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Clin Exp Immunol. Sep 2004; 137(3): 546–551.
PMCID: PMC1809129

Effect of tamoxifen on serum IL-18, vascular endothelial growth factor and nitric oxide activities in breast carcinoma patients

Abstract

Vascular endothelial growth factor (VEGF) is a multi-functional cytokine that has been suggested to be a major angiogenic factor in breast cancer. Nitric oxide (NO) is a potent biological molecule that partipicates in the multi-step process of carcinogenesis. Interleukin (IL)-18 has been shown to have potent anti-tumour effects. In this study, we investigated the effect of tamoxifen therapy on serum VEGF, NO and IL-18 activity in breast cancer patients. Serum levels of VEGF, nitrate + nitrite and IL-18 were measured in 34 postmenopausal breast cancer patients before and 3 months after the tamoxifen therapy. Both serum VEGF and IL-18 levels decreased after tamoxifen therapy (P = 0·051, P < 0·05, respectively). Serum VEGF levels increased in patients with endometrial thickness, while patients without endometrial thickness had a significant reduction in serum VEGF levels after therapy (P < 0·05). Serum nitrate + nitrite levels increased after the therapy, but this was not statistically significant (P > 0·05). A decrease in serum VEGF levels with tamoxifen therapy may be a reflection of reduced angiogenic activity in patients without endometrial thickness. The negative effect of tamoxifen therapy on IL-18, which is known to have a potent antitumour activity, may be related to the decreased tumour growth by induction of NO and reduction of VEGF activity as a feedback mechanism.

Keywords: angiogenesis, apoptosis, breast cancer, hormone therapy, nitrate, nitrite

INTRODUCTION

Tamoxifen is a non-steroidal antiestrogen agent that is used frequently in the hormonal treatment of breast cancer patients [1]. The antitumour activity of tamoxifen is attributed mainly to its anti-oestrogenic activity, but it has a number of alternative therapeutic mechanisms, including induction of apoptosis [2], modulation of growth factor synthesis [3] and inhibition of angiogenesis [3]. Tamoxifen influences a number of cytokines involved in the regulation of apoptosis and angiogenesis, including nitric oxide (NO) [4] and vascular endothelial growth factor (VEGF) [5].

NO is a potent biological molecule that is involved in the multi-step process of tumorigenesis, including induction of apoptosis [6] and promotion of angiogenesis [7]. It has been reported that increased NO levels in response to tamoxifen may have a functional importance in terms of antiproliferative and apoptotic tumour suppressive effects [8].

VEGF is a potent mitogen that stimulates angiogenesis probably by stimulating NO activity [9,10]. It has been suggested that increased NO synthase activity is necessary for VEGF to stimulate angiogenesis [10]. It has been reported that VEGF expression in tumour tissue correlates with the degree of angiogenesis and can be used as an independent prognostic indicator for breast cancer patients [11,12]. It has been suggested that tamoxifen exerts some of its antitumour activity by affecting VEGF expression in tumour tissue [13]. It has been shown that tamoxifen induces NO production by stimulating combinations of cytokines, tumour necrotizing factor-α, interleukin-1β and interferon (IFN)-γ [14].

Interleukin (IL)-18), termed initially as an interferon-γ inducing factor, has multiple biological functions including promoting the production of granulocyte macrophage stimulating factor and interleukin-2, activating natural killer cells and macrophages [15]. Moreover, IL-18 has been shown to have potent antitumour effects that are mediated by induction of apoptosis [16] and inhibition of angiogenesis [17]. It has been reported that serum IL-18 levels may be used as a serum marker for monitoring the clinical course of patients with some cancer types, including gastric [18] and colon carcinoma [19]. Recently, we have shown that serum IL-18 levels can be a useful marker in monitoring breast cancer patients [20].

In this study, we investigated the effect of tamoxifen therapy on serum IL-18, VEGF and NO activity in breast cancer patients.

MATERIALS AND METHODS

Patients

Thirty-four postmenopausal female patients with histologically confirmed breast cancer were included in this study. Median age was 53·5 years (range: 23–73 years). Seven patients had chemotherapy-induced menopause. Informed consent was obtained from all patients. All patients were in complete remission and treated with adjuvant chemotherapy after surgery. Oestrogen receptor status was found to be positive in all patients and tamoxifen therapy was started at a dose of 10 mg twice a day as adjuvant setting. Patients with metastatic breast cancer and synchoronous secondary malignancies were excluded. Before and after the treatment, endometrium was evaluated by pelvic ultrasonography. Serum samples were obtained from the patients before and 3 months after the tamoxifen therapy between 9 a.m. and 11 a.m. to minimize possible circadian variations after an overnight fasting. Samples were stored at –30°C until analysis.

Methods

VEGF measurement

VEGF was measured in serum by enzyme-linked immunosorbent assay (ELISA) using commercial reagents [21]. The minimum detectable dose of VEGF is <5 pg/ml. Linear regression analysis of samples versus the expected concentration yielded a correlation coefficient of 0·99 in both cases. The recovery of hVEGF added to human serum averaged 95% (Biosource International, Camarillo, CA, USA).

Nitrite and nitrate measurement

Nitrite was measured by using the Griess reaction and the results are given as micromoles per litre [22]. Nitrate was measured by using the enzymatic one-step assay with nitrate reductase [23]. The method was based on the reduction of nitrate to nitrite by nitrate reductase in the presence of β-NADPH. We equilibrated tubes at 25°C containing 250 µl of 100 mmol/l potassium phosphate buffer (pH 7·5) and 50 µl of 12 mmol/l β-NADPH with 100 µl of sample. To start the enzymatic reaction, we added 40 µl of 500 U/l nitrate reductase. We incubated the tubes in the dark for 45 min. The concomitant oxidation of β-NADPH was monitored by the decrease in absorbance at 340 nm. The method of standard addition was used to minimize the effect of interfering substances via serum. The results were expressed as µmol/l. We also used samples with internal standard, serum blanks and reagent blank.

IL-18 measurement

ELISA for determination of IL-18 in serum was performed according to a previously described method [24]. Immediately after blood sampling, serum was obtained by centrifugation at 800 g at 4°C for 15 min. The IL-18 level in each sample was determined by using commercially available ELISA kits (human IL-18 colorimetric solid phase sandwich ELISA; BioSource International). Sensitivity was determined by assaying serially diluted hIL-18 calibrator. The mean absorbance plus 2 standard deviations (s.d.) for calibrator diluted to 6·25 pg/ml was lower than the mean absorbance minus 2 s.d. for calibrator diluted to 12·5 pg/ml. The minimal detectable dose is therefore 12·5 pg/ml.

Statistical analysis

The results were presented as mean ± s.d. All statistical analyses were performed using SPSS for Windows (version 10·0). Wilcoxon's rank sum test and paired t-tests were used in the statistical analysis. P-values less than 0·05 were accepted as significant.

RESULTS

No serious side-effect was observed during tamoxifen treatment. Before and after the treatment, the endometrium was evaluated by pelvic ultrasonography. Patients with a 5 mm or higher endometrium were accepted to have endometrial thickness. No patients had endometrial thickness before the tretment, but 20 patients had endometrial thickness 3 months after the tamoxifen therapy. All the patients who had endometrial thickness underwent pelvic examination, pap smear and transvaginal ultrasonography. Six patients who were suspected for endometrial malignancy also underwent endometrial biopsy, but no endometrial carcinoma was detected.

Serum VEGF levels decreased from 170·2 ± 111·3 pg/ml to 130·6 ± 78·9 pg/ml (23% ↓) after 3 months’ tamoxifen treatment in 34 breast cancer patients (P = 0·051) (Table 1 and Fig. 1). Changes in serum VEGF levels in terms of having endometrial thickness, tumour size, lymph node status, degree of oestrogen receptor (ER) positivity and tumour grade are shown in Table 1. While serum VEGF levels decreased significantly in patients without endometrial thickness (from 178·9 ± 118·0 pg/ml to 105·1 ± 71·6 pg/ml, n = 22, 42% ↓, P < 0·05), these levels increased in patients who had endometrial thickness (n = 12, from 154·1 ± 100·7 pg/ml to 177·4 ± 72·6 pg/ml, 15% ↑, P > 0·05) (Fig. 2).

Fig. 1
Changes of serum IL-18, nitrate + nitrite and VEGF levels before and after tamoxifen therapy (N: nitrate + nitrite).
Fig. 2
Changes of serum IL-18, nitrate + nitrite and VEGF levels in patients according to endometrial thickness before and after tamoxifen therapy (N: nitrate + nitrite).
Table 1
Serum VEGF, nitrate + nitrite and IL-18 levels before and 3 months after tamoxifen therapy (mean ± s.d.)

In subgroup analysis, decrease in serum VEGF levels were found to be significant only in patients whose tumour size were ≥5 cm (n = 5, 55% ↓, P < 0·05). Patients whose tumour size were ≤2 cm and between 2 and 5 cm had non-significant reductions in serum VEGF levels (P > 0·05) (Table 1). Changes in serum VEGF levels were not found to be significantly different in terms of axillary nodal status, oestrogen receptor status and tumour grade (P > 0·05).

Serum nitrate + nitrite levels increased from 295·8 ± 134·4 µmol/l to 321·8 ± 107·1 µmol/l (9% ↑) after 3 months’ tamoxifen treatment in 34 breast cancer patients, but this was not statistically significant (P > 0·05) (Table 1 and Fig. 1). Changes in serum nitrate + nitrite levels in terms of having endometrial thickness, tumour size, lymph node status, degree of oestrogen receptor (ER) positivity and tumour grade are shown in Table 1. In this subgroup analysis, only patients whose tumour sizes were between 2 and 5 cm (15% ↑) and patients who had 1–3 positive ALN (n = 12, 12% ↑) had a significant increase in serum nitrate + nitrite levels (P < 0·05) (Table 1).

Serum IL-18 levels decreased from 375·7 ± 11·5 pg/ml to 310·1 ± 73·7 pg/ml (17% ↓) after 3 months’ tamoxifen treatment in 34 breast cancer patients (P < 0·05) (Table 1 and Fig. 1). Serum IL-18 levels decreased from 419·0 ± 188·7 pg/ml to 319·5 ± 80·7 pg/ml in patients who had endometrial thickness 3 months after tamoxifen treatment (n = 12, 23% ↓, P < 0·05). However, the decrease in serum IL-18 levels was not statistically significant in patients without endometrial thickness (n = 22, from 352·1 ± 139·8 pg/ml to 304·9 ± 71·0 pg/ml, 13% ↓, P > 0·05) (Fig. 2).

Changes in serum IL-18 levels in terms of tumour size, lymph node status, degree of oestrogen receptor (ER) positivity and tumour grade are shown in Table 1. In this subgroup analysis, patients whose tumour sizes were between 2 and 5 cm (18% ↓), patients who had negative axillary lymph nodes (19% ↓), patients who had mild ER positivity (29% ↓) and patients who had grade 2 disease (22% ↓) showed a significant decrease in serum nitrate + nitrite levels (P < 0·05) (Table 1).

DISCUSSION

Tamoxifen is a non-steroidal antiestrogen agent used both in ER positive or unknown breast carcinoma as an endocrine therapy [1]. Although the main therapeutic efficacy of tamoxifen in breast cancer is thought to depend on its anti-oestrogenic activity it also possess other mechanisms, including inhibition of protein kinase C [3], modulation of growth factor synthesis [3], inhibition of endothelial cell growth and angiogenesis [25], inhibition of cell proliferation and induction of apoptosis [2].

VEGF is a multi-functional cytokine that has been suggested to be the major angiogenic factor in human tumours, including breast cancer [26]. VEGF expression has been suggested to be an independent prognostic factor for breast cancer [11,12]. Tamoxifen has been reported to have an important role in the regulation of angiogenic factors such as VEGF in both breast carcinoma and normal target tissue [13]. Maity et al. [27] suggested that tamoxifen induces hypoxia in breast carcinoma cells by inhibiting VEGF expression, resulting in decreased angiogenesis. Donovan et al. [28] reported that tamoxifen reduced preoperative serum VEGF levels by 30% in breast cancer patients. It has been suggested that tamoxifen has additional effects on angiogenesis mediated by reducing levels of potently proangiogenic cytokine VEGF [29]. In contrast, in another study tamoxifen has been suggested to have agonistic effects on VEGF expression, although they are antagonistic for tumour growth [5]. They hypothesized that deleterious effects of tamoxifen-increased VEGF expression in the adjuvant treatment of breast cancer may be overcome by its other effects, such as induction of apoptosis and inhibition of cell proliferation [5]. In another hypothesis, tamoxifen has been suggested to increase VEGF expression in parallel with an extreme elevation in vascular permeability and so this increased permeability interferes with vessel functionality by reducing its perfusion capacity and is therefore destructive to tumour cells [13]. In our study, there was a 23% reduction in serum VEGF levels after 3 months tamoxifen therapy (P = 0·051). Our results were similar to the results of Maity's [27] and Donovan's [28] studies. A decrease in serum VEGF levels may be a result of reduced angiogenic activity by tamoxifen treatment.

In a recent study, the increase in plasma VEGF levels after tamoxifen therapy has been suggested to be related to tamoxifen-associated endometrial hyperplasia [30]. It has been reported that tamoxifen can promote angiogenesis in the rat uterus where administration of tamoxifen increased the production of VEGF mRNA, apparently via a combination of inhibitory and stimulatory elements in the gene promoter [31]. It has also been shown that in Ishikawa cells (human uterine adenocarcinoma cells), tamoxifen induces a significant VEGF gene promoter activation [32]. In association with these suggestions, in our study serum VEGF levels increased in patients with endometrial thickness, whereas there was a marked decrease in patients with normal endometrium after tamoxifen therapy. Serum VEGF levels can be used to follow-up tamoxifen-induced endometrial hyperplasia, and a persistent increase in these levels may be an early sign of the progression of endometrial hyperplasia which has a predisposition for endometrial carcinoma.

Serum and plasma VEGF levels have been found to be elevated in patients with larger tumours and with metastatic disease [33]. Similar to this finding, in our study, despite statistical insignificance, serum VEGF levels were higher in patients whose tumour size was ≥5 cm than other patients before tamoxifen therapy (Table 1). Interestingly, a higher reduction rate in serum VEGF levels was observed in this group (55%). Although only five patients were found and there was a relatively lower incidence of endometrial thickness (one patient) in this group, this may be a reflection of more potent antiangiogenic activity of tamoxifen therapy in subjects with increased angiogenesis such as these patients.

Tamoxifen has been hypothesized to regulate VEGF expression by a mechanism thought to be independent of ER [5]. In our study, the reduction rates of tamoxifen therapy in serum VEGF levels were not different in patients with mild or moderate ER positivity. This result is a supportive finding for this hypothesis. There was no significant difference in reduction rates of serum VEGF levels of patients in terms of lymph node status and tumour grade.

NO is a potent biological molecule that partipicates in the multi-step process of carcinogenesis, including induction of angiogenesis [7] and promotion of apoptosis [6]. It has been reported that tamoxifen can exert some of its biological effects by stimulation of NO synthesis in various tissues, including uterine tissue [34]. It has been suggested that tamoxifen induces apoptosis in human erythroleukaemia cells by activating NO synthase [4]. In another study, it has been reported that increased NO production with tamoxifen therapy has an important role in terms of antiproliferative and apoptotic tumour suppressive effects [8]. In contrast, Kimelberg et al. [35] has reported that tamoxifen is a potent inhibitor of NO synthase activity. Recently, Chen et al. [36] reported that tamoxifen antagonized oestradiol-stimulated NO release in endothelial cells. As a result, the effect of tamoxifen on NO expression in carcinogenesis seems to be complex and sometimes contradictory. In our study, serum nitrate + nitrite levels have been measured as an index of NO generation [37]. Serum nitrate + nitrite levels were found to be elevated by a ratio of 9% after tamoxifen therapy, but this was not statistically significant (P > 0·05).

Some specific actions of NO in tumour biology are considered to be related to its interactions with other molecules and IL-18 and IFN-γ [15,38]. It has been shown recently that tamoxifen increased NO synthesis by stimulation of cytokines including IFN-γ [14]. IL-18 is a novel cytokine that was termed initially an IFN inducing factor. IL-18 has been shown to have potent antitumour effects which are mediated by inhibition of angiogenesis [17], induction of apoptosis [16] and reduction of tumorigenesis [39]. It has been suggested that serum IL-18 levels may be considered to be a prognostic factor in patients with gastric and colon cancer [18,19]. In a recent study we demonstrated that serum IL-18 activity may be used as a marker to evaluate disease activity in breast cancer [20]. In this study, serum IL-18 levels were found to be decreased by a ratio of 17% after tamoxifen therapy (P < 0·05). This finding was not unexpected and does not seem to be a desirable effect of tamoxifen therapy, because both tamoxifen and IL-18 have well-known antitumour activities. We hypothesized that decreased VEGF may inhibit angiogenesis and increased NO may induce apoptosis with tamoxifen therapy; therefore, serum IL-18 levels can be found to be reduced by a feedback mechanism in IL-18, NO and VEGF activity. Moreover, it can also be considered that the antitumour action of tamoxifen is not mediated by IL-18, and changing levels of IL-18 with tamoxifen therapy may be related to its interactions with other cytokines.

In conclusion, serum VEGF levels were found to be decreased in patients without endometrial thickness after tamoxifen therapy. However, patients with endometrial thickness had increased levels of VEGF. Decreased levels in patients without endometrial thickness may be a result of decreased angiogenic activity because of tamoxifen treatment. Serum VEGF levels can be used to follow-up patients with endometrial hyperplasia, which has a predisposition for endometrial carcinoma during tamoxifen therapy and can provide misleading results in evaluating angiogenic activity for these patients. Despite statistical insignificance, serum nitrate + nitrite levels were found to be elevated after tamoxifen therapy. This elevation may be related to the antitumour activity of tamoxifen, probably through apoptosis induction. There was a significant reduction in serum levels of IL-18 after tamoxifen therapy. The decrease in serum levels of IL-18, which is known to have a potent antitumour activity, can be a result of feedback mechanisms in VEGF, NO and IL-18. Further studies are needed to clarify the effects of tamoxifen therapy on VEGF, NO and IL-18 activity and the interactions of these cytokines with tamoxifen therapy.

REFERENCES

1. Coskun U, Toruner FB, Gunel N. Tamoxifen therapy and hepatic steatosis. Neoplasma. 2002;49:61–4. [PubMed]
2. Mandlekar S, Kong AN. Mechanisms of tamoxifen-induced apoptosis. Apoptosis. 2001;6:469–77. [PubMed]
3. Bagheri-Yarmand R, Hamma-Kourbali Y, Bissieres P, Morere JF, Crepin M. Carboxymethyl benzylamide dextran and tamoxifen combination inhibits tumor growth and angiogenesis. Clin Cancer Res. 2001;7:1805–11. [PubMed]
4. Maccarrone M, Fantini C, Ranalli M, Melino G, Agro AF. Activation of nitric oxide synthase is involved in tamoxifen-induced apoptosis of human erythroleukemia K562 cells. FEBS Lett. 1998;434:421–4. [PubMed]
5. Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K, Harkonen PL. Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Mol Cell Endocrinol. 1999;149:29–40. [PubMed]
6. Cui S, Reicher JS, Mateo RB, Albino JE. Activated murine macrophage induce apoptosis in tumour cells through nitric oxide dependent or independent mechanisms. Cancer Res. 1994;54:2462–7. [PubMed]
7. Ohshima H, Baithch H. Chronic infections and inflammatory process as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res. 1994;305:253–64. [PubMed]
8. Shao ZM, Radziszewski WJ, Barsky SH. Tamoxifen enhances myoepithelial cell suppression of human breast carcinoma progression in vitro by two different effector mechanisms. Cancer Lett. 2000;157:133–44. [PubMed]
9. Plate KH, Breier G, Millauer B, Risau W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res. 1993;53:5822–7. [PubMed]
10. Ku DD, Zaleski JK, Liu S, Brock TA. Vascular endothelial growth factors induced EDRF-dependent relaxation in coronary arteries. Am J Physiol. 1993;265:586–92. [PubMed]
11. Linderholm B, Tavelin B, Grankvist K, Henriksson R. Vascular endothelial growth factor is of high prognostic value in node negative breast carcinoma. J Clin Oncol. 1998;16:3121–8. [PubMed]
12. Gasparani G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997;89:139–47. [PubMed]
13. Bogin L, Degani H. Hormonal regulation of VEGF in orthotopic MCF7 human breast cancer. Cancer Res. 2002;62:1948–51. [PubMed]
14. van Bezooijen RL, Van der Bent C, Papapoulos SE, Lowik CW. Oestrogenic compounds modulate cytokine-induced nitric oxide production in mouse osteoblast-like cells. J Pharm Pharmacol. 1999;51:1409–14. [PubMed]
15. Chikano S, Sawada K, Shimoyama T, et al. IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner. Gut. 2000;47:779–86. [PMC free article] [PubMed]
16. Ohtsuki T, Micallef MJ, Tanimoto T, Kohno K, Ikeda M, Kurimoto M. Interleukin-18 enhances Fas ligand expression and induces apopitosis in Fas-expressing human myelomonocytic KG-1 cells. Anticancer Res. 1997;17:3253–8. [PubMed]
17. Park CC, Morel JC, Amin MA, Connors MA, Harlow LA, Koch AE. Evidence of IL-18 as a novel angiogenic mediator. J Immunol. 2001;167:1644–53. [PubMed]
18. Kawabata T, Ichıkura T, Majima T, et al. Preoperative serum interleukin-18 level as a postoperative prognostic marker in patients with gastric carcinoma. Cancer. 2001;92:2050–5. [PubMed]
19. Pages F, Berger A, Henglein B, et al. Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance. Int J Cancer. 1999;84:326–30. [PubMed]
20. Gunel N, Coskun U, Sancak B, Gunel U, Hasdemir O, Bozkurt S. Clinical importance of serum interleukin-18 and nitric oxide activities in breast carcinoma patients. Cancer. 2002;95:663–7. [PubMed]
21. Dirix LY, Vermeulen PB, Pawinski A, et al. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of patients. Br J Cancer. 1997;76:238–43. [PMC free article] [PubMed]
22. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite and (15N) nitrate in biological fluids. Ann Biochem. 1982;126:131–8. [PubMed]
23. Bories PN, Bories C. Nitrate determination in biological fluids by an enzymatic one-step assay with nitrate reductase. Clin Chem. 1995;4:904–7. [PubMed]
24. Taniguchi M, Nagaoka K, Kunikata T, et al. Characterization of antihuman interleukin-18 (IL-18) interferon-gamma-inducing factor (IGIF) mononclonal antibodies and their application in the measurement of human IL-18 by ELISA. J Immunol Meth. 1997;206:107–13. [PubMed]
25. Gagliardi AR, Hennig B, Collins DC. Antiestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors. Anticancer Res. 1996;16:1101–6. [PubMed]
26. Scott PA, Smith K, Poulsom R, De Benedetti A, Bicknel R, Harris AL. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer. 1998;77:2120–8. [PMC free article] [PubMed]
27. Maity A, Sall W, Koch CJ, Oprysko PR, Evans SM. Low pO2 and beta-estradiol induce VEGF in MCF-7 and MCF-7–5C cells: relationship to in vivo hypoxia. Breast Cancer Res Treat. 2001;67:51–60. [PubMed]
28. Donovan D, Harmey JH, Redmond HP, Bouchier-Hayes D. Ascites revisited: a novel role for tamoxifen. Eur J Surg Oncol. 1997;23:570. [PubMed]
29. McNamara DA, Harmey J, Wang JH, Kay E, Walsh TN, Bouchier-Hayes DJ. Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo. Eur J Surg Oncol. 2001;27:714–8. [PubMed]
30. Adams J, Carder PJ, Downey S, et al. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res. 2000;60:2898–905. [PubMed]
31. Hyder SM, Chiappetta C, Stancel GM. Triphenylethylene antiestrogens induce uterine vascular endothelial growth factor expression via their partial estrogen agonist activity. Cancer Lett. 1997;120:165–71. [PubMed]
32. Mueller MD, Pritts EA, Zaloudek CJ, Dreher E, Taylor RN. Regulation of vascular endothelial growth factor by tamoxifen in vitro and in vivo. Gynecol Obstet Invest. 2003;55:119–24. [PubMed]
33. Yamamoto Y, Toi M, Kondo S, et al. Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients. Clin Cancer Res. 1996;2:821–6. [PubMed]
34. Renodon A, Boucher JL, Sari MA, Delaforge M, Quazzani J, Mansuy D. Strong inhibition of neuronal nitric oxide synthase by the calmodulin antagonist and anti-estrogen drug tamoxifen. Biochem Pharmacol. 1997;54:1109–14. [PubMed]
35. Kimelberg HK, Feustel PJ, Jin Y, et al. Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuroreport. 2000;11:2675–9. [PubMed]
36. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mandelsohn MH, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999;103:401–6. [PMC free article] [PubMed]
37. Langrehr JM, Murase N, Markus PM, et al. Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat. J Clin Invest. 1992;90:679–83. [PMC free article] [PubMed]
38. Brennan P, Zaki G, Spedding A, Langdon J. Type II nitric oxide synthase expression corralates with lymph node status in oral squamous cell carcinoma. J Oral Pathol Med. 2001;30:129–34. [PubMed]
39. Fukumoto H, Nishio M, Nishio K, et al. Interferon-gamma inducing factor gene transection into Lewis lung carcinoma cells reduces tumorigenicity in vivo. Jpn J Cancer Res. 1997;88:501–5. [PubMed]

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