Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1522282 (EMT)
 2,868 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cell survival assay in the FSaIIC murine fibrosarcoma demonstrated that when the modulator Fluosol-DA (0.3 ml; 12 ml/kg i.v.) was administered just prior to an alkylating agent plus carbogen breathing for 6 h or the modulator etanidazole (1 g/kg i.p.) was administered just prior to an alkylating agent, the combination treatment produced significantly more tumor cell killing across the dosage range of each alkylating agent tested compared with the alkylating agent alone. Each alkylating agent produced a dose-dependent log-linear tumor cell survival curve. There was an increase in tumor cell killing of 5-10-fold when either Fluosol-DA/carbogen or etanidazole was added to treatment with the alkylating agent. For cis-diamminedichloroplatinum(II) (CDDP) and N,N',N''-triethylenethiophosphoramide, the modulators used in combination increased tumor cell killing by only 2-3-fold over that obtained with a single modulator, but for the other alkylating agents, tumor cell killing was increased by 10-50-fold when the combination of modulators was used. Bone marrow granulocyte-macrophage colony-forming unit survival assays showed that the combination of modulators with the alkylating agents resulted in only small increases in bone marrow toxicity of the alkylating agents except for N,N',N''-triethylenethiophosphoramide and L-phenylalanine mustard (L-PAM), for which the toxicity to the bone marrow granulocyte-macrophage colony-forming unit was increased by 5-10-fold compared with the alkylating agents alone. The Hoechst 33342 dye diffusion defined tumor cell subpopulation assay, also in the FSaIIC tumor, demonstrated that the combination of modulators increased the toxicity of CDDP, cyclophosphamide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea by 9-55-fold compared with the alkylating agent alone in both the bright (euxoic-enriched) and dim (hypoxic-enriched) cells. For each alkylating agent except 1,3-bis(2-chloroethyl)-1-nitrosourea, the increase in tumor cell killing was greater in the dim cells than in the bright cells. Finally, tumor growth delay studies in both the FSaIIC tumor and the EMT-6 murine mammary adenocarcinoma confirmed that the combination of modulators significantly increased the tumor growth delay caused by CDDP, carboplatin, cyclophosphamide, N,N'N"-triethylenethiophosphoramide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea. The greatest increases (4-5-fold) were observed for carboplatin and L-PAM in the FSaIIC tumor and CDDP and cyclophosphamide in the EMT-6 tumor. These results suggest that Fluosol-DA/carbogen together with etanidazole may be an effective modulator combination of alkylating agents in the clinic.
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PMID:Modulation of alkylating agents by etanidazole and Fluosol-DA/carbogen in the FSaIIC fibrosarcoma and EMT6 mammary carcinoma. 182 74

Treatment of malignant brain tumors with chloroethylnitrosoureas (CENUs) in addition to surgical resection and radiotherapy remains the foundation of glioma therapy. However, the clinical response to CENUs is at best modest. A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), as compared to the standard CENU, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), has been demonstrated to have increased anticancer effects both in vitro and in vivo. Unfortunately, many human tumors have been known to be resistant to CENUs since they express DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In order to assess whether SarCNU has an effect on MGMT positive tumors, we evaluated its antitumor efficacy using an MGMT positive human glioma (SF-767) nude mouse xenograft model. Since SF-767 has high MGMT levels, BCNU treatment (20 mg/kg, Q4D x 3 i.p.) alone did not result in a satisfactory anticancer effect (p > 0.05). As expected, O6-benzylguanine (O6-BG) (100 mg/kg), which was given prior to BCNU treatment, by depleting MGMT activity, significantly enhanced BCNU antitumor efficacy (p < 0.001). Moreover, SarCNU treatment (167 mg/kg, Q4D x 3 i.p.) alone had a better antitumor effect than O6-BG plus BCNU treatment (F = 51.7, p = 0.0004). However, in this xenograft model, O6-BG did not significantly enhance the anticancer efficacy of SarCNU (F = 0.8, p = 0.411). The SF-767 human glioma xenograft is positive for extraneuronal monoamine transporter EMT (EMT) as determined by reverse-transcription polymerase chain reaction (RT-PCR). Our present results suggest that SarCNU is also effective for MGMT positive tumor if they exhibit EMT.
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PMID:Antitumor efficacy of SarCNU in a human glioma xenograft model expressing both MGMT and extraneuronal monoamine transporter. 1134 76