title: Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin.
abstract: Target of Rapamycin (TOR) is involved in cellular and organismal aging. Rapamycin extends lifespan and delays cancer in mice. It is important to determine the minimum effective dose and frequency of its administration that still extends lifespan and prevents cancer. Previously we tested 1.5 mg/kg of rapamycin given subcutaneously 6 times per two weeks followed by a two-week break (1.5 × 6/bi-weekly schedule: total of 6 injections during a 4-week period). This intermittent treatment prolonged lifespan and delayed cancer in cancer-prone female FVB/N HER-2/neu mice. Here, the dose was decreased from 1.5 mg/kg to 0.45 mg/kg per injection. This treatment was started at the age of 2 months (group Rap-2), 4 months (Rap-4), and 5 months (Rap-5). Three control groups received the solvent from the same ages. Rapamycin significantly delayed cancer and decreased tumor burden in Rap-2 and Rap-5 groups, increased mean lifespan in Rap-4 and Rap-5 groups, and increased maximal lifespan in Rap-2 and Rap-5 groups. In Rap-4 group, mean lifespan extension was achieved without significant cancer prevention. The complex relationship between life-extension and cancer-prevention depends on both the direct effect of rapamycin on cancer cells and its anti-aging effect on the organism, which in turn prevents cancer indirectly. We conclude that total doses of rapamycin that are an order of magnitude lower than standard total doses can detectably extend life span in cancer-prone mice.
authors.affiliation: Department of Carcinogenesis and Oncogerontology; N.N. Petrov Research Institute of Oncology; St. Petersburg, Russia.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Popovich
authors.affiliation: Department of Carcinogenesis and Oncogerontology; N.N. Petrov Research Institute of Oncology; St. Petersburg, Russia.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Anisimov
authors.affiliation: Department of Carcinogenesis and Oncogerontology; N.N. Petrov Research Institute of Oncology; St. Petersburg, Russia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zabezhinski
authors.affiliation: Department of Carcinogenesis and Oncogerontology; N.N. Petrov Research Institute of Oncology; St. Petersburg, Russia.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Semenchenko
authors.affiliation: Department of Carcinogenesis and Oncogerontology; N.N. Petrov Research Institute of Oncology; St. Petersburg, Russia.
authors.forename: Margarita L
authors.initials: ML
authors.lastname: Tyndyk
authors.affiliation: Department of Carcinogenesis and Oncogerontology; N.N. Petrov Research Institute of Oncology; St. Petersburg, Russia.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Yurova
authors.affiliation: Department of Cell Stress Biology; Roswell Park Cancer Institute; Buffalo, NY USA.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D063646:Carcinogenesis / Q000187:drug effects; D005260:Female; D008136:Longevity / Q000187:drug effects*; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D020123:Sirolimus / Q000627:therapeutic use*
chemical_list: D016588:Anticarcinogenic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; C524056:Erbb2 protein, mouse
keywords: anti-aging agents; cancer; longevity; rapalogs