Discodermolide analogues as the chemical component of combination bacteriolytic therapy.
The marine natural product (+)-discodermolide (1) and several simplified analogues of this microtubule-stabilizing agent have proven to be potent in vitro cell growth inhibitory agents in several human cancer cell lines. Here, we demonstrate the in vivo efficacy of discodermolide and several simplified congeners, both as stand-alone anti-tumor agents and, in the case of (+)-2,3-anhydrodiscodermolide (3), as a chemical component of the combination bacteriolytic therapy. A single intravenous injection of (+)-3 plus genetically modified Clostridium novyi-NT spores caused rapid and complete regressions of tumors in mice bearing HCT116 colorectal cancer xenografts.
Smith
Amos B
AB
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Freeze
B Scott
BS
LaMarche
Matthew J
MJ
Sager
Jason
J
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000473:pathology; D003131:Combined Modality Therapy; D007275:Injections, Intravenous; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D011753:Pyrones; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000662:veterinary; D014407:Tumor Cells, Cultured
D000473:Alkanes; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D002219:Carbamates; C075216:Clostridium novyi alpha-toxin; D007783:Lactones; D011753:Pyrones; C071229:discodermolide