PMID- 12912932
OWN - NLM
STAT- MEDLINE
DCOM- 20040610
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 9
IP  - 8
DP  - 2003 Aug 1
TI  - Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients.
PG  - 2887-92
AB  - CCI-779 is an ester of rapamycin and inhibitor of mammalian target of rapamycin 
      (mTOR) currently in Phase II clinical development for the treatment of patients 
      with cancer. CCI-779 interacts with mTOR and inhibits its kinase activity, 
      resulting in inhibition of the mTOR-regulated translational controllers p70(s6) 
      kinase and 4E-BP1. Ultimately, CCI-779 decreases the translation of mRNAs 
      involved in the control of the cell cycle, resulting in cell cycle arrest. The 
      objective of this study was to develop a method to determine the pharmacodynamic 
      effects of CCI-779 suitable for use in clinical trials. Exposure of Raji 
      lymphoblastoid cells to increasing concentrations of rapamycin resulted in a 
      linear concentration-dependent inhibition of p70(s6) kinase activity, suggesting 
      that p70(s6) kinase activity could be an appropriate marker for mTOR-interacting 
      agents. In subsequent experiments, treatment of nude mice bearing the CCI-779 
      susceptible breast cancer cell line MDA-468 with a single dose of 10 mg/kg 
      CCI-779 resulted in a >80% inhibition of p70(s6) kinase activity in peripheral 
      blood mononuclear cells (PBMCs) 72 h after treatment. Importantly, the degree of 
      p70(s6) kinase inhibition was identical in PBMCs and simultaneously collected 
      tumor tissue, suggesting that the PBMCs are an adequate surrogate tissue for 
      p70(s6) kinase activity in vivo. The intrasubject coefficient of variation of 
      p70(s6) kinase activity measured in PBMCs collected from five healthy volunteers 
      on days 1, 4, and 8 was 14%, indicating that p70(s6) kinase activity in PBMCs 
      remains relatively stable over time. Finally, p70(s6) kinase activity was 
      measured in PBMCs from nine patients with renal cell cancer treated with a single 
      dose of 25, 75, or 250 mg of CCI-779 i.v. (three patients each). PBMCs were 
      collected on days 2, 4, and 8 after CCI-779 treatment. In this small data set, 
      eight of the nine patients had evidence of p70(s6) kinase activity inhibition 
      after treatment that was independent of the administered dose. There was a 
      significant linear association between time to disease progression and inhibition 
      of p70(s6) kinase activity 24 h after treatment. In conclusion, these results 
      indicate that the pharmacodynamic effects of CCI-779 can be determined using a 
      p70(s6) kinase assay in PBMCs. This assay is currently being incorporated in 
      Phase I and II studies with CCI-779 to determine its relationship with dose and 
      plasma concentration of the agent and its value as a predictor of treatment 
      efficacy.
FAU - Peralba, Josep Maria
AU  - Peralba JM
AD  - The University of Texas Health Science Center at San Antonio, Institute for Drug 
      Development, Cancer Therapy and Research Center, San Antonio, Texas, USA.
FAU - DeGraffenried, Linda
AU  - DeGraffenried L
FAU - Friedrichs, William
AU  - Friedrichs W
FAU - Fulcher, Letitia
AU  - Fulcher L
FAU - Grunwald, Viktor
AU  - Grunwald V
FAU - Weiss, Geoffrey
AU  - Weiss G
FAU - Hidalgo, Manuel
AU  - Hidalgo M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Clin Cancer Res. 2003 Aug 1;9(8):2882-6. PMID: 12912931
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Carcinoma, Renal Cell/drug therapy
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Clinical Trials as Topic
MH  - Disease Progression
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Immunoblotting
MH  - Kidney Neoplasms/drug therapy
MH  - Leukocytes, Mononuclear/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Neoplasms/*drug therapy
MH  - Neoplasms, Experimental/drug therapy
MH  - *Protein Kinase Inhibitors
MH  - *Protein Kinases
MH  - Sirolimus/*analogs & derivatives/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
EDAT- 2003/08/13 05:00
MHDA- 2004/06/21 10:00
CRDT- 2003/08/13 05:00
PHST- 2003/08/13 05:00 [pubmed]
PHST- 2004/06/21 10:00 [medline]
PHST- 2003/08/13 05:00 [entrez]
PST - ppublish
SO  - Clin Cancer Res. 2003 Aug 1;9(8):2887-92.