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Women with ovarian cancer have a low survival rate and develop resistance to chemotherapy, so new approaches to treatment are needed. We unexpectedly found administration of a replication-deficient adenovirus containing human growth hormone sequences (AdXGH) was beneficial in a mouse model of human ovarian cancer. Intraperitoneal injections of AdXGH prolonged median survival from a mean of 31 ± 1.2 to 40 ± 1.4 days in immunodeficient SCID mice given SKOV3.ip1 human ovarian cancer cells in the peritoneal cavity. Adenovirus containing human prolactin or del32-71growth hormone sequences had no effect. Repeated injection of growth hormone or implantation of tablets with sustained growth hormone release did not increase survival. Control mice had overlapping tumors throughout the peritoneal cavity and liver and frequent lung metastases 24 days after tumor cell injection. Mice that received two injections of AdXGH had no lung metastases. Mice that received four injections had no lung or liver metastases and peritoneal fibrosis. They did not survive longer than mice that received two injections, but they had enlarged livers with hepatocellular changes, indicating that a limitation of increasing the dose is liver toxicity. [ABSTRACT FROM AUTHOR]

Estimates of the frequency of GH deficiency range from 1:4,000 to 1:10,000. Most cases are sporadic and presumed to be secondary to a wide variety of aetiologies. However, in families with consanguinity, or when a second case occurs in the same family, a genetic cause may be suspected. Given that the patient is isolated GH deficient four distinct familial types of isolated GH deficiencies (IGHD) are well-differentiated on the basis of inheritance, hormonal deficiencies as well as molecular analyses. Two forms are autosomal recessively (IGHD type IA and IB), one is autosomal dominantly (IGHD type II) and one X-linked inherited. In this review, we focus on the secretory pathway of peptide hormones in general and on the possible mechanisms causing IGHD type II in detail. Most interestingly, in IGHD type II the apparently same phenotype of IGHD is caused by distinct GH-1 gene alterations leading to different blockades within the secretory pathway. Furthermore, this type of IGHD, in addition to some other specific GH-1 gene mutations, provides the most important opportunity to shed light on cell-biological mechanisms far beyond its pure description at the DNA/RNA level.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Myoblasts transfected with HB10D insulin secrete more hormone than those transfected with wild-type insulin, as published previously, indicating that production of wild-type insulin is not efficient in these cells. The ability of non-beta-cells to produce insulin was examined in several cell lines. In clones of neuroendocrine GH(4)C(1) cells stably transfected with proinsulin, two thirds of (35)S-proinsulin was degraded within 3 h of synthesis, whereas (35)S-prolactin was stable. In transiently transfected neuroendocrine AtT20 cells, half of (35)S-proinsulin was degraded within 3 h after synthesis, whereas (35)S-GH was stable. In transiently transfected fibroblast COS cells, (35)S-proinsulin was stable for longer, but less than 10% was secreted 8 h after synthesis. Proinsulin formed a concentrated patch detected by immunofluorescence in transfected cells that did not colocalize with calreticulin or BiP, markers for the endoplasmic reticulum, but did colocalize with membrin, a marker for the cis-medial Golgi complex. Proinsulin formed a Lubrol-insoluble aggregate within 30 min after synthesis in non-beta-cells but not in INS-1E cells, a beta-cell line that normally produces insulin. More than 45% of (35)S-HB10D proinsulin was secreted from COS cells 3 h after synthesis, and this mutant formed less Lubrol-insoluble aggregate in the cells than did wild-type hormone. These results indicate that proinsulin production from these non-beta-cells is not efficient and that proinsulin aggregates in their secretory pathways. Factors in the environment of the secretory pathway of beta-cells may prevent aggregation of proinsulin to allow efficient production.

Estimates of the frequency of growth hormone deficiency (GHD) range from 1:4,000 to 1:10,000. Most cases are sporadic and presumed to be secondary to one of a wide variety of causes. However, in families with consanguinity, or when a second case occurs in the same family, a genetic cause may be suspected. Four distinct familial types of isolated GHD (IGHD) have been well differentiated on the basis of inheritance, hormonal deficiencies, and molecular analyses. Two forms are inherited autosomal recessively (IGHD type IA and IB); one is inherited autosomal dominantly (IGHD type II); and one is inherited in an X-linked manner. This review focuses on the secretory pathway of GH and the possible mechanisms causing IGHD type II. In IGHD type II, the apparently same phenotype results from several distinct GH-1 gene alterations leading to different blockades within the secretory pathway. This type of IGHD, in addition to some other specific GH-1 gene mutations, provides the most important opportunity for shedding light on cellular biological mechanisms beyond its description at the DNA/RNA level.