title: Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity.
abstract: Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Charlie.Albright@BMS.com
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Nilsa
authors.initials: N
authors.lastname: Graciani
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Eddy
authors.initials: E
authors.lastname: Yue
authors.forename: Ross
authors.initials: R
authors.lastname: Stein
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Melody
authors.initials: M
authors.lastname: Diamond
authors.forename: Randine
authors.initials: R
authors.lastname: Dowling
authors.forename: Lisa
authors.initials: L
authors.lastname: Grimminger
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.forename: Davette
authors.initials: D
authors.lastname: Behrens
authors.forename: Amy
authors.initials: A
authors.lastname: Musselman
authors.forename: Robert
authors.initials: R
authors.lastname: Bruckner
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Jiang
authors.forename: Daniel
authors.initials: D
authors.lastname: Hu
authors.forename: Anne
authors.initials: A
authors.lastname: Higley
authors.forename: Susan
authors.initials: S
authors.lastname: Dimeo
authors.forename: Maria
authors.initials: M
authors.lastname: Rafalski
authors.forename: Sandya
authors.initials: S
authors.lastname: Mandlekar
authors.forename: Bruce
authors.initials: B
authors.lastname: Car
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Andrew
authors.initials: A
authors.lastname: Stern
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Andrew
authors.initials: A
authors.lastname: Combs
authors.forename: Steve P
authors.initials: SP
authors.lastname: Seitz
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taub
authors.forename: Pearl
authors.initials: P
authors.lastname: Huang
authors.forename: Allen
authors.initials: A
authors.lastname: Oliff
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D064420:Drug-Related Side Effects and Adverse Reactions; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D015260:Neprilysin / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D010446:Peptide Fragments; D011355:Prodrugs; D004317:Doxorubicin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D015260:Neprilysin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9