[Müllerian adenosarcoma].
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Biomedical subjects
Publications and source records attributed to C Delattre.
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Early trophoblastic cells share several features with neoplastic cells. Based on that observation, we attempted to identify genes overexpressed in tumors by analyzing genes preferentially expressed in trophoblasts. A subtracted library enriched in complementary DNA from early cytotrophoblasts was constructed, and the expression level of selected recombinants was analyzed on a large panel of normal and tumor tissues. The library was prepared using a polymerase chain reaction-based complementary DNA subtraction method with 6-week amenorrhea cytotrophoblast endoplasmic reticulum-bound RNA as target, and a mixture of complementary DNA prepared from terminal placenta and activated T-lymphocytes as driver. Two rounds of screening were performed to isolate clones preferentially expressed in early placenta. From a total number of recombinant clones estimated at 32,000 in the subtracted library, 594 inserts were analyzed by Southern blot and 21 sequences were isolated as corresponding to genes highly expressed in early placenta. Eleven encoded known molecules, such as carcinoembryonic antigen, human chorionic gonadotropin, and mitochondrial rRNAs. Ten sequences represented novel genes. Northern blot analysis confirmed that most of these genes were preferentially expressed in early trophoblast in comparison to terminal placenta. Three clones that gave detectable hybridization signals on total RNA were extensively studied and were found to be overexpressed in various tumors. Two of these clones, designated B9 and E4, were later identified as corresponding to genes coding for the putative ribosomal protein S18 and the bifunctional enzyme ADE2H1 involved in purine biosynthesis, respectively. Expression of the third clone, E9, was increased up to 10-fold in breast cancer tissues in comparison with normal counterparts. Present results confirm that many genes expressed in the trophoblast are overexpressed in malignant cells. This approach could provide a general targeted method for the identification of genes overexpressed in various neoplastic cell types.
Metoclopramide was administered by continuous infusion to two groups each of 14 patients on chemotherapy, randomized to receive either doses adjusted to individual pharmacokinetic parameters or doses adjusted as usual to body weight. The mean plasma concentration at the end of the infusion in the adjusted group was 1.01 mg.l-1, close to that aimed for (1.20 mg.l-1). It was significantly different from that in the other group. v 0.54 mg.l-1. Antiemetic efficacy, defined as less than or equal to 2 emetic events in the 24 h following cisplatin, was similar in both groups (being found in 12/14 (86%) and 10/14 patients (71%), respectively). Analysis of the cumulative percentage of responders according to plasma concentration showed a clear plasma concentration-effect relationship. Routine MCP pharmacokinetic dosage adjustment is not indicated, but this therapeutic approach can be used to optimize antiemetic therapy in poor responder patients.
Ten patients under cisplatin-containing chemotherapeutic regimens received constant rate continuous infusions of metoclopramide in doses adjusted to each individual case for optimal plasma concentration. Dosage adjustment was based on simple pharmacokinetics with determination of metoclopramide distribution and elimination values in each patient. From these values were calculated the individual loading and maintenance dosages required to obtain the sustained plasma concentration of 0.85 mg/l reported in the literature as being correlated with a good antiemetic effectiveness. The mean plasma concentration in the 10 patients studied was 0.84 +/- 0.19 mg/l with doses which varied considerably owing to marked scattering of pharmacokinetic parameters. Treatment was effective in 6 out of 10 patients and well tolerated by all.
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