Past studies have shown that epidermal growth factor (EGF) is able to mimic the uterotropic effects of estrogen in the rodent. These studies have suggested a "cross-talk" model in which EGF receptor (EGF-R) signaling results in activation of nuclear estrogen receptor (ER) and its target genes in an estrogen-independent manner. Furthermore, in vitro studies have indicated the requirement for ER in this mechanism. To verify the requirement for ER in an in vivo system, EGF effects were studied in the uteri of ER knockout (ERKO) mice, which lack functional ER. The EGF-R levels, autophosphorylation, and c-fos induction were observed at equivalent levels in both genotypes indicating that removal of ER did not disrupt the EGF responses. Induction of DNA synthesis and the progesterone receptor gene in the uterus were measured after EGF treatment of both ERKO and wild-type animals. Wild-type mice showed increases of 4.3-fold in DNA synthesis, as well as an increase in PR mRNA after EGF treatment. However, these responses were absent in ERKO mice, confirming that the estrogen-like effects of EGF in the mouse uterus do indeed require the ER. These data conclusively demonstrate the coupling of EGF and ER signaling pathways in the rodent reproductive tract.Estradiol, epidermal growth factor (EGF), and insulin-like growth factors are known mitogens in the rodent reproductive tract (1-3). Estrogen has been shown to increase the uterine levels of both EGF and its receptor (EGF-R) (3-10), suggesting a link between the mitogenic effects of estrogens and growth factors. Furthermore, EGF has been shown to mimic the effects of estrogen in the mouse reproductive tract in terms of increased DNA synthesis and cornification of the vaginal epithelium (11), as well as increased phosphorylation and nuclear retention of the estrogen receptor (ER) (12). When estradiol is administered in conjunction with an EGF-specific antibody, a 60-70% reduction in the hormone-induced proliferation of the epithelium is observed in the mouse uterus and vagina (11). These data indicate a possible role for EGF as a mediator of estrogen action. Further evidence of EGF/ estrogen cross-talk was provided by experiments showing that pre-treatment of mice with the pure anti-estrogen ICI 164,384 greatly diminished the uterine response to EGF (12). Because ICI 164,384 significantly reduces the level of uterine ER (13), these studies suggest the necessity for the ER in the mitogenic actions of EGF. This was supported by studies in Ishikawa cells, a human endometrial carcinoma cell line devoid of ER, in which an estrogen-responsive chloramphenicol acetyltransferase reporter gene could only be activated by EGF after cotransfection with an ER-expression plasmid (14).These studies have led to a model in which EGF plays a role in ER-mediated events in a ligand-independent manner. To gain further insight into the role of the ER in this cross-talk mechanism, EGF studies were carried out in the ER "knockout" (ERKO) mice. In the ERKO, both alleles of the ER gene have b...

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.

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Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis in female rats. A common effect shared by many non-genotoxic hepatic promoters is the stimulation of hyperplastic growth. However, studies by others with several hepatic promoters have shown that following an initial, transient increase in liver growth, continued exposure causes an inhibition in basal and/or induced growth. We have shown that EE also causes an initial, transient increase in hepatocyte proliferation (Carcinogenesis, 7, 2007-20014, 1986). The objective of the investigation reported here was to determine whether chronic EE treatment also becomes inhibitory to basal and/or induced liver growth. Female Lewis rats were treated with EE at 2.5 and 5.0 micrograms/rat/day using time-release tablets. Seven days prior to sacrifice, the rats were implanted with osmotic minipumps containing bromodeoxyuridine (BrdU) to allow the cumulative labeling of replicating hepatocytes. At sacrifice, liver tissue was fixed, sectioned and the percent labeled hepatocyte nuclei determined by immunohistochemistry. The results of these experiments revealed that, as expected, during the first 7 days of treatment, EE increased hepatocyte proliferation. However, after 28 and 42 days of EE treatment, the basal level of liver growth was dramatically inhibited. Thus, hepatocyte nuclear labeling indices, compared to controls, were reduced by 72 and 88% after 28 and 42 days of treatment respectively. An analysis of 125I-labeled EGF binding to isolated liver membranes revealed that EGF receptor levels decreased during the initial period of growth, but had returned to control levels by day 21 when replication had ceased. In another experiment, rats were treated with EE at 5.0 micrograms/rat/day for 21 days; control rats received placebo time-release tablets. At the end of that time, the rats were surgically partially hepatectomized and the level of subsequent regenerative DNA synthesis was determined using [3H]thymidine administered 2 h prior to sacrifice 24, 48, 72 and 96 h later. The results showed that EE caused an inhibition of regenerative growth. While at each time point the level of DNA synthesis in EE-treated rats was not significantly less than in corresponding controls, statistical analysis indicated that overall, EE caused a significant reduction in liver growth. The results of these studies demonstrate that chronic EE treatment leads to the appearance of a mitosuppressed state in the liver which is characterized by reduced cell turnover and decreased growth responsiveness.(ABSTRACT TRUNCATED AT 400 WORDS)

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