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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2003-1-20
pubmed:abstractText
Soluble copolymers of camptothecin (CPT), based on poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA), were obtained by conjugation through the degradable spacers -Gly-Phe-Leu-Gly- or -Gly-6-aminohexanoyl-Gly-. We investigated to what extent passive accumulation and retention of hydroxypropyl methacrylamide copolymer of CPT (pHPMA-CPT) in tumors and modulation of the drug release influence efficacy. Release of CPT in vivo was detected by time-resolved phase-shift fluorescence imaging on tumor specimens, based on the evidence that free and bound drug had different fluorescence lifetimes in solution. HT-29 murine specimens, obtained at several times after treatment with (3)H-labeled free CPT, pHPMA-Gly-Phe-Leu-Gly-CPT, or pHPMA-Gly-6-aminohexanoyl-Gly-CPT, were either imaged for time-resolved phase-shift fluorescence or subjected to autoradiography. Phase shifts of CPT conjugates were equal or longer than those of free CPT, indicating the presence of both free and polymer-bound drug in the tumor, in agreement with autoradiograms. pHPMA-Gly-Phe-Leu-Gly-CPT underwent relevant intratumor hydrolysis during the first 24 h, whereas the hydrolysis of pHPMA-Gly-6-aminohexanoyl-Gly-CPT was slow. The latter showed antitumor activity at doses from 10 to 22.5 mg/kg/day against s.c. HT-29, A2780, M14, and A549 s.c. xenografts. Moreover, inhibition of tumor growth lasted for up to 73-88 days, and cures were observed on mice with orthotopic implanted HT-29; pHPMA-Gly-Phe-Leu-Gly-CPT was 2-fold more potent than pHPMA-Gly-6-aminohexanoyl-Gly-CPT but less tolerated. Our data suggest that the efficacy of pHPMA-CPT copolymers is related to their intratumor accumulation, and in vivo properties of releasing CPT by esterolytic and proteolytic degradation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
2
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
29-40
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12533670-Acrylamides, pubmed-meshheading:12533670-Animals, pubmed-meshheading:12533670-Antineoplastic Agents, Phytogenic, pubmed-meshheading:12533670-Breast Neoplasms, pubmed-meshheading:12533670-Camptothecin, pubmed-meshheading:12533670-Esters, pubmed-meshheading:12533670-Female, pubmed-meshheading:12533670-Humans, pubmed-meshheading:12533670-Lung Neoplasms, pubmed-meshheading:12533670-Male, pubmed-meshheading:12533670-Methacrylates, pubmed-meshheading:12533670-Mice, pubmed-meshheading:12533670-Mice, Nude, pubmed-meshheading:12533670-Prostatic Neoplasms, pubmed-meshheading:12533670-Spectrometry, Fluorescence, pubmed-meshheading:12533670-Structure-Activity Relationship, pubmed-meshheading:12533670-Tissue Distribution, pubmed-meshheading:12533670-Transplantation, Heterologous
pubmed:year
2003
pubmed:articleTitle
Camptothecin poly[n-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-I tumor therapy: intratumor release and antitumor efficacy.
pubmed:affiliation
Discovery Research Oncology, Pharmacia Corporation, 20014 Nerviano (MI), Italy. moreno.zamai@pharmacia.com
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't