{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T14:58:19Z","timestamp":1772895499833,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2006,7,14]],"date-time":"2006-07-14T00:00:00Z","timestamp":1152835200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2006,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease\u2010causing mutations in the <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic> gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon\u2010gamma (IFN\u2010\u03b3) is another potential therapeutic agent for TSC. A high\u2010expressing IFN\u2010\u03b3 allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN\u2010\u03b3 reduces the severity of TSC\u2010related disease in mouse models. Here, we examine the effects of treating tumor\u2010bearing nude mice with a combination of a rapamycin analog (CCI\u2010779) and IFN\u2010\u03b3. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI\u2010779 plus IFN\u2010\u03b3 had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI\u2010779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC\u2010related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/gcc.20357","type":"journal-article","created":{"date-parts":[[2006,7,14]],"date-time":"2006-07-14T16:17:08Z","timestamp":1152893828000},"page":"933-944","source":"Crossref","is-referenced-by-count":37,"title":["Combination of a rapamycin analog (CCI\u2010779) and interferon\u2010\u03b3 is more effective than single agents in treating a mouse model of tuberous sclerosis complex"],"prefix":"10.1002","volume":"45","author":[{"given":"Laifong","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Sudentas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra L.","family":"Dabora","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,7,14]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-0929"},{"key":"e_1_2_6_3_1","unstructured":"BisslerJ FranzD McCormackFX ChuckG LeonardJ YoungL ElwingJ.2004.Rapamycin therapy of AMLs in patients with TSC and sporadic LAM. 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