RESUMEN
TCF transcription factors are mediators of the WNT signaling pathway and are antagonized by the transforming growth factor beta signaling pathway. Here human TCF-3 has been cloned and characterized. Differential expression analyses of TCF genes in gastric cancer revealed that TCF-1 was expressed in most cases of primary gastric cancer at almost the same level as in normal gastric mucosa and that TCF-3 was occasionally up-regulated in primary gastric cancer. The TCF-3 expression vector was transfected to gastric cancer cell line MKN28 to establish stable transformants. Three independent MKN28 transformants overexpressing TCF-3 showed about 8-fold resistance to mitomycin C (MMC; IC50, 2.4 microg/ml) compared with MKN28 vector transfectants (IC50 = 0.3 microg/ml). Among the 10 drug resistance-associated genes examined in this study, the DT-diaphorase (DTD) gene was down-regulated in three MKN28 transformants overexpressing TCF-3. DTD mRNA was also down-regulated in primary gastric cancer with TCF-3 up-regulation. In addition, DTD protein was down-regulated in three MKN28 transformants overexpressing TCF-3 compared with MKN28 vector transfectants. DTD is implicated in the activation of MMC in target cells, and DTD down-regulation explains MMC resistance. MMC resistance induced by TCF-3 overexpression is probably due to DTD down-regulation, which might provide a possible target for new therapy of drug-resistant gastric cancer.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Proteínas HMGB , Mitomicina/farmacología , NAD(P)H Deshidrogenasa (Quinona)/biosíntesis , Neoplasias Gástricas/metabolismo , Factores de Transcripción/biosíntesis , Secuencia de Aminoácidos , Clonación Molecular , ADN Complementario/genética , ADN Complementario/aislamiento & purificación , ADN de Neoplasias/genética , Regulación hacia Abajo , Resistencia a Antineoplásicos , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Datos de Secuencia Molecular , NAD(P)H Deshidrogenasa (Quinona)/genética , Homología de Secuencia de Aminoácido , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Factores de Transcripción TCF , Proteína 1 Similar al Factor de Transcripción 7 , Factores de Transcripción/genética , Transfección , Transformación Genética , Células Tumorales CultivadasRESUMEN
Preoperative intra-arterial infusion neo-adjuvant chemotherapy, in combination with local vein blocking, was administered to thirty-one patients with locally advanced stage III breast cancer. The anti-cancer drugs and dosages used were 500 mg of 5-Fluorouracil (5FU), which was infused daily for 7-14 days, and 20 mg of Adriamycin (ADM), which was administered as a bolus dose twice into the subclavian and internal mammary arteries. The response rate of this method on the primary tumor was 48.4 per cent, and, histologically it was found to be as high as 90.3 per cent. The response rate of the clinical effects on the regional lymph nodes was 50.0 per cent, however, histologically, it was found to be lower than that of the primary tumor. In the long-term follow-up study the 5-year survival rate was 72.2 per cent. Thus, this method seems to be effective as a combined modality in cases of locally advanced stage III breast cancer.