Effects of 9-cis-retinoic acid on the insulin-like growth factor axis in former smokers.

PURPOSE: Insulin-like growth factor (IGF) axis has been associated with the risk of lung cancer. 9-cis-retinoic acid (9-cis-RA) has shown potential chemopreventive activities in former smokers. This study was designed to evaluate the effects of 9-cis-RA on IGF axis in former smokers to identify any benefit the retinoid may have in preventing lung cancer. PATIENTS AND METHODS: Serum concentrations of IGF-I, IGF binding protein (IGFBP)-3, and their molar ratio (IGF-I/IGFBP-3) were measured with radioimmunoassay kits in stored blood samples from the participants of an original chemoprevention trial. The participants had ceased smoking for at least 12 months and were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg) or placebo. All statistical tests were two-sided. RESULTS: A total of 111 samples from the study's baseline and 84 samples from the 3 months treatment were analyzed. The serum concentrations of IGF-I and IGF-I/IGFBP-3 at baseline were significantly lower in female than in male participants. After 3 months of treatment, the serum level of IGF-I and IGF-I/IGFBP-3 were significantly lower in the 9-cis-RA group than in the placebo group (P = .03 and P < .01, respectively), but the IGFBP-3 level was significantly higher (P = .03). CONCLUSION: 9-cis-RA treatment modulated the IGF axis in former smokers, suggesting that the IGF axis is a potential target for the chemopreventive activities of 9-cis-RA and that the serum concentrations of IGF, IGFBP-3, and IGF-I/IGFBP-3 could serve as surrogate end point biomarkers of 9-cis-RA treatment.     

Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: results from a randomized placebo-controlled trial

BACKGROUND: Loss of retinoic acid receptor beta (RAR-beta) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus alpha-tocopherol (AT), could reverse RAR-beta expression loss in former smokers after 3 months of treatment. METHODS: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-beta expression. McNemar's test was used to test changes in RAR-beta expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. RESULTS: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-beta was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-beta expression (P =.03) and reduction of metaplasia (P =.01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-beta expression compared with placebo (P =.03). CONCLUSION: 9-cis-RA treatment can restore RAR-beta expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.     

Effects of retinoids on cell toxicity and apoptosis in leukemic blast cells from patients with non-M3 AML

All-trans retinoic acid (ATRA) induces complete remission in acute promyelocytic leukemia (APL or M3). In this study we measured the effect of retinoids alone and in combination with daunorubicin (DNR) on cell growth and apoptosis in blast cells from patients with non-M3 AML. Cells from 21 patients were incubated in 0.2 microM daunorubicin for 1 h or in 1 microM ATRA or 9-cis-RA continuously and in the combinations of DNR with both retinoids. Cell toxicity and apoptosis were analyzed after 96 h. Both ATRA and 9-cis-RA reduced the viability significantly to 86 and 84%, respectively (P = 0.003 for ATRA and 0.02 for 9-cis-RA). The expression of CD34 correlated to a higher sensitivity to ATRA (P = 0.003). When retinoids were added to DNR the mean decrease in viability was 11 percentage points with ATRA (P = 0.003) and nine percentage points with 9-cis-RA (P = 0.02). Apoptosis was induced by both retinoids and the percentage of apoptotic cells was increased from 16% in the controls to 24% with ATRA (P = 0.03) and to 26% with 9-cis-RA (P = 0.04). When the retinoids were added to DNR the apoptotic rate increased from 41% with DNR alone to 51% with ATRA (P = 0.01) and to 49% with 9-cis-RA (P = 0.03). We conclude that ATRA and RA exert a slight but clear cytotoxic and apoptotic effect on AML blast cells after 96 h incubation and that retinoids can have an additive or synergistic effects on cell toxicity when added to daunorubicin.     

The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial.

beta-Carotene and Retinol Efficacy Trial is a nationwide chemoprevention trial that recruited 18,314 high-risk individuals to test the effect of supplemental beta-carotene and retinol on lung cancer incidence. In this report, we conducted a prospective nested case-control study of the association between serum carotenoids, retinoids, and tocopherols on both lung and prostate cancer incidence. Prerandomization serum samples were selected from 278 lung cancer cases and 205 prostate cancer cases, and 483 controls matched by high-risk population, study center location, age, sex (lung cancer only), smoking status, and year of randomization. Carotenoids, retinoids, and tocopherols were analyzed by high-performance liquid chromatography. Endpoints were confirmed by pathology review (lung cancer) or review of the pathology report (prostate cancer). In the control-only population, there was a significant association between tobacco use and serum micronutrient concentration. Current smokers compared with former smokers had lower mean levels of all of the micronutrients tested with zeaxanthin, beta-cryptoxanthin, alpha-carotene, alpha-tocopherol, retinol, and retinyl palmitate reaching statistical significance at P = 0.05. In the overall population, the mean serum concentrations of all of the micronutrients except gamma-tocopherol were lower for lung cancer cases than controls. Statistically significant trends across quartiles were observed in lutein (P = 0.02), zeaxanthin (P = 0.02), and alpha-tocopherol (P = 0.03). The carotenoid findings in the overall population were because of the strong inverse association between serum micronutrients and lung cancer in females. Statistically significant odds ratios (ORs) comparing 4(th) to 1st quartiles in the female population were seen in lutein [OR, 0.31; confidence interval (CI), 0.13-0.75], zeaxanthin (OR, 0.31; CI, 0.12-0.77), and beta-cryptoxanthin (OR, 0.34; CI, 0.14-0.81). For prostate cancer, mean serum concentrations were lower in cases for all of the nutrients except alpha-carotene. Only for alpha-tocopherol (P(trend) = 0.04) were the findings statistically significant. There was no statistically significant association between serum carotenoids and prostate cancer. Our findings provide additional support for the association between physiological levels of dietary micronutrients and cancer incidence.     

Nuclear retinoid acid receptor beta in bronchial epithelium of smokers before and during chemoprevention.

BACKGROUND: Retinoids can reverse neoplastic lesions and prevent second primary tumors in the aerodigestive tract. These effects are thought to be mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each receptor group including three subtypes (alpha, beta, and gamma). Previously, we found that RARbeta expression was suppressed in lung cancer. In this study, we investigated whether expression of RARbeta is modulated by chemopreventive intervention. METHODS: Using in situ hybridization, we analyzed RARbeta messenger RNA (mRNA) expression in bronchial biopsy specimens from heavy smokers, at baseline and after 6 months of treatment with 13-cis-retinoic acid (13-cis-RA) or placebo. Since we had previously detected RARbeta expression in 90% of bronchial specimens from nonsmokers, we considered loss of RARbeta mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant. RESULTS: RARbeta mRNA expression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA group and in 24 (72.7%) of 33 subjects in the placebo group. After 6 months of 13-cis-RA treatment, the number of subjects who were RARbeta positive in all six biopsy specimens increased from five of 35 to 13 of 35 (2.6-fold), so that the percentage of individuals with aberrant RARbeta expression decreased to 62.9% (22 of 35), which represents a statistically significant difference from baseline expression (two-sided P =.01). In the placebo group, no statistically significant difference in RARbeta expression was observed between baseline and 6 months. RARbeta expression was not related to current smoking status or reversal of squamous metaplasia. CONCLUSIONS: These results indicate that RARbeta is an independent marker of response to 13-cis-RA and may serve as an intermediate biomarker in chemoprevention trials of upper aerodigestive tract cancers.     

A comparison of carotenoids, retinoids, and tocopherols in the serum and buccal mucosa of chronic cigarette smokers versus nonsmokers.

BACKGROUND: Cigarette smoking, a major risk factor for oropharyngeal cancer, is reported to alter oral levels of carotenoids and tocopherols. Such effects may be important because these nutrients, as well as retinoids, are putative chemoprotective agents. OBJECTIVES: To determine whether chronic smoking is associated with altered concentrations of these nutrients in serum and buccal mucosa; to distinguish whether such effects are ascribable to diet; and to determine whether oral concentrations of these nutrients correlate with a putative biomarker of oral cancer risk. METHODS: Serum and buccal mucosal cells (BMC) were analyzed for these nutrients and for BMC micronuclei in smokers (n = 35) and nonsmokers (n = 21). RESULTS: General linear regression with adjustments for dietary intake showed that smokers possess lower serum concentrations of beta- and alpha-carotene, cryptoxanthin, lutein, and zeaxanthin (P 相似文献   

A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia

BACKGROUND: Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia. METHODS: One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided. RESULTS: One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication. CONCLUSION: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.     

Randomized, placebo-controlled pilot trial of the effects of alpha-tocopherol supplementation on levels of autoantibodies against 5-hydroxymethyl-2-deoxyuridine in melanoma patients

We conducted a randomized, placebo-controlled pilot trial to assess whether supplementation of 1000 mg/day alpha-tocopherol for 3 months offered protection against DNA base damage in melanoma outpatients (n=46). Plasma autoantibodies (aAbs) against 5-hydroxymethyl-2-deoxyuridine (HMdU) were measured as an immune marker of DNA base damage. After 3 months of supplementation (final level), plasma levels of alpha-tocopherol increased significantly (P<0.0005) in the alpha-tocopherol compared with the placebo treatment group. Supplementation with alpha-tocopherol also resulted in a significant (P=0.04) decrease in plasma gamma-tocopherol levels among males. Overall, we did not find any significant differences in the plasma anti-HMdU aAb levels between the two treatment groups. However, when the patients were stratified by the clinical characteristics of the melanoma, we found that alpha-tocopherol supplementation resulted in a borderline significant (P=0.06) 48% decrease in plasma anti-HMdU aAb levels in patients with less aggressive melanomas (Breslow thickness 相似文献   

Oral iloprost improves endobronchial dysplasia in former smokers

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.     

Randomized, placebo-controlled trial of dietary supplementation of alpha-tocopherol on mutagen sensitivity levels in melanoma patients: a pilot trial

We evaluated the effects of vitamin E (dl-alpha-tocopherol) on mutagen sensitivity levels in a randomized placebo-controlled pilot trial. In brief, a dietary supplement of 1000 mg/day vitamin E or a placebo was randomly administered for 3 months to melanoma outpatients clinically free of the disease. Plasma vitamin E and mutagen sensitivity levels were measured at baseline and at the end of the trial after 3 months. At baseline, we found no significant differences in plasma vitamin E and mutagen sensitivity levels between the two groups. We also measured dietary intake at baseline and found dietary vitamin E to be a poor predictor of plasma levels of vitamin E. After 3 months of supplementation, we found that plasma levels of alpha-tocopherol increased significantly (P = 0.0005) in the vitamin E compared to the placebo group. We also found a non-significant, but consistent decrease in plasma gamma-tocopherol concentrations in the vitamin E supplemented compared to the placebo group. We did not find any significant difference between the vitamin E and placebo groups in mutagen sensitivity levels either at baseline or after 3 months of supplementation. We conclude that short term vitamin E supplementation, although it causes increased blood levels of alpha-tocopherol, does not provide protection against bleomycin-induced chromosome damage.     

Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum.

beta-carotene has been hypothesised to reduce lung cancer risk. We studied the effect of 14 weeks of beta-carotene supplementation (20 mg d-1) on the frequency of micronuclei in sputum in 114 heavy smokers in a double-blind trial. Micronuclei reflect DNA damage in exfoliated cells and may thus provide a marker of early-stage carcinogenesis. Pre-treatment blood levels of cotinine, beta-carotene, retinol and vitamins C and E were similar in the placebo group (n = 61) and the treatment group (n = 53). Plasma beta-carotene levels increased 13-fold in the treatment group during intervention. Initial micronuclei counts (per 3,000 cells) were higher in the treatment group than in the placebo group (5.0 vs 4.0, P < 0.05). During intervention, the treatment group showed a 47% decrease, whereas the placebo group showed a non-significant decrease (16%). After adjustment for the initial levels, the treatment group had 27% lower micronuclei counts than the placebo group at the end of the trial (95% CI: 9-41%). These results indicate that beta-carotene may reduce lung cancer risk in man by preventing DNA damage in early-stage carcinogenesis.     

Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers

A number of retinoid X receptor (RXR) agonists have proven to be highly effective in preventing methylnitrosourea (MNU) induced mammary cancers. However, these agonists have side effects; particularly causing an increase in serum triglyceride levels. A series of ligands for RXR were designed based on computer modeling to the ligand binding domain (LBD) of the RXR receptors and on structure-activity relationships. The chemopreventive effects of these retinoids were evaluated in the relatively long-term MNU model. As a short-term assay to predict their efficacy, the ability of the retinoids to modulate cell proliferation and apoptosis was also determined in mammary cancers after only 7 days of treatment. The five UAB retinoids evaluated included two Class I UAB retinoids (UAB20, UAB112) and three Class II UAB retinoids (UAB30, 4-methyl-UAB30 and the benzosuberone-analog of UAB30). The previously evaluated RXR agonist targretin and the pan-agonist 9-cis-retinoic acid (9-cis-RA), which interacts with both RAR and RXR receptors, were included as positive agonists known to prevent cancer in the MNU model. In the prevention studies, in which the agents were administered beginning 5 days after MNU until the end of the study, targretin (150 mg/kg diet) and 4-methyl-UAB30 (200 mg/kg diet) were highly effective in decreasing cancer numbers by 75-85%. UAB30 (200 mg/kg diet) and 9-cis-RA (60 mg/kg diet) gave intermediate inhibitions of 60 and 45%, respectively. Targretin (15 mg/kg diet), UAB20 (200 mg/kg diet) and the benzosuberone analog of UAB30 (200 mg/kg diet) showed limited activity by decreasing cancer multiplicity 25-30%, while UAB112 had no effect on mammary cancer multiplicity. A direct correlation was observed between the long-term chemopreventive efficacy of these agents and their ability to decrease cell proliferation in mammary cancers after short-term treatment. Furthermore, the highly effective agents (4-methyl-UAB30 and targretin at 150 mg/kg diet) increased apoptosis 3-5 times, while agents with moderate or limited preventive efficacy failed to significantly increase apoptosis. Although the more effective retinoid treatments increased serum triglycerides 2.5- to 4.0-fold, one moderately effective agent (UAB30) had no significant effect on lipid levels. In summary, a short-term in vivo method has been identified for screening newly synthesized retinoids both for chemopreventive efficacy and for their adverse effect on serum triglycerides.     

Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat.

BACKGROUND: 9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. METHODS: Male Fischer 344 rats were randomly assigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O(6)-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided. RESULTS: Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O(6)-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi. CONCLUSIONS: Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.     

急性白血病患者血清MMP-2及MMP-9的检测及其临床意义

目的:检测急性白血病(acute leukemia,AL)患者不同发展阶段血清基质金属蛋白酶-2（MMP-2）及基质金属蛋白酶-9（MMP-9）水平,探讨这些活性物质在AL的诊断、治疗及预后判断中的临床意义。方法:选择初诊AL患者60例,正常对照组40例,测定其血清MMP-2及MMP-9水平并对结果比较分析,并对AL患者进行治疗前、后不同阶段的动态检测。骨髓涂片在显微镜下按常规分类计数200个有核细胞,计算原始加幼稚细胞比例。结果:AL组初诊时血清MMP-2含量明显升高,与正常对照组比较有显著性差异(P<0.05)。 AL组初诊时血清MMP-9含量明显升高,与正常对照组比较有显著性差异(P<0.05)。AL髓外浸润患者组MMP-2与MMP-9水平明显高于无髓外浸润患者组,差异有统计学意义(P<0.05)。经过2~3个疗程的治疗后,达到完全缓解（CR）时,血清MMP-2及MMP-9 含量恢复正常,与正常对照组比较无显著差异(P>0.05)。经过2~3个疗程的治疗后,复发组患者血清MMP-2及MMP-9 含量明显高于正常对照组,比较差异有统计学意义(P<0.05)。经过2~3个疗程的治疗后,未达到缓解［包括部分缓解（PR）和未缓解（NR）］时,上述因子与治疗前比较差异无统计学意义(P>0.05)。AL初诊患者治疗前血清MMP-2及MMP-9水平与骨髓原始加幼稚细胞数呈正相关(P<0.05,r=0.618和P<0.05,r=0.368)。结论:动态监测AL患者血清MMP-2及MMP-9水平,可作为白血病病情进展、疗效过程及判断预后的重要参考指标。     

TACE联合血管内皮抑制素治疗肝癌的短期疗效及其对患者血清VEGF、MMP-9、OPN的影响

目的:探讨经肝动脉化疗栓塞（TACE）联合血管内皮抑制素治疗肝癌的短期疗效及其对患者血清VEGF、MMP-9、OPN的影响。方法:选取2012年4月-2013年4月我院收治的原发性肝细胞癌（简称肝癌）患者80例,按照随机对照法分为观察组和对照组各40例,其中观察组给予TACE联合重组人血管内皮抑制素（恩度）治疗,对照组采用单纯的TACE治疗,观察两组患者治疗前、治疗后1、3、7、15、30d血清血管内皮生长因子（VEGF）、基质金属蛋白酶9（MMP-9）、骨桥蛋白（OPN）水平的变化,观察两组患者肿瘤新生血管抑制情况、肿瘤控制情况及1年生存率。结果:治疗前两组的血清VEGF、MMP-9、OPN水平比较差异无统计学意义（P＞0.05）;治疗后各时间节点观察组血清VEGF、MMP-9、OPN水平与治疗前比较差异无统计学意义（P＞0.05）;而对照组治疗后各时间节点血清VEGF、MMP-9、OPN水平均较治疗前明显升高,差异具有统计学意义（P＜0.05）;观察组患者新生血管控制率、疾病控制率（DCR）及术后1年生存率均明显优于对照组,差异具有统计学意义（P＜0.05）。两组的不良反应发生率比较差异无统计学意义（P＞0.05）。结论:TACE联合血管内皮抑制素治疗肝癌可以有效抑制肿瘤新生血管的形成,降低肿瘤复发转移的几率,延长患者的生存时间,提高生存率,其作用机制可能与抑制TACE术后血浆VEGF、MMP-9、OPN水平有关。     

不可切除或转移性胃肠道间质瘤患者伊马替尼治疗前后血清胰岛素样生长因子-1水平及其临床意义

 目的　探讨不可切除或转移性胃肠道间质瘤（GIST）患者伊马替尼治疗前后血清胰岛素样生长因子-1（IGF-1）水平变化及其临床意义。方法　收集27例不可切除或转移性GIST患者伊马替尼治疗前（治疗前组）、伊马替尼治疗3个月后（治疗后组）及20名健康志愿者（健康对照组）血清标本。用酶联免疫吸附法检测各血清标本IGF-1水平。结果　不可切除或转移性GIST患者伊马替尼治疗前组血清IGF-1平均水平为（463.61±120.98）ng／ml,高于健康对照组的（115.75±39.27 ）ng／ml,差异有统计学意义（t＝12.355,P＝0.000）。伊马替尼治疗后组血清IGF-1平均水平为（244.64±100.11）ng／ml,较治疗前组的（463.61±120.98）ng／ml明显降低,差异有统计学意义（t＝7.582,P＝0.000）。结论　血清IGF-1水平可能有助于判断GIST的疗效、进展、复发或转移。     

Sex differences in the effects of retinoids on carcinogenesis by N-nitrosobis(2-oxopropyl)amine in Syrian hamsters

Syrian hamsters were given in a single dose of N-nitrosobis(2-oxopropyl)-amine (BOP) (40 mg/kg, s.c.) and 1 week later were fed 1 of 4 retinoid types (13-cis-retinoic acid (13-cis-RA), N-ethylretinamide (ERA), 2-hydroxyethylretinamide (OH-ERA), or 4-hydroxyphenylretinamide (PRA)) each at 3 levels (0.05, 0.1, 0.2 mM/kg diet). The pancreatic carcinoma incidence was not influenced significantly by feeding retinoids. The pancreatic adenoma incidence, however, was reduced by feeding each of the retinoids to female hamsters, with the reduction varying with the retinoid fed (13-cis-RA greater than ERA and OH-ERA greater than PRA). In male hamsters increased numbers of pancreatic adenomas were observed after feeding OH-ERA and PRA. Tumors induced in other tissues were reduced by retinoids in females, but not in males. Females fed 13-cis-RA and ERA had a lower incidence of gall bladder polyps, and feeding OH-ERA reduced the liver tumor incidence. Food consumption and serum alkaline phosphatase ans aspartate amino transferase activities were not influenced by BOP or retinoid type or level. Body and pancreas weight were influenced by retinoid level, but the effects were not consistently dose-related.     

Is there a role for retinoids to treat minimal residual disease in neuroblastoma?

A variety of pre-clinical and clinical data point toward high drug levels of retinoids being required to achieve optimal efficacy against neuroblastoma. The results of the Kohler trial reported in this issue demonstrate that low-dose 13-cis-RA does not have clinical efficacy against neuroblastoma in a setting of minimal residual disease. A comparison of the Kohler trial with the US CCG trial provides clinical evidence that high-dose levels of retinoids are optimal for treating minimal residual disease in neuroblastoma. The comparison of high-dose and low-dose 13-cis-RA studies in neuroblastoma suggests the intriguing possibility that high dose, pulse schedules of other retinoids could be effective as therapeutic and chemopreventive agents in diseases where low-dose, chronic retinoid administration was not effective. Pre-clinical and perhaps clinical studies of the latter concept should be considered.     

Antioxidant vitamin supplementation reduces benzo(a)pyrene-DNA adducts and potential cancer risk in female smokers.

BACKGROUND: Elevated benzo(a)pyrene [B(a)P]-DNA adducts have been associated with 3-fold increased risk of lung cancer in current smokers. We assessed the chemopreventive effects of antioxidant supplementation using B(a)P-DNA adducts in leukocytes as an intermediate cancer risk marker.METHODS: Subjects were randomized to a double-blinded placebo-controlled clinical trial of antioxidant vitamin supplementation [500 mg vitamin C and 400 IU vitamin E (dl-alpha-tocopherol) daily] or placebo. Smokers with > or =10 cigarettes per day and serum cotinine > or =25 ng/mL were eligible for the study. B(a)P-DNA adduct level was the outcome. The randomization was stratified by gender and cigarettes per day (< or =20 or >20). Smoking habits and blood samples were collected every 3 months during the 15-month treatment period. Samples were analyzed for B(a)P-DNA adducts (high-performance liquid chromatography), plasma cotinine, vitamin levels, and GSTM1 genotype. The intent-to-treat model adjusted for B(a)P-DNA and cotinine at randomization.RESULTS: Overall and among men, there was no effect of treatment on B(a)P-DNA adduct levels. Among treated women, B(a)P-DNA adducts decreased by 31% compared with women on placebo (P = 0.03). Among treated women with the GSTM1 genotype, there was a 43% decrease in adducts (P = 0.04).CONCLUSION: Our primary hypothesis that the mean level of smoking-related B(a)P-DNA adducts would be lower in all subjects in the vitamin treatment group compared with all placebo-treated subjects was not substantiated. However, oursecondary gender-specific analysis found a significant reduction in B(a)P-DNA adducts in women with vitamin treatment, suggesting that antioxidant supplementation maymitigate some of the procarcinogenic effects of exposuretoB(a)P. The effect in GSTM1-null women suggeststhat certain subgroups may derive more benefit fromsupplementation. Although the results of this trial showthe potential chemopreventive role of antioxidants, thebest way for smokers to reduce their cancer risk remains smoking cessation.