Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells.

We investigated the effects of all-trans retinoic acid (ATRA) and fenretinide (4-HPR) on c-erbB-2 expression in SK-BR-3, BT-474 and MCF-7 breast cancer cells and on the growth, differentiation, apoptosis and cisplatin (CDDP) sensitivity of SK-BR-3 cells. It has been reported that oestrogen inhibits c-erbB-2 in oestrogen receptor-positive breast cancer cells. Using ELISA, Western and Northern analysis we have demonstrated that ATRA and 4-HPR exert similar effects down-regulating c-erbB-2 protein and mRNA in c-erbB-2-overexpressing SK-BR-3 and BT-474 and in normally expressing MCF-7 cells. Both retinoids inhibit SK-BR-3 cell growth. ATRA induces cellular enlargement and flattening, suggesting epithelial differentiation. 4-HPR causes nuclear and cytoplasmic condensation, DNA fragmentation and externalization of phosphatidylserine, indicating apoptosis. c-erbB-2 expression/activity has been linked to sensitivity against CDDP. Therefore, combinations of ATRA or 4-HPR with CDDP were tested for their anti-proliferative activity. Retinoid-conditioned cells were either exposed to retinoid and CDDP (schedule I, ''continuous retinoid treatment'') or to CDDP alone (schedule II, ''retinoid pretreatment''). This retinoid-conditioning followed by CDDP +/- retinoid yields stronger growth inhibition compared with unconditioned cells, which were exposed to CDDP +/- retinoid (schedule III, ''no retinoid pretreatment''). The inefficacy of schedule III indicates that retinoid-conditioning is essential for the improvement of the antiproliferative effect. The interactions in schedules I and II are synergistic for ATRA and CDDP, but slightly antagonistic for 4-HPR and CDDR However, 4-HPR + CDDP is more effective in growth inhibition than each drug alone.     

Relationships between plasma insulin-like growth factor-I and insulin-like growth factor binding protein-3 and second breast cancer risk in a prevention trial of fenretinide.

PURPOSE: High circulating insulin-like growth factor (IGF) -I and/or low IGF-binding protein (IGFBP) -3 levels are associated with increased breast cancer risk in unaffected premenopausal women. We determined whether IGF-I and IGFBP-3 predict second breast cancer risk, and whether their changes during fenretinide explain observed reductions in second breast cancer in women 相似文献   

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.

BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.     

The insulin-like growth factor system as a target in breast cancer

Summary Evidence from several experimental systems has shown that the insulin-like growth factors (IGFs) can stimulate breast cancer proliferation. Since IGF action is mediated by interaction with specific cell surface receptors, interruption of these signalling pathways could result in inhibition of cellular growth. In all extracellular fluids, the IGFs are associated with high affinity binding proteins, the IGFBPs. Although the function of each IGFBP is not known, it is clear that under certain circumstances the IGFBPs can bind the IGFs and prevent receptor activation, and thus might have a role in a targeted approach to breast cancer therapy. Here we present our studies using IGFBP-1 to inhibit growth of the breast cancer cell line MCF-7.     

Effect of fenretinide on bone mineral density and metabolism in women with early breast cancer

Prolonged administration of natural or synthetic retinoids has been associated with significant skeletal abnormalities, including osteoporosis. We studied the effects of the synthetic retinoid fenretinide (N-4-hydroxyphenylretinamide, or 4-HPR) administered for a mean of 40 months on bone mineral density and metabolism in 66 consecutive women with early breast cancer belonging to a secondary prevention trial. The mean (±SD) bone mineral density at the distal and ultradistal forearm were, respectively, 0.61±0.08 and 0.30±0.05 g/cm2 in 33 treated women and 0.62±0.07 and 0.29±0.07 g/cm2 in 33 control women (p = ns for both). Also, no significant difference was observed in markers of bone formation such as bone alkaline phosphatase and osteocalcin, nor in urinary bone resorption markers such as calcium, hydroxyproline, and type I bone collagen cross-linked N-telopeptide (NTx). However, a border-line higher excretion of urinary calcium and NTx was found in the 4-HPR group after adjustment for menopausal status. We conclude that prolonged administration of 4-HPR is not associated with significant alterations of bone mineral density of the forearm. However, a trend towards an increase in bone resorption markers suggests the need for further assessment at different skeletal sites.     

Tamoxifen and fenretinide in women with metastatic breast cancer

Background: Tamoxifen and fenretinide combination therapy has been shown to be an active treatment regimen in metastatic breast cancer patients. This pilot study sought to determine whether the addition of fenretinide to tamoxifen would be associated with antitumor activity in metastatic breast cancer patients who had been previously treated with tamoxifen or who had hormone receptor negative disease. The effect of this therapy on circulating plasma transforming growth factorbeta (TGF) levels and serum lipids was also examined.Patientsand Methods: Thirtyone patients were treated with tamoxifen (20mg po daily), and fenretinide (400mg po daily with a 3day drug holiday each month). Plasma TGF testing was performed using isoform specific sandwich ELISA.Results: Twenty four of the 31 patients were evaluable for an antitumor response including 14 estrogen receptor (ER) positive patients who had failed prior tamoxifen therapy, seven ERnegative patients, and three hormone therapy naive ERpositive patients. There were no objective antitumor responses; three patients had stable disease for 8, 8, and 24 months. Five patients (16%) discontinued therapy for toxicity (one for grade 3 skin rash and four for abnormal dark adaptation). There was a statistically significant decrease in total cholesterol (median change per patient of –13.5mg/dl; p=0.049, a 6.5% decrease), and an increase in HDL levels (median change per patient of +18mg/dl, p=0.0001, a 35% increase) with tamoxifen and fenretinide therapy.TGF-1 plasma levels were normal in 26 of 28 patients, and no changes in these levels post-treatment were demonstrated.Conclusions: Tamoxifen and fenretinide therapy is not an active combination in ER negative metastatic breast cancer or in patients whose disease has progressed on tamoxifen. This combination had a beneficial effect on total serum cholesterol and HDL levels with no associated rise in serum triglyceride levels. The 400mg dose of fenretinide was associated with symptomatic nyctalopia in one-third of patients making it an unsuitable dose for use in breast cancer prevention studies.     

Alterations in the insulin-like growth factor system during treatment with diethylstilboestrol in patients with metastatic breast cancer.

Alterations in the insulin-like growth factor (IGF)-system were evaluated in 16 patients treated with diethylstilboestrol 5 mg 3 times daily. Fasting blood samples were obtained before treatment and after 2 weeks, 1 month and/or 2-3 months on therapy. Insulin-like growth factor (IGF)-I, IGF-II, free IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3 were measured by radioimmuno-/immunoradiometric-assays. All samples were subjected to Western ligand blotting as well as immunoblotting for IGFBP-3. We observed a significant decrease (percentage of pretreatment levels with 95 confidence intervals of the mean) in IGF-I [2 weeks 63% (49-79); 1 month 56% (44-73); 2-3 months 66% (53-82)], IGF-II [2 weeks 67% (56-80); 1 month 60% (52-68); 2-3 months 64% (55-75)], free IGF-I [2 weeks 29% (19-42); 1 month 25% (18-36); 2-3 months 31% (21-46)], IGFBP-2 [2 weeks 53% (18-156); 1 month 69% (61-78); 2-3 months 66% (57-78)], IGFBP-3 [2 weeks 74% (63-85); 1 month 69% (62-76); 2-3 months 71% (63-80)], as well as IGFBP-3 protease activity [2 weeks 71% (54-95); 1 month 78% (64-94); 2-3 months 71% (54-93)]. Contrary, the plasma levels (percentage of pretreatment levels with 95 confidence intervals of the mean) of IGFBP-1 [2 weeks 250% (127-495); 1 month 173% (138-542); 2-3 months 273% (146-510)] and IGFBP-4 [2 weeks 146% (112-192); 1 month 140% (116-169); 2-3 months 150% (114-198)] increased significantly. While this study confirms previous observations during treatment with oral oestrogens in substitution doses, the reduction in plasma IGF-II, free IGF-I, IGFBP-2 and -3 are all novel findings. A profound decrease in free IGF-I suggests a reduced bioavailability of IGFs from plasma to the tissues. These observations may be of significance to understand the mechanisms of the antitumour effect of diethylstilboestrol in pharmacological doses.     

Effect of the synthetic retinoid fenretinide on circulating free prostate-specific antigen, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 levels in men with superficial bladder cancer.

PURPOSE: Fenretinide (4-HPR) is a synthetic retinoid that has shown a preventive activity in prostate cancer animal models. EXPERIMENTAL DESIGN: We measured the changes in total and free prostate-specific antigen (PSA) and its association with insulin-like growth factor I (IGF-I) and IGFBP-3 levels after 1 year of treatment in 24 subjects given 4-HPR and 24 control subjects enrolled in a randomized bladder cancer prevention trial. RESULTS: No significant effect of 4-HPR was observed on total and free fraction of PSA levels. The median percentage [95 confidence interval (95% CI)] change for % free PSA and total PSA in the 4-HPR and the control group were, respectively, 7.6 (95% CI, -4.0 to 69.3) versus 5.1 (95% CI, -21.4 to 59.8) and -7.8 (95% CI, -18.2 to 52.5) versus -12.3 (95% CI, -44.6 to 9.6). However, in patients ages <60 years, there was a trend to an increase of total free PSA and % free PSA after treatment with 4-HPR that was different from a trend to a decrease in the control group (P = 0.002 and 0.052, respectively). The interaction between age and treatment was statistically significant on free PSA (P = 0.001). A similar pattern was noted with smoking status (P = 0.011 for the interaction on free PSA). No association was observed between PSA levels and IGF-I or IGFBP-3 levels. CONCLUSIONS: We conclude that 4-HPR has no significant effect on circulating PSA, but it increases significantly free PSA levels in subjects younger than 60 years and in nonsmokers. These effects might support an activity in prostate cancer prevention but further studies are required.     

Effect of raloxifene on insulin-like growth factor-I, insulin-like growth factor binding protein-3, and leptin in premenopausal women at high risk for developing breast cancer.

Elevated insulin-like growth factor I (IGF-I) is associated with an increased risk for developing breast cancer in premenopausal women, whereas lower leptin levels have been documented in premenopausal breast cancer cases. We determined the effect of raloxifene on IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), and leptin in premenopausal women at high risk for developing invasive breast cancer. Twenty-eight premenopausal women (median age 43 years) participating in a pilot breast cancer prevention trial provided 56 matched serum samples. Specimens were collected at baseline and after treatment with 60 mg of raloxifene daily. Median treatment duration was 3 months (range: 6 weeks to 12 months). Samples were frozen at -70 degrees C until analysis. IGF-I, IGFBP-3, and leptin were measured by ELISA. Significance was evaluated by the Wilcoxon signed rank test. Raloxifene administration increased serum IGFBP-3 [mean change 245 ng/ml; P = 0.017; 95% confidence interval (CI), 76-415] and leptin (mean change 2.1 ng/ml; P = 0.005; 95% CI, 0.6-3.7). No significant change in serum IGF-I was detected (mean change 2.6 ng/ml; P = 0.84; 95% CI, -15.4 to 20.6). IGF-I:IGFBP-3 molar ratio was stable (mean change -0.014; P = 0.30; 95% CI, -0.041 to 0.012). Raloxifene administration is associated with an increase in IGFBP-3 and leptin in premenopausal high risk women. Increases in IGFBP-3 may potentially decrease the activity of circulating IGF-I. The effect of modulating the IGF pathway and leptin on breast cancer risk needs additional evaluation.     

Loss of growth inhibitory effects of retinoic acid in human breast cancer cells following long-term exposure to retinoic acid

Although retinoids are known to be inhibitory to breast cancer cell growth, a key remaining question is whether they would remain effective if administered long-term. We describe here the long-term effects of all- trans retinoic acid on two oestrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1. Although both cell lines were growth inhibited by retinoic acid in the short-term in either the absence or the presence of oestradiol, prolonged culture with 1 microM all- trans retinoic acid resulted in the cells acquiring resistance to the growth inhibitory effects of retinoic acid. Time courses showed that oestrogen deprivation of the cell lines resulted in upregulation of the basal non-oestrogen stimulated growth rate such that cells learned to grow at the same rate without as with oestradiol, but the cells remained growth inhibited by retinoic acid throughout. Addition of 1 microM all- trans retinoic acid to steroid deprivation conditions resulted in reproducible loss of growth response to both retinoic acid and oestradiol, although the time courses were separable in that loss of growth response to retinoic acid preceded that of oestradiol. Loss of growth response to retinoic acid did not involve loss of receptors, ER as measured by steroid binding assay or RARalpha as measured by Northern blotting. Function of the receptors was retained in terms of the ability of both oestradiol and retinoic acid to upregulate pS2 gene expression, but there was reduced ability to upregulate transiently transfected ERE- and RRE-linked reporter genes. Despite the accepted role of IGFBP3 in retinoic acid-mediated growth inhibition, progression to retinoic acid resistance occurred irrespective of level of IGFBP3, which remained high in the resistant MCF7 cells. Measurement of AP1 activity showed that the two cell lines had markedly different basal AP1 activities, but that progression to resistance was accompanied in both cases by a lost ability of retinoic acid to reduce AP1 activity. These results warn of potential resistance which could arise on long-term treatment with retinoic acid in a clinical situation and echo the problems of progression to endocrine resistance. It seems that whatever the constraints imposed on growth, these cells have a remarkable ability to escape from growth inhibition. However, the ability of retinoic acid to delay progression to oestrogen resistance is encouraging for endocrine therapy, and the concentration-dependence of retinoic acid resistance suggests that progression is not absolute but could be manipulated by dose.     

胰岛素样生长因子/胰岛素系统与乳腺癌靶向治疗研究进展

目的 胰岛素样生长因子/胰岛素系统参与乳腺癌肿瘤细胞的增殖、分化、浸润和转移过程,这为乳腺癌靶向治疗提供了一个新方向.本研究旨在总结国内外该系统抑制剂在乳腺癌靶向治疗方面的研究进展.方法 利用PubMed、SciencceDirect和万方数据知识服务平台等数据库,以“胰岛素样生长因子/胰岛素系统、乳腺癌和靶向治疗”等为关键词,检索1995-10-2015-10的相关文献,其中英文文献1 431条,中文文献46条.纳入标准:(1)关于胰岛素样生长因子/胰岛素系统抑制剂和乳腺癌靶向治疗的临床和基础研究;(2)胰岛素样生长因子/胰岛素系统与乳腺癌患病风险的流行病学调查;(3)胰岛素样生长因子/胰岛素系统的构成及信号通路的相关研究.剔除标准:(1)存在研究设计缺陷或统计方法错误,质量差;(2)数据不完整,结局效应不明确.根据上述标准纳入67篇文献进行分析.结果 外周血的高胰岛素样生长因子水平、高配体结合蛋白水平与乳腺癌的患病风险相关,而乳腺癌组织中的胰岛素样生长因子受体也呈现高表达趋势.大量实验表明,作用于胰岛素样生长因子/胰岛素系统的配体、配体结合蛋白、受体及下游信号通路等的抑制剂,以及与其他相关系统的联合抑制剂,具有抗肿瘤作用,且部分抑制剂已进入临床Ⅰ～Ⅲ期研究,并取得有效成果.然而也出现了一些失败的例子,这可能与该系统的复杂性和多变性相关.结论 以胰岛素样生长因子/胰岛素系统为靶点的药物研究是乳腺癌治疗领域的新热点,但对该系统的作用机制和如何更好地应用于临床的研究还有待进一步完善和深入.     

Plasma insulin-like growth factor in primary breast cancer patients treated with adjuvant chemotherapy.

Insulin-like growth factor 1 (IGF-1) plasma level was assayed in 60 breast cancer patients undergoing six courses of adjuvant chemotherapy. The only observed variation was a slight decrease (10%) in IGF-1 concentrations, assayed before treatment, between the first and the second courses of chemotherapy. During chemotherapy courses, there were no statistically significant variations in IGF-1. These results suggest that chemotherapy, unlike the specific hormonal treatments tamoxifen and somatostatin, certainly does not act via a decrease in plasma IGF-1.     

The insulin-like growth factor system as a therapeutic target in colorectal cancer.

The purpose of this review is to examine recent evidence that investigates the role of the insulin-like growth factor (IGF) system in colorectal cancer. We concentrate on the evidence that makes the case for the investigation of strategies that might be used to disrupt the IGF system in prevention and treatment. Even though the weight of evidence suggests that components of the IGF system may be appropriate targets, there are a lack of studies that make a systematic characterisation of all the system components in human colorectal cancer. It is anticipated that this information, and the new therapeutic molecules which follow, will impact on the prevention and treatment of patients with this disease.     

Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review.

We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5' to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5' to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.     

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

Prospective studies have shown an association between elevated plasma levels of insulin-like growth factor-I (IGF-I) and/or decreased levels of its major circulating carrier protein insulin-like growth factor binding protein-3 (IGFBP-3) and increased risk of major cancers. Identifying the factors which affect these biomarkers is of particular interest as subjects at increased risk could benefit from lifestyle changes, and/or chemoprevention intervention. We evaluated the association between constitutional, hormonal and clinical factors and IGF-I and IGFBP-3 in 740 women, including 376 unaffected women and 364 women with intraepithelial neoplasia (IEN) or early invasive breast cancer enrolled in breast cancer chemoprevention trials, conducted at a single institution. Age, body mass index (BMI), height, waist to hip girth ratio (WHR), parity, menopausal status, age at menarche, number of affected first degree relatives, number of biopsies and breast cancer status were considered in the analysis. Women with early breast cancer had 21% higher IGF-I levels ( p=0.033) and 19% higher IGF-I/IGFBP-3 molar ratio ( p=0.047) than unaffected women. In unaffected women, age was negatively associated with IGF-I ( p=0.002) and IGF-I/IGFBP-3 ( p=0.001), while age at menarche was negatively associated with IGFBP-3 levels ( p=0.043). In women with IEN or early breast cancer, IGF-I levels were negatively associated with age ( p < 0.001), and positively associated with prior biopsies for benign disease ( p=0.013), while age, parity and menopausal status were significant predictors of IGF-I/IGFBP-3 molar ratio. We conclude that circulating IGF-I levels are higher in women with prior breast cancer compared to unaffected women, and that IGF-I and/or IGFBP-3 levels are influenced by age and by reproductive and hormonal factors. These findings support their putative role as breast cancer risk biomarker.     

Effect of tamoxifen on plasma insulin-like growth factor I in patients with breast cancer

Human breast cancer cells secrete and have membrane receptors for insulin-like growth factor I (IGF-I), a growth hormone-dependent peptide that stimulates cell replication. However, little is known about plasma concentrations of IGF-I in breast cancer patients. Plasma IGF-I levels are decreased in malnutrition, decline with advancing age, and are influenced by estrogen. We evaluated the effect of the antiestrogen agent tamoxifen on plasma IGF-I in 32 ambulatory breast cancer patients. Treatment with tamoxifen was associated with lower concentrations of plasma IGF-I (0.48 +/- 0.3 unit/ml in treated versus 1.03 +/- 0.6 units/ml in nontreated patients, P less than 0.01). However, patients treated with tamoxifen did not differ from nontreated patients in age, menopause, duration since diagnosis, metastatic disease, recent weight loss, or measures of nutritional status. We conclude that tamoxifen therapy results in a reduction of plasma IGF-I concentration. We speculate that the antitumor action of tamoxifen in breast cancer is due in part to suppression of IGF-I.     

Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor binding protein I in breast cancer patients.

Plasma levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein I (IGFBP-I) were measured in fasting blood samples obtained from 16 postmenopausal breast cancer patients before and during tamoxifen treatment for 1 to 6 months. Tamoxifen suppressed total plasma IGF-I by a mean of 28.5% (P less than 0.001) but elevated plasma IGFBP-I by a mean value of 78% (P less than 0.001). Changes in plasma levels of growth hormone, insulin, or insulin C-peptide were not observed. These findings suggest that tamoxifen exerts its influence on plasma IGF-I and IGFBP-I by mechanisms other than those known to regulate the plasma levels of these peptides, primarily growth hormone and insulin, respectively. A dual effect suppressing plasma IGF-I and elevating plasma IGFBP-I suggests that tamoxifen may have a significant influence on endocrine and possibly paracrine delivery of IGF-I to breast cancer cells in vivo.     

Nested case-control study of the association of circulating levels of serum insulin-like growth factor I and insulin-like growth factor binding protein 3 with breast cancer in young women in Norway

BACKGROUND: High circulating levels of insulin-like growth factor (IGF-I) may elevate the risk of breast cancer in premenopausal women, possibly by increasing cell proliferation and reducing apoptosis. METHODS: We conducted a nested case-control study among 35,105 Norwegian women who participated in a health screening survey, ages 40 to 42 years, and who were subsequently followed for a mean period of 4.3 years. During this period, 325 women were diagnosed with breast cancer; 647 women without breast cancer, matched on age and time of blood sampling, were selected as controls. Serum concentrations of IGF-I and its main binding protein (IGFBP-3) were measured with radioimmunoassay, and logistic regression analysis was used to adjust for relevant covariates. RESULTS: The mean age at blood collection was 41.1 years in both groups, and the mean age at diagnosis for the cases was 45.4 years (range, 40-51 years). The median IGF-I level did not differ between cases (205 ng/mL) and controls (202 ng/mL). When analyzed by categories of serum IGF-I, the relative risk for women in the highest versus the lowest quintile was 1.46 (95% confidence interval, 0.93-2.32; P(trend) = 0.15) after adjusting for serum IGFBP-3, age, and year of blood collection. The exclusion of cases that were diagnosed within 2 years after blood collection did not materially affect the results. CONCLUSION: We found only a modest positive association between serum IGF-I levels and risk of breast cancer in women younger than 50 years of age.     

胰岛素样生长因子系统在结直肠癌中的应用

 胰岛素样生长因子（IGF）系统具有调节细胞增殖、分化及抑制凋亡等多种生物活性。体内外试验研究证实,IGF系统参与细胞的恶性转化,与肿瘤的生长、浸润及转移密切相关,将应用于结直肠癌的早期诊断和靶向治疗。