Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor

Guba, Markus; Breitenbuch, Philipp von; Steinbauer, Markus; Koehl, Gudrun E.; Flegel, Stefanie; Hornung, Matthias; Bruns, Christiane; Zuelke, Carl; Farkas, S.; Anthuber, Matthias; Jauch, Karl‐Walter; Geissler, Edward K.

doi:10.1038/nm0202-128

Cited by 1,598 publications

(1,294 citation statements)

References 29 publications

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“…VEGF concentrations in conditioned media, total cell lysates from homogenised tumour specimens and serum of sacrificed mice were determined by ELISA (Guba et al, 2002). The absorbance was measured at 490 nm on a microplate reader (Bio-Rad, Hercules, CA, USA) and VEGF concentrations were determined using linear regression analysis.…”

Section: Elisa Assaymentioning

confidence: 99%

“…Based on the reported ability of mTOR to affect VEGF levels (Guba et al, 2002), we evaluated the effect of everolimus on VEGF production in our cancer cell lines. As shown in Figure 3A, everolimus reduces human VEGF (hVEGF) secretion of 20 -45% both in wild type and in resistant cell lines, compared with untreated controls.…”

Section: Everolimus Reduces the Secretion Of Vegf In Wild Type And Rementioning

confidence: 99%

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Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

et al. 2008

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Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo . We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

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Section: Elisa Assaymentioning

confidence: 99%

Section: Everolimus Reduces the Secretion Of Vegf In Wild Type And Rementioning

confidence: 99%

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

et al. 2008

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“…Immunosuppression consisted of tacrolimus and prednisolone, which were followed by sirolimus monotherapy because of its potential antitumoral activity. 20 Two patients developed bile leakages from the hepatic resection line that requiredpercutaneous (Patient 7) and surgical drainage (Patient 6). In addition, reoperation was necessary for Patient 2 due to insufficiency of the pancreatic anastomosis and for Patient 4 because of an infected subdiaphragmatic hematoma.…”

Section: Surgical Procedures and Complicationsmentioning

confidence: 99%

Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma

Wiedmann

Caca

Berr

et al. 2003

Cancer

161

105

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BACKGROUNDOnly 20–30% of patients with hilar cholangiocarcinomas (CC) are candidates for potentially curative resection. However, even after curative (R0) resection, these patients have a disease recurrence rate of up to 76%. The current prospective Phase II study investigated photodynamic therapy (PDT) as a neoadjuvant treatment for CC.METHODSSeven patients with advanced proximal bile duct carcinoma were evaluated. Patients were treated with PDT at the area of tumor infiltration and 2 cm beyond and underwent surgery after a median period of 6 weeks (range, 3–44 weeks).RESULTSOne patient had a Bismuth–Corlette Type II tumor, two patients had Type IIIa, one patient had Type IIIb, and three patients had Type IV. Cholestasis parameters after PDT decreased significantly. No relevant adverse events from PDT occurred except for minor intraoperative phototoxicity in one patient. Three patients underwent right‐sided liver resections, two patients underwent left‐sided liver resections, and one patient received a combined hilar resection with partial pancreatoduodenectomy (PD) due to tumor extension into the distal bile duct. Liver transplantation and PD were performed in another patient. In all patients, R0 resection was achieved. Four patients developed minor surgical complications, even though the bilioenteric anastomoses were sewn to PDT‐pretreated bile ducts. No viable tumor cells were found in the inner 4 mm layer of the surgical specimens. The PDT‐pretreated epithelium of the tumor‐free proximal resection margins exhibited only minimal inflammatory infiltration. Tumors recurred in 2 patients 6 and 19 months after surgery. The 1‐year recurrence free survival rate was 83%.CONCLUSIONSNeoadjuvant PDT for hilar CC is a low‐risk procedure with efficient selective destruction of the superficial 4 mm layer of bile duct tumor without complications exceeding series without neoadjuvant PDT. Neoadjuvant PDT should be evaluated prospectively to determine whether it reduces the rate of local disease recurrence after potentially curative resection. Cancer 2003;97:2783–90. © 2003 American Cancer Society.DOI 10.1002/cncr.11401

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“…Indeed, even when the treatment was started after the formation of liver metastases, rapamycin was able to slow tumor growth, likely as a result of a combination of a direct antiproliferative action and of possible indirect effects, such as antiangiogenic properties. 13,14 The inhibitory effects of rapamycin on tumor growth in vivo resulted in prolonged survival and improved clinical status.…”

Section: Discussionmentioning

confidence: 99%

“…Rapamycin and LY294002 were administered intraperitoneally at the dose of 1.5 mg/kg daily and 25 mg/kg three times a week, respectively, in accordance with previous studies. [13][14][15][16][17] Three protocols of administration were tested in STC-1 tumor-bearing mice. In the first protocol, 8 days after intrasplenic STC-1 injection to allow liver engraftment and early growth of tumor cells, mice were randomized into two groups.…”

Section: Animal Studiesmentioning

confidence: 99%

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

Couderc

Poncet

Villaume

et al. 2011

The American Journal of Pathology

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The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/ mTOR pathway.

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Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor

Cited by 1,598 publications

References 29 publications

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

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