Effect of zidovudine (ZDV) on the transplacental pharmacokinetics of dideoxyinosine (ddI)

ROLE OF TRANSFORMING GROWTH FACTOR (TGF-)a AND EPIDERMAL GROWTH FACTOR @4X) ON PROLIFERATION, INYASION, AND hCG PRODUCTION BY NORMAL AND MALIGNANT TROPHOBLAST. Jeff Lysialr’, Nelson Khoo’, Ian Connelly’, William Stettler-Stevensor? and Pee h Lala’. ‘Department of Anatomy, University of Western Ontario, London, ON. Canada, N6 IY Xl, and laboratory of Pa’hology, NCI, Bethesda MD. Numerous studies have demonstrated the presence of the EGF-receptor on human trophoblast cells yet its functional role remains unknown. In this study we employed cultures of pure first trimester human trophoblast (I-IT) cells and two human choriocarcinoma cell lines (JAR and JEG3) to examine the roles of TGFa and EGF on proliferation, invasion, and hCG production by these cells. Proliferation was measured from ‘H-TdR uptake (24h incubation with growth factors, 10 nglml, 8h pulse ‘H-TdR). Invasion was measured with a matrigel transwell invasion assay (72h). mRNA levels of the invasion regulating proteins, tissue inhibttor of metalloprotease (TIMP) 1, TIMP2, and 72 kD collagenase were assayed by Northern blot analysis. Total hCG was measured by a RIA. Both TGFa and EGF stimulated proliferation of HT cells but had no significant effect on JAR and JEG3. TGFa enhanced invasion by JAR but had no significant effect on JEG3 and HT cells. In normal trophoblast cells both TGFa and EGF increased TIMPl mRNA levels and the 3.5 kb message of TIMP2; 72 kJI collagenase mRNA was slightly increased with EGF but not with TGFa. In the choriocarcinomas TIMPI message was undetectable; EGF increased the 1.0 Lb TIMP2 mRNA level in JEG3; and the 72 kD collagenase message remained unchanged in JAR treated with either growth factor. Total hCG production was significantly increased in JAR and JEG3 treated with both TGFa and EGF. Thus, TGFa and EGF are important molecules having differential regulatory functions for normal first trimester trophoblast cells and choriocarcinoma cells. (Supported by the MRC and NC1 Canada).

TROPHOBLASTIC LOCALIZATION AND PRODUCTION OF IMMUNOREACTIVE ENDOTHELIN1 IN HUMAN PLACENTA. Andre Malassini, Laurent Cronier, Francoise Mondon*, The&e-Marie Mignot* and Francoise FerrC*. Physiologie Cellulaire, URA CNRS 290, Universite de Poitiers ; *INSERM U.36 I, 750 I4 Paris (France). Regarding their endocrine and paracrine activities, endothelins can be considered as peptide hormones and growth factors. The presence of endothelin- I (ETI) binding sites on smooth muscle of villous vessels, on villous trophoblast and on purified trophoblast in culture raises the question of the origin of the peptide. Therefore the ET1 localization was immunocytochemically investigated in human placenta. In placental sections, ETI immunoreactivity (ETI IR) was specifically detected not only in the villi : endothelium of vessels and trophoblastic layer, but also in the basal plate : decidual like cells and extravillous cytotrophoblast (ECT) and in the chorionic plate. After various times of culture of purified cytotrophoblasts, ETI IR was observed in 95 % of cells : cytotrophoblasts, trophoblast aggregates and syncytiotrophoblast. The presence of ETl-2 IR in the culture media was confirmed by RIA. A stable daily production of the peptide was observed during at least 5 days (about 50 fmol/lO” cells04 h). Furthermore, 5 days cultured trophoblast contained significant amount of ETI-2 IR (24 fmoV106 cells). These results suggest a trophoblastic origin for endothelins and argue for a patacrine and autocrine action of the peptide in the physiology of the trophoblast.