SERUM LEVELS OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 IN BENIGN AND MALIGNANT BREAST DISEASE

Background : The insulin-like growth factors IGF-I and IGF-II and their major binding protein IGFBP-3 influence the growth of breast cancer cells in vitro. Some benign non-breast tumours appear to be associated with increased serum IGFBP-3 levels which would tend to reduce bioactive-free IGF concentrations. The present study investigates whether this pattern also occurs in neoplastic breast disease. Methods : Serum IGF-I, IGF-II and IGFBP-3 were measured by specific radioassay in 12 women with benign breast disease, 31 patients with breast cancer and in age-matched controls. Results : The mean (± SD) serum IGFBP-3 concentration was higher in benign breast disease (3.6 ± 0.7 mg/L) than in controls (2.7 ± 0.6 mg/L) or in breast cancer patients (2.7 ± 0.5 mg/L) (P = 0.001). Serum IGF-I and IGF-II levels were not significantly different among the groups. However, the index of free unbound IGF measured as the molar ratio of IGF-I plus IGF-II divided by IGFBP-3 was significantly lower in benign breast disease than in the other subjects. Conclusions : Either the production or clearance of IGFBP-3 is altered in benign breast disease so that there is less free IGF available to cells. This may serve to protect against malignant transformation in patients with benign breast disorders.     

Insulin-like growth factors and risk of benign prostatic hyperplasia

BACKGROUND: Insulin-like growth factors (IGFs) have potent growth mitogenic and anti-apoptotic effects on prostate tissue, whereas IGF binding proteins (IGFBPs) inhibit growth of prostatic tissue. The IGF axis has been implicated in prostate cancer risk, but its role in benign prostatic hyperplasia (BPH) is unclear. METHODS: Plasma levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were determined from the fasting bloods of 206 BPH cases admitted for treatment and 306 randomly selected population controls in Shanghai, China. RESULTS: Relative to the lowest tertile, men in the highest tertile of IGF-I levels had a significantly elevated risk of BPH (odds ratio [OR] = 2.80, 95% confidence interval [95% CI] = 1.60-4.92; P(trend) < 0.001). Results for IGF-I were more pronounced after adjustment for serum androgens. In contrast, men in the highest IGFBP-3 tertile had a significantly reduced risk (OR = 0.40; 95% CI = 0.23-0.69; P(trend) < 0.001). No associations of BPH with IGF-II and IGFBP-1 were observed. CONCLUSION: As has been previously observed for prostate cancer, we found that IGF-I and IGFBP-3 are associated with BPH risk in China. Further investigation is needed to elucidate the role of the IGF axis in BPH etiology.     

Serum measurements of testosterone, insulin-like growth factor 1, and insulin-like growth factor binding protein-3 in the diagnosis of prostate cancer among Korean men

Aim： To investigate the relationships of serum testosterone, insulin-like growth factor （IGF）- 1 and IGF-binding protein （IGFBP）-3 levels with prostate cancer risk and also with known prognostic parameters of prostate cancer in Korean men who received radical retropubic prostatectomy （RRP） for clinically-localized prostate cancer. Methods： Serum levels of total testosterone, free testosterone, IGF-1 and IGFBP-3 were determined in 592 patients who subsequently received prostate biopsy. Results were compared between patients who eventually received RRP for prostate cancer （n = 159） and those who were not diagnosed with prostate cancer from biopsy （control group, n = 433）. Among the prostate cancer only patients, serum hormonal levels obtained were analyzed in relation to serum prostate specific antigen （PSA）, pathological T stage and pathological Gleason score. Results： Prostate cancer patients and the control group demon- strated no significant differences regarding serum levels of total testosterone, free testosterone, IGF-I and IGFBP-3 across the different age groups. Among the cancer only patients, no significant associations were observed for serum levels of total testosterone, free testosterone, IGF-1 and IGFBP-3 levels with pathological T stage, pathological Oleason score and preoperative PSA. Conclusion： Our data indicate that simple quantifications of serum testosterone and IGF-1 along with IGFBP-3 levels might not provide useful clinical information in the diagnosis of clinically localized prostate cancer in Korean men. Also, our results suggest that serum levels of testosterone, IGF-1 and IGFBP-3 might not be significantly associated with known prognostic factors of clinically localized prostate cancer in Korean men. （Asian J Androl 2008 Mar; 10： 207-213）     

Regulation of DUI45 human prostate cancer cell proliferation by insulin-like growth factors and its interaction with the epidermal growth factor autocrine loop

The DU145 human prostate cancer cell line was shown to possess type I insulin-like growth factor receptors (IGFR). The addition of either IGF-I or IGF-II, but not insulin, to serum-free culture medium increases the rate of thymidine incorporation by the cells, a response which is suppressed by specific blockade of the previously described epidermal growth factor (EGF) autocrine growth regulatory loop. The DU145 cells secrete into conditional medium a specific IGF-binding protein (IGFBP) precipitated by an antibody to IGFBP-1, and whose secretion is also suppressed by interruption of the EGF autocrine loop. This IGFBP may modulate the bioactivity of IGFs arising from endocrine or paracrine sources in vivo. After removal of IGFBPs from the conditioned medium, no secretion of either IGF-I or IGF-II by this prostate cancer cell line is detected by radioimmunoassay and radioreceptor assay, respectively. © 1994 Wiley-Liss, Inc.     

Growth hormone/insulin-like growth factor system in children with chronic renal failure

Disturbances of the somatotropic hormone axis play an important pathogenic role in growth retardation and catabolism in children with chronic renal failure (CRF). The apparent discrepancy between normal or elevated growth hormone (GH) levels and diminished longitudinal growth in CRF has led to the concept of GH insensitivity, which is caused by multiple alterations in the distal components of the somatotropic hormone axis. Serum levels of IGF-I and IGF-II are normal in preterminal CRF, while in end-stage renal disease (ESRD) IGF-I levels are slightly decreased and IGF-II levels slightly increased. In view of the prevailing elevated GH levels in ESRD, these serum IGF-I levels appear inadequately low. Indeed, there is both clinical and experimental evidence for decreased hepatic production of IGF-I in CRF. This hepatic insensitivity to the action of GH may be partly the consequence of reduced GH receptor expression in liver tissue and partly a consequence of disturbed GH receptor signaling. The actions and metabolism of IGFs are modulated by specific high-affinity IGFBPs. CRF serum has an IGF-binding capacity that is increased by seven- to tenfold, leading to decreased IGF bioactivity of CRF serum despite normal total IGF levels. Serum levels of intact IGFBP-1, -2, -4, -6 and low molecular weight fragments of IGFBP-3 are elevated in CRF serum in relation to the degree of renal dysfunction, whereas serum levels of intact IGFBP-3 are normal. Levels of immunoreactive IGFBP-5 are not altered in CRF serum, but the majority of IGFBP-5 is fragmented. Decreased renal filtration and increased hepatic production of IGFBP-1 and -2 both contribute to high levels of serum IGFBP. Experimental and clinical evidence suggests that these excessive high-affinity IGFBPs in CRF serum inhibit IGF action in growth plate chondrocytes by competition with the type 1 IGF receptor for IGF binding. These data indicate that growth failure in CRF is mainly due to functional IGF deficiency. Combined therapy with rhGH and rhIGF-I is therefore a logical approach.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 for prostate cancer detection in patients undergoing prostate biopsy

PURPOSE: Laboratory and epidemiological studies suggest that high circulating insulin-like growth factor (IGF)-1 and low IGF binding protein-3 are associated with increased prostate cancer risk. However, the usefulness of serum IGF-1 or IGF binding protein-3 for predicting pathology results in men undergoing prostate biopsy is unclear. We examined the relationships of serum IGF-1, IGF binding protein-3 and the results of prostate biopsy. MATERIALS AND METHODS: A total of 652 consecutive patients with elevated serum prostate specific antigen (PSA) or abnormal digital rectal examination who were referred for transrectal ultrasound sextant prostate needle biopsy underwent blood sampling before biopsy. PSA, free PSA, IGF-1 and IGF binding protein-3 were measured. There were 244 men (37.4%) with cancer and 408 controls with benign conditions. RESULTS: Mean IGF-1 plus or minus SD in the cancer and control groups was 176.1 +/- 58.3 and 178.7 +/- 54.7 ng./ml., respectively (p = 0.57). Mean IGF binding protein-3 in the cancer and control groups was 2,724 +/- 647 and 2,673 +/- 589 ng./ml., respectively (p = 0.3). Adjustment for age and PSA showed significantly lower IGF-1 in cancer cases, while IGF binding protein-3 was not significant. ROC values were significantly higher for free-to-total PSA and PSA than for crude and age adjusted IGF-1 and IGF binding protein-3. CONCLUSIONS: Our data indicate that serum IGF-1 or IGF binding protein-3 does not predict the results of prostate biopsy in men with elevated PSA or abnormal digital rectal examination. This finding implies that while there is evidence that the IGF-1 level is a risk factor for prostate cancer, neither IGF-1 nor IGF binding protein-3 can be used as a tumor marker for this disease.     

Serum insulin-like growth factors and their binding proteins in children with end-stage renal disease

Serum levels of insulin-like growth factor-I (IGF-I), IGF-II, and IGF binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured in 54 children with end-stage renal disease (ESRD). The results were compared with their respective age-dependent normal ranges. IGFs and IGFBPs were quantified by specific radioimmunoassay. Serum IGF-I in children with ESRD tended to cluster in the low-normal range. Mean age-related serum IGF-I levels were slightly, but significantly decreased (–1.08±0.17 SDS). In view of the prevailing elevated growth hormone levels in ESRD, these serum, IGF-I levels must be interpreted as inadequately low. In contrast to IGF-I, individual serum IGF-II levels were either in the uppernormal range or clearly elevated. Mean age-related IGF-II (1.09±0.15 SDS) was lightly, but significantly elevated. Mean age-related IGFBP-1 serum levels (2.20±0.10 SDS) were moderately increased, while mean age-related serum IGFBP-2 (5.65±0.36) and IGFBP-3 levels (3.60±0.19) were markedly elevated. Affinity cross-linking of¹²⁵iodine-IGF-II to sera from patients with ESRD and immunoprecipitation with a specific antiserum showed that low molecular weight IGFBP-3 fragments in ESRD serum are capable of binding IGF. In patients with ESRD, a rapid and persistent decline of immunoreactive IGFBP-3 in response to restoration of renal function by renal transplantation was observed. This finding indicates that renal dysfunction contributes to high immunoreactive, IGFBP-3 levels in ESRD. In conclusion, the imbalance between normal total IGF levels and the excess of IGFBPs in ESRD is likely to play a role in growth failure in these children.     

Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy.

BACKGROUND: Formation of advanced glycation end-products (AGEs) has been implicated in the development of diabetic complications. As well as causing changes in structural proteins, AGEs may also alter gene expression of growth factors in vitro. The insulin-like growth factor (IGF) system, including IGF-I and modulatory IGF binding proteins (IGFBPs), is dysregulated during the development of diabetic nephropathy. METHODS: Quantitative in situ hybridization histochemistry and immunohistochemistry were used to determine the effects of aminoguanidine, an inhibitor of AGE formation, on gene expression of IGF-I and IGFBPs in kidneys of long-term (8 months duration) streptozotocin-diabetic rats. RESULTS: Diabetes was associated with increased renal expression of IGFBP-1 mRNA (diabetes 824+/-236 vs control 264+/-76 arbitrary units, P<0.01) and decreased expression of mRNAs for IGF-I (diabetes 39+/-7 vs control 185+/-23 arbitrary units, P<0.001) and IGFBP-4 (diabetes 139+/-25 vs control 383+/-54 arbitrary units, P<0.001). Aminoguanidine treatment inhibited the effects of diabetes on renal expression of mRNA for IGF-I, IGFBP-1 and IGFBP-4. The changes in IGF-I and IGFBP-1 mRNA levels were reflected in altered peptide levels. In diabetic kidneys, IGFBP-5 mRNA levels were slightly decreased to 75% of control levels (P<0.01); aminoguanidine had no effect on IGFBP-5 mRNA levels. CONCLUSIONS: These results suggest that amelioration of changes in the renal IGF system by aminoguanidine may contribute to the renoprotective effects of the latter, which have been previously shown to inhibit structural and functional aspects of diabetic nephropathy in the rat.     

Expression of osteotropic growth factors and growth hormone receptor in a canine distraction osteogenesis model

Osteotropic growth factors play an important role in bone metabolism. Nevertheless, knowledge about their expression in relation to distraction osteogenesis remains limited. The aim of the present study was to determine the expression of growth hormone (GH), growth hormone receptor (GHR), insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), and bone morphogenetic protein 2 (BMP-2) in distraction-induced bone regeneration. Expression of these factors was assessed during the consolidation phase, comparing distraction osteogenesis with osteotomy-induced bone formation. Real-time PCR was performed as a semiquantitative measurement of mRNA, and the relative expression levels of these factors were determined. In addition, plasma GH profiles and plasma concentrations of IGF-I, IGF-II, and insulin-like growth factor-binding protein 4 and -6 (IGFBP-4 and -6) were measured to assess their potential systemic role during bone formation. Expression of GHR, IGF-I, and BMP-2 had significantly increased in comparison with the expression of these factors in mature bone. Expression of GHR was significantly higher in distraction-induced bone regenerate than in osteotomy-induced bone. No significant differences were found for the expression of IGF-I and BMP-2 between distraction and osteotomy. Plasma concentrations of GH, IGF-I, IGF-II, IGFBP-4, and IGFBP-6 did not demonstrate any significant differences between treatment groups and controls. Upregulation of GHR expression in distraction osteogenesis may enhance sensitivity to endogenous systemic GH and thus promote consolidation of the regenerated bone. Changes in the systemic osteotropic growth factors GH, IGF-I, IGF-II, IGFBP-4, and IGFBP-6 do not seem to be of importance during distraction osteogenesis.     

Implications of insulin-like growth factor-I for prostate cancer therapies

In the last decade, abundant evidence has suggested that the insulin-like growth factor (IGF) family comprises a multi-component network of molecules involved in the regulation of both physiological and pathological growth processes in the prostate. The IGF axis plays an important role in the tumorigenesis and neoplastic growth of prostate cancer. Epidemiological observations indicate that circulating IGF-I levels are positively associated with increased risk of prostate cancer. Activation of IGF-I receptor (IGF-IR) by IGF-I has mitogenic and anti-apoptotic effects on normal and malignant prostate cells. Therapeutic alternatives in men with progressive prostate cancer after androgen ablation are very limited and more effective therapies are needed for such patients. Inactivation of the IGF-I axis represents a potential target to treat androgen-independent prostate cancer. This review addresses epidemiological studies of IGF-I and therapeutic strategies including reduction of IGF-I levels, inhibition of IGF-IR and the signaling mechanisms involved.     

Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer

PURPOSE: We determine whether the nadir prostate specific antigen (PSA) level after hormone therapy can be used to predict the progression to hormone refractory prostate cancer. MATERIALS AND METHODS: We reviewed the progressive status and survival of 177 patients with stage C or D prostate cancer who had received hormone therapy at our institution. The overall survival rate, incidence of progression to hormone refractory prostate cancer and interval until progression were analyzed with reference to the nadir PSA level. Multiple regression analysis was used to analyze the predictive factors for progression to hormone refractory prostate cancer, and the relative efficacy of the nadir PSA level in predicting progression was evaluated by receiver operating characteristics analysis. RESULTS: Median followup was 39 months (range 3 to 89) and 85.4% of patients (151) responded to treatment, of whom 77.5% (117) had progression to hormone refractory prostate cancer. Median time until nadir PSA levels were reached after hormone therapy was 8.1 months and median time until hormone refractory prostate cancer was 24.0 months. Nadir PSA levels were less than 0.2 ng./ml. in 31% of respondents, 0.2 to 1.0 ng./ml. in 23%, 1.1 to 10 ng./ml. in 42% and greater than 10 ng./ml. in 5%. These groups had similar clinicopathological characteristics. Nadir PSA levels correlated significantly with pretreatment PSA levels, Gleason scores and progression to hormone refractory prostate cancer (p = 0.01, p <0.01 and p <0.001, respectively), and inversely correlated with the interval to the establishment of hormone refractory prostate cancer (r = -0.465, p <0.05). By univariate analysis bone metastasis, nadir PSA, PSA at 6 months after treatment and pretreatment PSA were significantly associated with progression to hormone refractory prostate cancer. Only the nadir PSA was calculated to be an independent factor by multivariate analysis. Receiver operating characteristics analysis indicated that nadir PSA predicted progression to hormone refractory prostate cancer after 2 years with an accuracy of 86.2%. With the lower limit of the nadir PSA level set to 1.1 ng./ml., sensitivity was 80.3% and specificity was 83.8%, and these levels were deemed the most appropriate. Furthermore, nadir PSA after hormone therapy was an independent prognosticator for survival, as were initial levels of hemoglobin and alkaline phosphatase. CONCLUSIONS: The nadir PSA level after hormone therapy may be the most accurate factor predicting the progression to hormone refractory prostate cancer and is an independent prognostic factor for survival. Furthermore, a lower limit for the nadir PSA level of 1.1 ng./ml. gives optimal sensitivity and specificity.     

Insulin-like growth factor binding protein 2: an androgen-dependent predictor of prostate cancer survival

BACKGROUND: Evidence suggests that the insulin-like growth factor (IGF) family is important in prostate cancer. We evaluate the ability of IGF markers to predict biochemical recurrence-free survival (bRFS) following radical prostatectomy (RRP). METHODS: Preoperative sera from 141 patients undergoing RRP were analyzed for IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3. A multivariate Cox model was created to assess the ability of these markers to predict bRFS. Preoperative covariables included: biopsy Gleason score, clinical TNM stage, serum PSA and neoadjuvant hormonotherapy. Kaplan-Meier curves were stratifying by IGF cutpoints (determined by ROC analysis) and hormonotherapy status. RESULTS: Average follow-up was 6.92 years, median PSA was 6.9 ng/ml and 85.1% of patients had cT2NxM0 disease. 49 patients experienced a PSA failure. Average levels of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 were 156.5 ng/ml, 48.1 ng/ml, 396.8 ng/ml and 3303.7 ng/ml, respectively. IGFBP-2 was an independent predictor of PSA failure. Patients treated with neoadjuvant ADT (n=71) and whom had high IGFBP-2 levels experienced a 5-year bRFS that was better than those with low IGFBP-2 levels (77.7% vs. 53.3%). Patients without neoadjuvant ADT whom had high IGFBP-2 levels had a 5-year bRFS that was worse than those with low IGFBP-2 levels (64.5% vs. 82.7%). CONCLUSIONS: Preoperative IGFBP-2 predicts post-radical prostatectomy bRFS and is independent of stage, Gleason score and PSA. Increased IGFBP-2 is associated with better survival in patients with neoadjuvant hormonotherapy but worse survival in those without, suggesting a dramatic switch in function of this protein dependent on the presence or absence of androgens.     

Inhibition of proliferation of PC-3 human prostate cancer by antagonists of growth hormone-releasing hormone: lack of correlation with the levels of serum IGF-I and expression of tumoral IGF-II and vascular endothelial growth factor

BACKGROUND: Antagonists of growth hormone-releasing hormone (GHRH) such as JV-1-38 can inhibit androgen-independent prostate cancer directly by several mechanisms and/or indirectly by suppressing growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. To shed more light on the mechanisms involved, the effects of JV-1-38 on PC-3 human prostate cancer were compared with those of somatostatin analog RC-160 in vivo and in vitro. METHODS: Nude mice bearing PC-3 tumors received JV-1-38 (20 microg), RC-160 (50 microg) or a combination of JV-1-38 and RC-160. The concentration of IGF-I in serum and the expression of mRNA for IGF-II and vascular endothelial growth factor (VEGF) in tumor tissue were investigated. RESULTS: In vivo, the final volume of PC-3 tumors treated with JV-1-38 was significantly lowered by 49% (P < 0.01), whereas RC-160 exerted only 30% inhibition (NS), compared with controls. Combined use of both compounds augmented tumor inhibition to 63% (P < 0.001). Serum IGF-I levels were decreased only in mice treated with RC-160. JV-1-38 suppressed mRNA for IGF-II in PC-3 tumors by 42%, whereas RC-160 alone or in combination with JV-1-38 caused a 65% reduction. JV-1-38 and RC-160 used as single drugs decreased the expression of VEGF by 50%, and their combination caused a 63% reduction. In vitro, JV-1-38 inhibited the proliferation of PC-3 cells by 39%. This effect could be partially reversed by addition of IGF-I to the serum-free medium. RC-160 alone did not affect the PC-3 cell growth in vitro, but in combination with JV-1-38 it augmented the antiproliferative effect of the GH-RH antagonist to 72%. Exposure to JV-1-38 in vitro reduced the expression of mRNA for IGF-II in PC-3 cells by 55% but did not change VEGF mRNA levels, whereas RC-160 had no effect. CONCLUSIONS: The antiproliferative effect of JV-1-38 was not associated with the suppression of serum IGF-I and was only partially correlated with the expression of IGF-II and VEGF in PC-3 tumors, suggesting that other mechanisms play a role in the antitumor action of GHRH antagonists. Nevertheless, the stronger inhibition of tumor growth after combined treatment with JV-1-38 and RC-160 indicates that the interference with multiple local stimulatory factors leads to an enhanced inhibition of prostate cancer.     

Serum levels of insulin-like growth factor binding protein-3 in benign and malignant breast disease.

BACKGROUND: The insulin-like growth factors IGF-I and IGF-II and their major binding protein IGFBP-3 influence the growth of breast cancer cells in vitro. Some benign non-breast tumours appear to be associated with increased serum IGFBP-3 levels which would tend to reduce bioactive-free IGF concentrations. The present study investigates whether this pattern also occurs in neoplastic breast disease. METHODS: Serum IGF-I, IGF-II and IGFBP-3 were measured by specific radioassay in 12 women with benign breast disease, 31 patients with breast cancer and in age-matched controls. RESULTS: The mean (+/-SD) serum IGFBP-3 concentration was higher in benign breast disease (3.6+/-0.7 mg/L) than in controls (2.7+/-0.6 mg/L) or in breast cancer patients (2.7+/-0.5 mg/L) (P = 0.001). Serum IGF-I and IGF-II levels were not significantly different among the groups. However, the index of free unbound IGF measured as the molar ratio of IGF-I plus IGF-II divided by IGFBP-3 was significantly lower in benign breast disease than in the other subjects. CONCLUSIONS: Either the production or clearance of IGFBP-3 is altered in benign breast disease so that there is less free IGF available to cells. This may serve to protect against malignant transformation in patients with benign breast disorders.     

Haemodialysis with the biocompatible high permeability AN-69 membrane does not alter plasma insulin-like growth factor-I and insulin-like growth factor binding protein-3.

BACKGROUND: Insulin-like growth factor-I (IGF-I) bioactivity has been reported to be decreased in maintenance haemodialysis patients and this may affect their nutritional status. Clearances of IGF-I and its binding proteins (IGFBPs) during haemodialysis sessions using a high permeability biocompatible membrane are unknown. METHODS: Five well nourished, non-diabetic adult patients were studied during one 4-h morning haemodialysis treatment using the high permeability biocompatible AN-69 dialyser. Blood was collected at the arterial and venous ports of the dialyser at 0, 1, 2 and 4 h of dialysis for haematocrit, plasma IGF-I, IGFBP-3 and insulin measurements. IGF-I, IGFBP-3 and insulin concentrations were adjusted for haemoconcentration before comparisons were made. RESULTS: At the beginning of the dialysis session, plasma IGF-I, IGFBP-3 and insulin levels were within the normal range (297 +/- 47 ng/ml (mean+/-SEM), 4.3 +/- 0.6 microg/ml and 11.8 +/- 3.4 microIU/ml, respectively). During the session, insulin tended to be cleared through the dialyser, whereas plasma IGF-I and IGFBP-3 values did not vary significantly. CONCLUSION: Dialysis with the high permeability AN69 membrane did not alter the main blood compounds of the IGF system in well nourished chronic haemodialysis patients, and it is unlikely that the malnutrition frequently observed in such patients would result from alterations of the IGF system during haemodialysis.     

Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways

BACKGROUND: In view of the involvement of various neuropeptides and growth factors in the progression of androgen-independent prostate cancer, we investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone or in combination with an antagonist of bombesin/gastrin-releasing peptide (BN/GRP) on PC-3 human prostate cancers. METHODS: Nude mice implanted with PC-3 tumors received GHRH antagonists MZ-5-156 or JV-1-38, each at 20 microgram/day s.c. In experiment 2, treatment consisted of daily injections of JV-1-38 (20 microgram), BN/GRP antagonist RC-3940-II (10 microgram), or a combination of JV-1-38 and RC-3940-II. Serum IGF-I levels, expression of mRNA for IGF-II, and characteristics of BN/GRP and EGF receptors in tumor tissue were investigated. RESULTS: JV-1-38 induced a greater inhibition of tumor growth and suppression of IGF-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum IGF-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparable reduction in tumor volume (65% and 61%, respectively), but a combination of both antagonists augmented tumor inhibition to 75%. Combined treatment with JV-1-38 and RC-3940-II also led to a greater suppression of IGF-II mRNA (92%), as compared with JV-1-38 (72%) or RC-3940-II (77%). Serum IGF-I concentration was lowered only in mice treated with JV-1-38, while the downregulation of BN/GRP and EGF receptors was specific for groups receiving RC-3940-II. CONCLUSIONS: The inhibitory effects of GHRH antagonists on PC-3 human androgen-independent prostate cancer can be potentiated by concomitant use of BN/GRP antagonists. The combination of both types of analogs apparently interferes with both IGF and bombesin/EGF pathways, and might be clinically useful for the management of androgen-independent prostate cancer.     

Increased apoptosis and decreased proliferation of colorectal cancer cells using insulin-like growth factor binding protein-4 gene delivered locally by gene transfer

OBJECTIVE: Insulin-like growth factor (IGF)-I induces proliferation of transformed cells. Its binding proteins (IGFBP) are involved in local regulation of IGF. This study assessed the effects of overexpression of IGFBP-4 on the development of cancer in vivo. METHOD: Nude mice were subcutaneously inoculated with HT-29 colorectal cancer cells (3 x 10(6)). When the tumour became visible (1 week after inoculation), animals received either 150 microg of mammalian expression vector containing IGFBP-4 cDNA or vector alone (n = 6 each) by peritumoural injection. Tumour size was measured during the growth. After 3 weeks of IGFBP-4 induction, animals were killed and tumour tissue samples were collected for examining the level of IGFBP-4 expression. Tumour mitotic activities were determined by counting numbers of mitotic cells on the tissue section. Apoptosis was investigated by terminal deoxynucleotidyl transferase-mediated dUDP nick end labelling assay. RESULTS: Following IGFBP-4 treatment, tumour showed large necrotic areas, significantly increased numbers of apoptotic cells (36.67 +/- 7.36 vs 7.07 +/- 1.91, P < 0.01 vs control), decreased cells undergoing mitosis (2.31 +/- 0.32 vs 3.61 +/- 0.27, P < 0.01 vs control) and higher expression of IGFBP-4 (P < 0.05 vs control). CONCLUSION: IGFBP-4 gene transfer increased apoptosis and decreased mitosis, but tumour volume was not significantly altered possibly due to cellular debris filling the centre of tumours.     

Insulin-like growth factors and their binding proteins in prostate cancer: Cause or consequence?☆

Insulin-like growth factors (IGFs) promote growth and survival of many types of tumor cells. Epidemiologic studies have implicated carcinogenesis with high levels of IGFs in circulation or in tissues. The levels of IGF binding proteins (IGFBPs) have been associated with reduced risk for prostate and other cancers. Experimental studies have implicated high levels of IGF-I directly and IGFBP-3 inversely in prostate cancer growth, survival, and progression. However, recent evidence suggests a much weaker association of IGF-I with prostate cancer development and a stronger antagonistic association of IGFBP-3 with prostate cancer progression. Considering the clonal heterogeneity and unpredictable progression pattern of prostate cancer, the role of any single growth factor or its regulator (IGFBP) as a single determining factor is limited. This review is a critical appraisal of the role of IGFs, IGFBP, and IGF-I receptor (the IGF axis) in both experimental and clinical prostate cancer genesis and progression.