title: Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors.
abstract: Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of thesein vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice. Previous results showed that diet restriction (DR) had minimal or no effect on the lifespan of Rb1+/- mice, suggesting that the beneficial response to DR is dependent on pRb1. Since long-term eRapa treatment may at least partially mimic chronic DR in lifespan extension, we predicted that it would have a minimal effect in Rb1+/- mice. Beginning at 9 weeks of age until death, we fed Rb1+/- mice a diet without or with eRapa at 14 mg/kg food, which results in an approximate dose of 2.24 mg/kg body weight per day, and yielded rapamycin blood levels of about 4 ng/ml. Surprisingly, we found that eRapa dramatically extended life span of both female and male Rb1+/- mice, and slowed the appearance and growth of pituitary and decreased the incidence of thyroid tumors commonly observed in these mice. In this model, eRapa appears to act differently than DR, suggesting diverse mechanisms of action on survival and anti-tumor effects. In particular the beneficial effects of rapamycin did not depend on the dose of Rb1.
authors: Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors: Carolina B
authors: CB
authors: Livi
authors: Rulon L
authors: RL
authors: Hardman
authors: Barbara A
authors: BA
authors: Christy
authors: Sherry G
authors: SG
authors: Dodds
authors: Diane
authors: D
authors: Jones
authors: Charnae
authors: C
authors: Williams
authors: Randy
authors: R
authors: Strong
authors: Alex
authors: A
authors: Bokov
authors: Martin A
authors: MA
authors: Javors
authors: Yuji
authors: Y
authors: Ikeno
authors: Gene
authors: G
authors: Hubbard
authors: Paul
authors: P
authors: Hasty
authors: Zelton Dave
authors: ZD
authors: Sharp
mesh_terms: D000818:Animals; D004032:Diet; D005260:Female; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D016160:Retinoblastoma Protein / Q000235:genetics*; D020123:Sirolimus / Q000008:administration & dosage*
chemical_list: D016160:Retinoblastoma Protein; D020123:Sirolimus