase by methionine in human tumour cells

Regulation of O6-methylguanine-DNA methyltransferase by methionine in human tumour cells

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

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