title: Camptothecin poly[n-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-I tumor therapy: intratumor release and antitumor efficacy.
abstract: 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.
authors.affiliation: Discovery Research Oncology, Pharmacia Corporation, 20014 Nerviano (MI), Italy. moreno.zamai@pharmacia.com
authors.forename: Moreno
authors.initials: M
authors.lastname: Zamai
authors.forename: Martin
authors.initials: M
authors.lastname: VandeVen
authors.forename: Mariella
authors.initials: M
authors.lastname: Farao
authors.forename: Enrico
authors.initials: E
authors.lastname: Gratton
authors.forename: Alberto
authors.initials: A
authors.lastname: Ghiglieri
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castelli
authors.forename: Erminia
authors.initials: E
authors.lastname: Fontana
authors.forename: Roland
authors.initials: R
authors.lastname: D'Argy
authors.forename: Antonio
authors.initials: A
authors.lastname: Fiorino
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Antonino
authors.initials: A
authors.lastname: Suarato
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Caiolfa
mesh_terms: D000178:Acrylamides; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004952:Esters; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008689:Methacrylates; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000178:Acrylamides; D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D008689:Methacrylates; C447720:methacryloylglycylglycine-4-nitrophenyl ester; D002166:Camptothecin