Disease relevance of rapamycin

• The tolerance of sirolimus has been excellent except for in one patient who developed severe interstitial pneumonitis [1].
• Combined with the Food and Drug Administration approval of rapamycin and broad clinical experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer [2].
• Based on our results using a novel genetically engineered mouse model and the fact that the Akt/mTOR pathway is activated in human gallbladder cancer, rapamycin and related drugs may be effective therapeutic agents for the treatment of human gallbladder cancer [3].
• In an intra-peritoneal model of hepatocellular carcinoma, bevacizumab plus rapamycin potently inhibited both intra-liver and intra-abdominal tumor growth, reduced ascites levels, and significantly prolonged mouse survival [4].
• Rapamycin effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS [5].
• Three patients in each group withdrew from the study; 2 of the withdrawals were treatment-related (severe hypertriglyceridemia associated with rapamycin, and pancytopenia associated with MTX), and 4 were SSc-related [6].
• At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations [7].
• We review the molecular mechanisms underlying the neuroprotective effects of rapamycin and discuss the therapeutic potential of this compound for neurodegenerative diseases [8].

Associations of rapamycin with other chemical compounds

• Tacrolimus use without sirolimus was not significantly protective in either model (adjusted HR, 0.66; P = .14 and P = .35, respectively) [9].
• The combination therapy significantly enhanced the effect of antitumor on primary tumor growth compared with single treatment with either rapamycin (P < 0.001) or sorafenib (P < 0.001) [10].
• Octreotide did not overcome rapamycin-induced Akt phosphorylation [11].
• The effects of rapamycin on glucose and thymidine metabolism could be imaged noninvasively by PET [12].
• In clonogenic assays, the combination treatment had a greater inhibitory effect in PC3 cells (93 +/- 1.4%) compared with single agents (66 +/- 9% rapamycin and 43 +/- 4% LBH589) [13].
• In contrast to single-agent therapy, xenografted tumors treated with combination of irinotecan and rapamycin showed potent inhibition of the mammalian target of rapamycin/HIF-1alpha axis, which was accompanied by a dramatic reduction in tumor volume [14].
• ABT-737 induced cleaved caspase-3, a marker of apoptosis, and rapamycin correlated with an increase in punctate localization of green fluorescent protein-LC3, characteristic of autophagy [15].
• Sirolimus can be safely combined with sorafenib or sunitinib [16].

Gene context of rapamycin

• Thirty-two hepatic or renal transplant patients randomized to calcineurin inhibitor-based or sirolimus-based immunosuppression were vaccinated against influenza and pneumococcus [17].
• Rapamycin inhibits S6K1-dependent IRS-1 serine phosphorylation, increases IRS-1 protein levels, and promotes association of tyrosine-phosphorylated IRS-1 with PI3K [18].
• In two subcutaneous models of glioblastoma, regulated expression of the VEGF inhibitor via recombinant AAV-mediated gene transfer, in combination with rapamycin, was shown to decrease tumor growth rate significantly [19].

References