Browsing by Author "CHIANALE, J"

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    EFFECT OF COLCHICINE AND HEAT-SHOCK ON MULTIDRUG-RESISTANCE GENE AND P-GLYCOPROTEIN EXPRESSION IN RAT-LIVER
    (ELSEVIER SCIENCE BV, 1994) VOLLRATH, V; WIELANDT, AM; ACUNA, C; DUARTE, I; ANDRADE, L; CHIANALE, J
    The multidrug resistance genes encode plasma membrane glycoproteins named P-glycoproteins, that act as an ATP-dependent drug efflux pump and decrease the cytosolic concentration of chemotherapeutic agents. It has been hypothesized that in rat liver, this protein may have a physiological role as a biliary transporter of xenobiotics and endobiotics. Some human tumor cell lines turn on the human multidrug resistance gene in response to high temperature and after exposure to toxic chemicals. Accordingly, it has been proposed that the human multidrug resistance gene is a heat shock gene. We have assessed whether two environmental stresses, heat shock or acute exposure to cytotoxic drugs (colchicine, vincristine, vinblastine and daunomycin), induce changes in the expression of multidrug resistance genes in the rat. Total cellular RNA extracted from rat liver was hybridized to a labeled human multidrug resistance gene cDNA probe. Temperature upshift did not increase the steady-state of mdf mRNA levels in the tissues studied, suggesting that the mdr genes are not activated as part of a heat shock response. The mdi mRNA levels increased in rat liver as early as 3 h after a single injection of colchicine, reached a peak (500%; p<0.05) after around 24 h and returned to constitutive levels after 48 h. Changes in the relative content of mdr mRNA were not detected in kidney, adrenal gland and small bowel, suggesting that the in vivo induction of the mdr gene in the liver is a tissue-specific response. The other cytotoxic drugs that were tested did not increase the steady-state of mdr mRNA levels. Using specific PCR-generated mouse mdr cDNA probes, we found that only the mdr 2 gene is overexpressed in the liver of colchicine-treated mouse. The mdr gene induction was followed at 48-72 h by a stronger immunostaining in rat liver of its encoded product, suggesting that the newly synthesized protein was incorporated into the canalicular domain of hepatocytes. This is the first evidence of modulation of mdr expression gene in rodent liver in response to colchicine, a substrate of P-glycoprotein in multidrug resistant cells. (C) Journal of Hepatology.
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    ENDOSCOPIC INTRASPHINCTERIC INJECTION OF BOTULINUM TOXIN FOR THE TREATMENT OF ACHALASIA
    (LIPPINCOTT-RAVEN PUBL, 1995) ROLLAN, A; GONZALEZ, R; CARVAJAL, S; CHIANALE, J
    Three patients with achalasia were treated with endoscopic injection of botulinum toxin (BoTx). BoTx (80 U) was injected via a sclerotherapy needle into the lower esophageal sphincter (LES). One patient complained of transient heartburn that resolved after omeprazole treatment. Two patients reported sustained symptomatic improvement. They were able to eat normally 48 h after treatment and have remained symptom free for 5 and 6.5 months, respectively. In these patients, esophageal manometry 4 months after treatment showed a marked reduction of resting LES pressure and the appearance of a previously absent LES relaxation after swallowing. The third patient had only a transient clinical improvement, with occasional dysphagia beginning 3 months after treatment. All patients showed unchanged aperistalsis of the esophageal body. Its less invasive nature compared with other therapeutic alternatives may give BoTX injection a role in the treatment of some patients with achalasia.
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    MULTIDRUG RESISTANCE GENE AND P-GLYCOPROTEIN EXPRESSION IN GASTRIC ADENOCARCINOMA AND PRECURSOR LESIONS
    (1991) VOLLRATH, V; CHIANALE, J; GONZALEZ, S; DUARTE, I; ANDRADE, L; IBANEZ, L
    Overexpression of the Multiple Drug Resistance gene (MDR1) has been proposed as a major mechanism related to both intrinsic and acquired resistance to chemotherapeutic agents. The gene product is a membrane protein (P-glycoprotein), that acts as an energy-dependent drug efflux pump decreasing drug accumulation in resistant tumor cells. We have characterized MDR1 and P-Glycoprotein expression in human gastric adenocarcinoma and in precursor lesions. MDR1 mRNAs, analyzed by dot-blot technique, were detected in 9 of 10 non-tumoral gastric mucoase and in 8 of 10 gastric adenocarcinomas. Immunohistochemical analysis, using the MRK16 monoclonal antibody, revealed heterogeneous expression of P-Glycoprotein in individual cells. The P-Glycoprotein was found on the surface of cells of gastric areas with intenstinal metaplasia subtype III. This type of intestinal metaplasia, also called "colonic metaplasia", has been strongly associated with a high risk for the development of gastric cancer. The fact that the P-Glycoprotein was detected in this precursor lesion is consistent with the intestinal metaplasiadysplasia and carcinoma sequence proposed in the histogenesis of this tumor. The finding that P-Glycoprotein was heterogeneously expressed in malignant cells of some gastric adenocarcinomas also suggests that this transporter system probably contributes to primary and secondary multidrug resistance in this neoplasm.