The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents

Targeted Oncology

Volumn 4, Issue 2, 2009, Pages 135-142

  Sankhala, Kamalesh ^a   Mita, Alain ^a   Kelly, Kevin ^a   Mahalingam, Devalingam ^a   Giles, Francis ^a   Mita, Monica ^a  

^a UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

Author keywords

Hyperlipidemia; MTOR inhibitors; Mucositis; Newer mTOR inhibitors; Pulmonary toxicity; Rapamycin; Toxicity

Indexed keywords

DEFOROLIMUS; EVEROLIMUS; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PLACEBO; PROTEIN KINASE B; RAPAMYCIN; STRESS ACTIVATED PROTEIN KINASE; TEMSIROLIMUS;

ABDOMINAL DISTENSION; ABDOMINAL PAIN; ANEMIA; ANOREXIA; ASTHENIA; BIPOLAR DISORDER; BONE MARROW SUPPRESSION; BRONCHIOLITIS OBLITERANS ORGANIZING PNEUMONIA; CANCER CHEMOTHERAPY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; COMPUTER ASSISTED TOMOGRAPHY; CONSTIPATION; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; DRUG TARGETING; DRY SKIN; ECZEMA; FATIGUE; GASTROINTESTINAL TOXICITY; GENE MUTATION; GLOMERULUS FILTRATION RATE; HEMATOLOGIC MALIGNANCY; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; HYPOKALEMIA; HYPOPHOSPHATEMIA; INFECTION; KIDNEY CARCINOMA; LEUKOPENIA; LUNG TOXICITY; LYMPHOPROLIFERATIVE DISEASE; MACULOPAPULAR RASH; MOLECULAR TARGETED THERAPY; MUCOSA INFLAMMATION; NAIL DYSTROPHY; NAUSEA; NEUTROPENIA; NONHUMAN; PANCREAS ISLET BETA CELL; PERIPHERAL EDEMA; PNEUMONIA; PRIORITY JOURNAL; PSORIASIS; RASH; REVIEW; SIDE EFFECT; SKIN DISCOLORATION; SKIN TOXICITY; STOMATITIS; STREPTOMYCES HYGROSCOPICUS; THROMBOCYTOPENIA; TUBULAR DYSFUNCTION; TUMOR SUPPRESSOR GENE; VOMITING; WEIGHT REDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG HYPERSENSITIVITY; GRAFT REJECTION; HUMANS; MUCOSITIS; NEOPLASMS; ORGAN TRANSPLANTATION; PNEUMONIA; PROGNOSIS; PROTEIN KINASES; SIROLIMUS; TH1 CELLS; TH2 CELLS; TREATMENT OUTCOME;

EID: 67349127898     PISSN: 17762596     EISSN: 1776260X     Source Type: Journal    
DOI: 10.1007/s11523-009-0107-z     Document Type: Review

References (41)

1. BT Hennessy 2005 Exploiting the PI3K/AKT pathway for cancer drug discovery Nat Rev Drug Discov 4 12 988 1004
2. M Scaltriti J Baselga 2006 The epidermal growth factor receptor pathway: a model for targeted therapy Clin Cancer Res 12 18 5268 5272 (Pubitemid 44497237)
3. H Yu T Rohan 2000 Role of the insulin-like growth factor family in cancer development and progression J Natl Cancer Inst 92 18 1472 1489
4. AS MacDonald 2001 A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts Transplantation 71 2 271 280 (Pubitemid 32126112)
5. S Huang PJ Houghton 2002 Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic Curr Opin Investig Drugs 3 2 295 304 (Pubitemid 34456089)
6. G Hudes 2007 Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma N Engl J Med 356 22 2271 2281 (Pubitemid 46849157)
7. E Raymond 2004 Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer J Clin Oncol 22 12 2336 2347 (Pubitemid 41115390)
8. MM Mita 2008 Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies J Clin Oncol 26 3 361 367
9. A O'Donnell 2008 Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors J Clin Oncol 26 10 1588 1595
10. E Morelon 2001 Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients Transplantation 72 5 787 790 (Pubitemid 32879846)
11. A Lennon 2001 Interstitial pneumonitis associated with sirolimus (rapamycin) therapy after liver transplantation Transplantation 72 6 1166 1167 (Pubitemid 32924098)
12. MB Atkins W Stadler 2002 A randomized double blind phase 2 study of intravenous CCI-779 administered weekly to patients with advanced renal cell carcinoma Proc Am Soc Clin Oncol 21 36 Abstract
13. MB Atkins 2006 Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma J Clin Oncol 22 5 909 918
14. I Duran 2004 Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus Eur J Cancer 42 12 1875 1880
15. PT Pham 2004 Sirolimus-associated pulmonary toxicity Transplantation 77 8 1215 1220
16. RJ Motzer 2008 Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial The Lancet 372 9637 449 456
17. C Brattstrom 1998 Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin) Transplantation 65 9 1272 1274 (Pubitemid 28224351)
18. FB Kraemer 1998 Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways Metabolism 47 5 555 559 (Pubitemid 28214005)
19. ZA Massy 2000 Hyperlipidaemia and post-heparin lipase activities in renal transplant recipients treated with sirolimus or cyclosporin A Nephrol Dial Transplant 15 6 928 (Pubitemid 30312033)
20. RC Hoogeveen 2001 Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients Transplantation 72 7 1244 250
21. BD Kahan 2000 Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group Lancet 356 9225 194 202 (Pubitemid 30446974)
22. M Hidalgo 2006 A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer Clin Cancer Res 12 19 5755 5763 (Pubitemid 44629606)
23. 23. Yee KW et al Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12(17):5165-5173
24. M Fraenkel 2008 mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes Diabetes 57 4 945 957
25. F Tremblay A Marette 2001 Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells J Biol Chem 276 41 38052 38060
26. E Galanis 2005 Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study J Clin Oncol 23 23 5294 5304 (Pubitemid 46206983)
27. J Bellmunt 2008 Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features Ann Oncol 19 8 1387 1392
28. JC Hong BD Kahan 2000 Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management Transplantation 69 10 2085 2090 (Pubitemid 30395038)
29. MM Mita E Poplin WD Tap A Carmona L Yonemoto DS Wages CL Bedrosian EH Rubin AW Tolcher 2008 Deforolimus trial 106- A Phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669) J Clin Oncol 26 3509 abstract
30. Kneteman N, Babini R et al (2000) Sirolimus immunosuppression for liver transplantation in the presence of malignancy. XVIII International Congress of the Transplantation Society: Abstract
31. G Stallone 2005 Sirolimus for Kaposi's sarcoma in renal-transplant recipients N Engl J Med 352 13 1317 1323 (Pubitemid 40411498)
32. G Stallone 2008 Kaposi's sarcoma and mTOR: a crossroad between viral infection neoangiogenesis and immunosuppression Transpl Int 21 9 825 832
33. BD Kahan JS Camardo 2001 Rapamycin: clinical results and future opportunities Transplantation 72 7 1181 1193 (Pubitemid 33026593)
34. CG Groth 1999 Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European renal transplant study group Transplantation 67 7 1036 1042
35. H Kreis 2000 Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients Transplantation 69 7 1252 1260 (Pubitemid 30238708)
36. JM Morales H Wramner D Kreis 2000 Sirolimus vs cyclosporin: a comparision of renal function over two years XVIII International Congress of the Transplantation Society 140 0428 Abstract
37. S Chan 2005 Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer J Clin Oncol 23 23 5314 5322 (Pubitemid 46206985)
38. TE Witzig 2005 Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma J Clin Oncol 23 23 5347 5356 (Pubitemid 46206988)
39. RJ Amato 2006 A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC) J Clin Oncol (Meeting Abstracts) 24 (18-suppl) 4530
40. SP Chawla AP Staddon SM Schuetze GZ D'Amato JY Blay KK Sankhala ST Daly VM Rivera GD Demetri 2006 Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas J Clin Oncol 24 18S 9505
41. DA Rizzieri 2008 A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies Clin Cancer Res 14 9 2756 2762