Growth hormone and insulin-like growth factor-I: effects on the growth of glioma cell lines.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are known to be mitogens for many types of neoplasms. To investigate their role in tumors of glial origin, in vitro and in vivo experiments were performed with a panel of immortalized glioma cell lines (D54, SNB-19, U87, U251 and U373). Initial analysis for mRNA expression demonstrated the following: GH receptor (5/5 cell lines positive), IGF-I (0/5), IGF-II (0/5), IGF-I receptor (5/5), IGF-II receptor (2/5). Thus, each cell line expressed the necessary receptors to respond to GH and the IGFs but there was no autocrine IGF production by the tumors themselves. IGF-I stimulated mitogenesis as measured by [(3)H]thymidine uptake experiments in U251 and U373 cells. However, when these two IGF-responsive cell lines were xenografted into mice, tumor development and growth rates were not significantly different in GH-deficient animals (despite having IGF-I serum concentrations only 31% of normal). Because our studies were performed in immunocompromised animals, GH or IGF effects on immune surveillance, known to be important from some syngeneic glioma models, would not be likely to contribute to our findings. Nevertheless, these studies are important because they demonstrate that the growth of glioma cell lines in an in vivo environment can remain robust in a GH/IGF-I-deficient setting, even if in vitro experiments indicate that IGF-I is mitogenic.

Corticosteroid-induced inhibition of adrenal androgen production in selected patients with prostate cancer.

OBJECTIVE: To determine the effect of administration of corticosteroids on adrenal androgen production and the serologic markers of prostate cancer. METHODS: Six patients with prostate cancer who had a serum testosterone concentration that exceeded 20 ng/dL despite treatment with medical or surgical castration were treated with dexamethasone. All patients were asymptomatic, but four were demonstrating progressive increases in serum prostate-specific antigen (PSA) concentrations. Dexamethasone, 1 mg at bedtime, was given initially and then increased to 1 mg twice daily if serum testosterone concentrations remained > or =10 ng/dL. The effect of treatment on PSA concentration was monitored. RESULTS: The mean testosterone concentration (and standard error of the mean) was 47.5 +/- 7.9 ng/dL before administration of dexamethasone; this decreased to 5.2 +/- 3.0 ng/dL during therapy (P = 0.002). The effect was rapid (overnight) and sustainable (for 6 months). Although the duration of follow-up is limited, PSA concentrations generally stabilized (23.5 +/- 6.1 ng/mL at baseline in comparison with 15.6 +/- 1.1 ng/mL approximately 2 months after initiation of dexamethasone therapy; P = 0.24). Two patients required 1 mg of dexamethasone twice daily to suppress serum testosterone levels to <10 ng/dL. CONCLUSION: Administration of corticosteroids in a manner opposing the normal circadian glucocorticoid production effectively and rapidly decreases adrenal androgen production in patients with prostate cancer treated with orchiectomy or luteinizing hormone-releasing hormone agonists. This reduction of androgen production was generally associated with a decrease or stabilization of PSA concentrations in all patients with increased PSA levels. Overnight dexamethasone suppression testing is useful in determining the minimal effective dose.

The effects of insulin-like growth factors on tumorigenesis and neoplastic growth.

Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies.