PMID- 20978165
OWN - NLM
STAT- MEDLINE
DCOM- 20110228
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 9
IP  - 11
DP  - 2010 Nov
TI  - Enzymatic depletion of tumor hyaluronan induces antitumor responses in 
      preclinical animal models.
PG  - 3052-64
LID - 10.1158/1535-7163.MCT-10-0470 [doi]
AB  - Hyaluronan (HA) is a glycosaminoglycan polymer that often accumulates in 
      malignancy. Megadalton complexes of HA with proteoglycans create a hydrated 
      connective tissue matrix, which may play an important role in tumor stroma 
      formation. Through its colloid osmotic effects, HA complexes contribute to tumor 
      interstitial fluid pressure, limiting the effect of therapeutic molecules on 
      malignant cells. The therapeutic potential of enzymatic remodeling of the tumor 
      microenvironment through HA depletion was initially investigated using a 
      recombinant human HA-degrading enzyme, rHuPH20, which removed HA-dependent tumor 
      cell extracellular matrices in vitro. However, rHuPH20 showed a short serum 
      half-life (t(1/2) < 3 minutes), making depletion of tumor HA in vivo impractical. 
      A pegylated variant of rHuPH20, PEGPH20, was therefore evaluated. Pegylation 
      improved serum half-life (t(1/2) = 10.3 hours), making it feasible to probe the 
      effects of sustained HA depletion on tumor physiology. In high-HA prostate PC3 
      tumors, i.v. administration of PEGPH20 depleted tumor HA, decreased tumor 
      interstitial fluid pressure by 84%, decreased water content by 7%, decompressed 
      tumor vessels, and increased tumor vascular area >3-fold. Following repeat 
      PEGPH20 administration, tumor growth was significantly inhibited (tumor growth 
      inhibition, 70%). Furthermore, PEGPH20 enhanced both docetaxel and liposomal 
      doxorubicin activity in PC3 tumors (P < 0.05) but did not significantly improve 
      the activity of docetaxel in low-HA prostate DU145 tumors. The ability of PEGPH20 
      to enhance chemotherapy efficacy is likely due to increased drug perfusion 
      combined with other tumor structural changes. These results support enzymatic 
      remodeling of the tumor stroma with PEGPH20 to treat tumors characterized by the 
      accumulation of HA.
CI  - (c)2010 AACR.
FAU - Thompson, Curtis B
AU  - Thompson CB
AD  - Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, CA 92121, 
      USA.
FAU - Shepard, H Michael
AU  - Shepard HM
FAU - O'Connor, Patrick M
AU  - O'Connor PM
FAU - Kadhim, Salam
AU  - Kadhim S
FAU - Jiang, Ping
AU  - Jiang P
FAU - Osgood, Ryan J
AU  - Osgood RJ
FAU - Bookbinder, Louis H
AU  - Bookbinder LH
FAU - Li, Xiaoming
AU  - Li X
FAU - Sugarman, Barry J
AU  - Sugarman BJ
FAU - Connor, Robert J
AU  - Connor RJ
FAU - Nadjsombati, Sinisa
AU  - Nadjsombati S
FAU - Frost, Gregory I
AU  - Frost GI
LA  - eng
PT  - Journal Article
DEP - 20101026
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Recombinant Proteins)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 9004-61-9 (Hyaluronic Acid)
RN  - EC 3.2.1.35 (Hyaluronoglucosaminidase)
RN  - EC 3.2.1.35 (hyaluronidase PH-20)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*therapeutic use
MH  - CHO Cells
MH  - Cell Adhesion Molecules/administration & 
      dosage/*metabolism/pharmacokinetics/*pharmacology
MH  - Cricetinae
MH  - Cricetulus
MH  - Drug Synergism
MH  - Humans
MH  - Hyaluronic Acid/*metabolism
MH  - Hyaluronoglucosaminidase/administration & 
      dosage/*metabolism/pharmacokinetics/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mice, Nude
MH  - Polyethylene Glycols/administration & dosage/pharmacokinetics/pharmacology
MH  - Rats
MH  - Recombinant Proteins/administration & 
      dosage/metabolism/pharmacokinetics/pharmacology
MH  - Tumor Cells, Cultured
MH  - Up-Regulation/genetics
MH  - Xenograft Model Antitumor Assays
EDAT- 2010/10/28 06:00
MHDA- 2011/03/01 06:00
CRDT- 2010/10/28 06:00
PHST- 2010/10/28 06:00 [entrez]
PHST- 2010/10/28 06:00 [pubmed]
PHST- 2011/03/01 06:00 [medline]
AID - 1535-7163.MCT-10-0470 [pii]
AID - 10.1158/1535-7163.MCT-10-0470 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2010 Nov;9(11):3052-64. doi: 10.1158/1535-7163.MCT-10-0470. Epub 
      2010 Oct 26.