PMID- 11193889
OWN - NLM
STAT- MEDLINE
DCOM- 20010201
LR  - 20190616
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 922
DP  - 2000
TI  - Conjugation of camptothecins to poly-(L-glutamic acid).
PG  - 136-50
AB  - Conjugation of water-insoluble cancer chemotherapeutic drugs to macromolecular 
      polymers can lead to improved pharmaceutical properties and improved therapeutic 
      ratios due to accumulation of the polymer-drug conjugate in tumor tissue through 
      the enhanced permeability and retention (EPR) to macromolecules associated with 
      tumor vasculature. Pharmaceutical shortcomings of certain active camptothecins 
      including difficulty in formulation and instability of the active lactone form 
      due to interactions with human albumin might be improved by conjugation to 
      polymers. In this report, conjugations of camptothecin (CPT), 10-hydroxy-CPT, and 
      9-amino-CPT to poly-(L-glutamic acid) (PG) are described; coupling was 
      accomplished either through the 20(S)-hydroxyl or 9 and 10 substituents with and 
      without the use of a glycine linker. Studies using a PG paclitaxel conjugate 
      (PG-TXL), which is currently in Phase I testing, demonstrated that PG enhanced 
      aqueous solubility, prolonged plasma residence time, and greatly increased the 
      distribution of paclitaxel to tumor tissue in a murine model. In this report, we 
      describe the use of similar conjugation technology for CPT derivatives and 
      demonstrate that these difficult to formulate compounds can be rendered water 
      soluble, that their maximum tolerated doses are increased, and that they retain 
      substantial anti-tumor activity in syngeneic and xenogeneic tumor models. 
      Preliminary data suggest that PG with molecular weights between 37 and 50 kDa 
      with CPT loading between 14% and 37% with or without glycine linkers display 
      enhanced efficacy compared with nonconjugated camptothecins administered at their 
      maximum tolerated dose.
FAU - Singer, J W
AU  - Singer JW
AD  - Cell Therapeutics Inc., 201 Elliott Avenue West, Seattle, WA 98119, USA. 
      jsinger@ctiseattle.com
FAU - De Vries, P
AU  - De Vries P
FAU - Bhatt, R
AU  - Bhatt R
FAU - Tulinsky, J
AU  - Tulinsky J
FAU - Klein, P
AU  - Klein P
FAU - Li, C
AU  - Li C
FAU - Milas, L
AU  - Milas L
FAU - Lewis, R A
AU  - Lewis RA
FAU - Wallace, S
AU  - Wallace S
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Drug Carriers)
RN  - 25513-46-6 (Polyglutamic Acid)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/*administration & dosage/chemistry
MH  - Camptothecin/administration & dosage/*analogs & derivatives/chemistry
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - Drug Carriers
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/drug therapy
MH  - Melanoma, Experimental/drug therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - Polyglutamic Acid/administration & dosage/*analogs & derivatives/chemistry
MH  - Solubility
MH  - Xenograft Model Antitumor Assays
EDAT- 2001/02/24 12:00
MHDA- 2001/02/28 10:01
CRDT- 2001/02/24 12:00
PHST- 2001/02/24 12:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2001/02/24 12:00 [entrez]
AID - 10.1111/j.1749-6632.2000.tb07032.x [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2000;922:136-50. doi: 10.1111/j.1749-6632.2000.tb07032.x.